Subcutaneous Administration (subcutaneous + administration)

Distribution by Scientific Domains
Distribution within Medical Sciences


Selected Abstracts


Alteration in Nature of Cluster Headache During Subcutaneous Administration of Sumatriptan

HEADACHE, Issue 1 2000
Rachel Hering-Hanit MD
Objectives., To document the relationship between the 5-HT receptor agonist sumatriptan and a change in the nature of cluster headache in four cases. To relate the findings to the literature on the use of sumatriptan in both cluster headache and migraine. Background., Studies of the efficacy and adverse effects of long-term treatment with sumatriptan in cluster headache are limited and report conflicting findings. Methods., Four cases are described. Results., All four patients developed a marked increase in the frequency of attacks 3 to 4 weeks after initiating treatment with the drug for the first time. Three patients also developed a change in headache character, and 2 experienced prolongation of the cluster headache period. Withdrawal of the drug reduced the frequency of headaches and eliminated the newly developed type of headache. Conclusions., Determination of the effects of long-term use of sumatriptan will result in more precise guidelines for the frequency and duration of treatment with this otherwise extremely beneficial drug. [source]


A modified MPTP treatment regime produces reproducible partial nigrostriatal lesions in common marmosets

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2005
Mahmoud M. Iravani
Abstract Standard MPTP treatment regimens in primates result in >,85% destruction of nigral dopaminergic neurons and the onset of marked motor deficits that respond to known symptomatic treatments for Parkinson's disease (PD). The extent of nigral degeneration reflects the late stages of PD rather than events occurring at its onset. We report on a modified MPTP treatment regimen that causes nigral dopaminergic degeneration in common marmosets equivalent to that occurring at the time of initiation of motor symptoms in man. Subcutaneous administration of MPTP 1 mg/kg for 3 consecutive days caused a reproducible 60% loss of nigral tyrosine hydroxylase (TH)-positive cells, which occurred mainly in the calbindin-D28k -poor nigrosomes with a similar loss of TH-immunoreactivity (TH-ir) in the caudate nucleus and the putamen. The animals showed obvious motor abnormalities with reduced bursts of activity and the onset of motor disability. However, the loss of striatal terminals did not reflect early PD because a greater loss of TH-ir occurred in the caudate nucleus than in the putamen and a marked reduction in TH-ir occurred in striatal patches compared to the matrix. Examination of striatal fibres following a partial MPTP lesion showed a conspicuous increase in the number and the diameter of large branching fibres in the putaminal and to some extent caudatal matrix, pointing to a possible compensatory sprouting of dopaminergic terminals. In addition, these partially lesioned animals did not respond to acute treatment with L-DOPA. This primate partial lesions model may be useful for examining potential neuroprotective or neurorestorative agents for PD. [source]


Prolonged activated partial thromboplastin time in thromboprophylaxis with unfractionated heparin in patients undergoing cesarean section

JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH (ELECTRONIC), Issue 1 2010
Shigeki Matsubara
Abstract Aim:, Hemorrhage is an important complication of heparin-thromboprophylaxis after surgery. We attempted to clarify the incidence rate of prolonged activated partial thromboplastin time (APTT), representative of hemorrhagic tendency, in Japanese women who received thromboprophylaxis with unfractionated subcutaneous heparin administration after cesarean section (CS). We also determined factors which affected postoperative APTT. Methods:, We studied 280 women who were administered thromboprophylaxis with unfractionated subcutaneous heparin 5000 IU two times per day after CS. Postoperative APTT under heparin was measured and the incidence of its prolongation was determined. Preoperative APTT, blood loss during surgery, postoperative hematocrit, postoperative serum total protein level, and postpartum body weight were measured, and their correlation with postoperative APTT was determined. Results:, Preoperative and postoperative APTT values were 28.3 (26.7,30.3) and 33.8 (31.0,37.5) seconds for median (interquartile range), respectively. Overall, 7.1% of patients showed ,45 s postoperative APTT. Two patients (0.7%) showed ,60 s APTT, one of whom suffered subcutaneous hemorrhage around the abdominal incision with complete healing. There were no other hemorrhagic complications. Preoperative APTT positively, and postpartum body weight inversely, correlated with postoperative APTT. The amount of blood loss, postoperative hematocrit, and postoperative serum total protein level did not correlate with postoperative APTT. No discernible deep vein thrombosis or pulmonary embolism occurred. Conclusion:, Although 7.1% of women under heparin-thromboprophylaxis showed a prolonged APTT that was 150% of the preoperative APTT, serious side effects were not observed. Subcutaneous administration of unfractionated heparin, if checking APTT prolongation 1 day after surgery, may be safe method of thromboprophylaxis after CS. [source]


In-vitro release and oral bioactivity of insulin in diabetic rats using nanocapsules dispersed in biocompatible microemulsion

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 4 2002
Suchat Watnasirichaikul
This study evaluated the potential of poly(iso -butyl cyanoacrylate) (PBCA) nanocapsules dispersed in a biocompatible microemulsion to facilitate the absorption of insulin following intragastric administration to diabetic rats. Insulin-loaded PBCA nanocapsules were prepared in-situ in a biocompatible water-in-oil microemulsion by interfacial polymerisation. The microemulsion consisted of a mixture of medium-chain mono-, di- and tri-glycerides as the oil component, polysorbate 80 and sorbitan mono-oleate as surfactants and an aqueous solution of insulin. Resulting nanocapsules were approximately 200 nm in diameter and demonstrated a high efficiency of insulin entrapment (> 80%). In-vitro release studies showed that PBCA nanocapsules could suppress insulin release in acidic media and that release at near neutral conditions could be manipulated by varying the amount of monomer used for polymerisation. Subcutaneous administration of insulin-loaded nanocapsules to diabetic rats demonstrated that the bioactivity of insulin was largely retained following this method of preparing peptide-loaded nanocapsules and that the pharmacodynamic response was dependent on the amount of monomer used for polymerisation. The intragastric administration of insulin-loaded nanocapsules dispersed in the biocompatible microemulsion resulted in a significantly greater reduction in blood glucose levels of diabetic rats than an aqueous insulin solution or insulin formulated in the same microemulsion. This study demonstrates that the formulation of peptides within PBCA nanocapsules that are administered dispersed in a microemulsion can facilitate the oral absorption of encapsulated peptide. Such a system can be prepared in-situ by the interfacial polymerisation of a water-in-oil biocompatible microemulsion. [source]


Pharmacokinetics, biodistribution, and antitumor efficacy of a human glandular kallikrein 2 (hK2)-activated thapsigargin prodrug

THE PROSTATE, Issue 4 2006
Samuel Janssen
Abstract BACKGROUND Prostate cancer cells secrete unique proteases such as prostate-specific antigen (PSA) and human glandular kallikrein 2 (hK2) that represent targets for the activation of prodrugs as systemic treatment of metastatic prostate cancer. Previously, a combinatorial peptide library was screened to identify a highly active peptide substrate for hK2. The peptide was coupled to an analog of the potent cytotoxin thapsigargin, L12ADT, to generate an hK2-activated prodrug that was efficiently hydrolyzed by purified hK2, stable to hydrolysis in human and mouse plasma in vitro and selectively toxic to hK2 producing prostate cancer cells in vitro. METHODS In the current study, toxicology, pharmacokinetics, prodrug biodistribution, and antitumor efficacy studies were performed to evaluate the hK2-activated prodrug in vivo. RESULTS The single intravenous maximally tolerated dose of prodrug was 6 mg/kg (i.e., 3.67 µmole/kg) which produced peak serum concentration of ,36 µM and had a half-life of ,40 min. In addition, over a 24 hr period <0.5% of free L12ADT analog was observed in plasma. The prodrug demonstrated significant antitumor effect in vivo while it was being administered, but prolonged intravenous administration was not possible due to local toxicity to tail veins. Subcutaneous administration of equimolar doses produced lower plasma AUC compared to intravenous dosing but equivalent intratumoral levels of prodrug following multiple doses. CONCLUSIONS The hK2-activated prodrug was stable in vivo. The prodrug, however, was rapidly cleared and difficult to administer over prolonged dosing interval. Additional studies are underway to assess antitumor efficacy with prolonged administration of higher subcutaneous doses of prodrug. Second-generation hK2-activated thapsigargin prodrugs with increased half-lives and improved formulations are also under development. © 2005 Wiley-Liss, Inc. [source]


Role of Cholecystokinin Receptors in Induction of Antinociception in Hot-Plate Test

BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2 2000
Mehdi Rezayat
In the present study, the antinociceptive effect of cholecystokinin receptor agonists in the hot-plate test in mice has been evaluated. Subcutaneous administration of cholecystokinin octapeptide (cholecystokinin-8; 0.001, 0.005, 0.01, 0.05, and 0.1 mg/kg), unsulfated cholecystokinin octapeptide (cholecystokinin-8U; 0.1 mg/kg) or caerulein (0.25 mg/kg) produced antinociception. Administration of the cholecystokinin tetrapeptide (cholecystokinin-4; 0.25, 0.5 and 1.0 mg/kg) had no effect in the hot-plate test. Subcutaneous injection of the selective cholecystokinin receptor antagonists, MK-329 (0.125, 0.25 and 0.5 mg/kg) or L-365,260 (0.125, 0.25 and 0.5 mg/kg), produced no antinociceptive response. When the animals were pretreated with the cholecystokinin receptor antagonists or naloxone (0.5 and 1 mg/kg), a significant decrease in the antinociceptive response induced by cholecystokinin-8 and caerulein was obtained. The results indicate that single administration of cholecystokinin receptor agonists could produce an antinociceptive effect which is probably mediated via cholecystokinin receptors. With respect to the results obtained from morphine and naloxone administration, it is concluded that there may be an interaction between cholecystokinin and opiate mechanisms. [source]


Subcutaneous administration of nitroglycerin to facilitate radial artery cannulation

CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS, Issue 3 2006
FSCAI, Samir B. Pancholy MD
Abstract Objectives: To study the effect of sublingual versus subcutaneous nitroglycerin on radial artery spasm caused by failed access attempts. Background: Radial artery spasm is the leading reason for failed radial access. We studied the efficacy of systemic versus local nitroglycerin in relieving radial artery spasm caused by needle entry resulting in failed cannulation. Methods: Fifty-two consecutive patients were studied. All patients had failed attempt at radial artery cannulation, resulting in loss of radial pulse. Patients were divided in three groups, group I (n = 11), observed without additional treatment, group II (n = 20), administered 400 mcg of sublingual nitroglycerin, and group III (n = 21), administered 400 mcg of subcutaneous nitroglycerin at the site of the lost radial pulse. All patients were monitored for the return of radial pulse. Demographics, hemodynamics, and time to return of radial pulse as well as ability to successfully cannulate the radial artery were recorded. Results: Seventy-two percent of group I patients, 90% of group II patients, and 100% of group III patients had re-establishment of radial pulse. The time to return of radial pulse was significantly shorter for group III compared with that for group II (3 ± 1 min vs. 8 ± 1 min respectively, P < 0.001). Re-establishment of radial pulse was faster in group II and group III compared with that in group I (18 ± 5 min, P < 0.001). Systolic blood pressure changes and headaches were less common in group III. Conclusion: Subcutaneous administration of nitroglycerin is superior in facilitating radial artery cannulation after initial failed attempt. © 2006 Wiley-Liss, Inc. [source]


Subcutaneous administration of collagen-polyvinylpyrrolidone down regulates IL-1,, TNF-,, TGF-,1, ELAM-1 and VCAM-1 expression in scleroderma skin lesions

CLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 1 2005
J. Furuzawa-Carballeda
Summary In this study the effect of collagen-polyvinylpyrrolidone (collagen-PVP) vs. triamcinolone acetonide (Triam) in scleroderma (SSc) skin lesions was evaluated. Ten SSc patients were treated weekly with subcutaneous injections of 0.2 mL Triam (8 mg/mL) or 0.2 mL collagen-PVP (1.66 mg collagen). Skin biopsies were obtained from lesions before and after treatment. Tissue sections were evaluated by histology and immunohistochemistry (ELAM-1, VCAM-1, IL-1,, TNF-,, TGF-,1 and PDGF). The corticoid-treated group showed abnormal tissue architecture while the biodrug-treatment restored cutaneous appendages and type I/III collagen proportion. Cytokine and adhesion molecule expression was almost inhibited with Triam, while collagen-PVP down-regulated it. Collagen-PVP improved the tissue architecture of SSc lesions and down-regulated some proinflammatory parameters, without the side effects induced by corticoids. [source]


Subcutaneous administration of hepatitis B immune globulin in combination with lamivudine following orthotopic liver transplantation: effective prophylaxis against recurrence

CLINICAL TRANSPLANTATION, Issue 4 2006
James J. Powell
Abstract:, Prophylaxis against recurrent hepatitis B virus (HBV) infection with hepatitis B immune globulin (HBIG), in combination with antiviral agents such as lamivudine, has allowed transplantation for this condition to become feasible and accepted. Current protocols allow for HBIG administration either intravenously or intramuscularly. To date, there has been no reported experience with the subcutaneous route of post-transplant HBIG delivery. We report our experience of a 60-yr-old man for whom liver transplantation was performed for chronic HBV. HBIG was administered intramuscularly during the anhepatic phase of surgery. The finding of a portal vein thrombosis requiring repeated thrombectomy necessitated chronic anticoagulation. Post-operatively, HBIG was administered subcutaneously, in four separate injections, for a daily dose of 2170 IU along with continued lamivudine dosing. Hepatitis B surface antibody (anti-HBs) titres reached a serum concentration of >500 IU/L by seven d post-transplant and approximately 1000 IU/L by nine d post-transplant. Five months post-transplant, with continued combination of subcutaneous HBIG and lamivudine, there has been no recurrent HBV infection and anti-HBs titres have been at target levels. Our experience suggests that subcutaneous delivery of HBIG may be a feasible consideration when intramuscular/intravenous dosing is not possible. [source]


Contact urticaria from Emla® cream

CONTACT DERMATITIS, Issue 5-6 2004
J. Waton
We report the first case of immediate-type hypersensitivity caused by Emla® cream. A 55-year-old woman, after using Emla® cream, went on to develop urticaria. An open test was positive to Emla® cream. Patch tests and prick tests were performed with Emla® cream, the components of Emla® cream (lidocaine, prilocaine and castor oil) and other local anaesthetics. The patch test with lidocaine and the prick test with Emla® cream were both positive. An intradermal test and subcutaneous administration of 3 anaesthetics that had negative patch tests and prick tests were performed and well tolerated, allowing their use. In the literature, anaphylactic reactions to lidocaine injections, delayed-type hypersensitivity after lidocaine subcutaneous injections and contact dermatitis from Emla® cream have all been described. This first case of contact urticaria from Emla® cream was due to lidocaine and did not show any cross-reaction with other local anaesthetics. [source]


Platelet activating factor (PAF) increases plasma protein extravasation and induces lowering of interstitial fluid pressure (Pif) in rat skin

ACTA PHYSIOLOGICA, Issue 1 2005
V. V. Iversen
Abstract Aim:, To investigate the ability of the microdialysis technique to measure capillary selectivity of different sized plasma proteins induced by local administration of platelet activating factor (PAF). Methods:, We used hollow plasmapheresis fibres with 3 cm membrane (cut off 3000 kDa) placed on the back of anaesthetized rats. Results:, Platelet activating factor (50 ,g mL,1) administered locally via the fibre, increased extravasation of radiolabelled 125I-HSA from plasma to the microdialysis fibre by approximately 900% compared both to baseline and the control fibre within 70 min (n = 6, P < 0.05). The extravasation in the control fibre did not change over time. HPLC measurement of plasma proteins in the microdialysis perfusate also demonstrated decreased capillary selectivity for proteins in the diameter range of 73 Ĺ, 56 Ĺ and 39 Ĺ after local administration of PAF (n = 6, P < 0.05). PAF also significantly lowered interstitial fluid (Pif) pressure after subcutaneous administration (50 ,g mL,1). Mean arterial pressure (MAP) after intravenous injection of PAF (0.4 ,g kg,1) fell instantly by about 50 mmHg, and stabilized at 50 mmHg after 15 min (n = 6). MAP was unaltered when PAF was given through the microdialysis fibre (n = 4). Both total tissue water (TTW) and extravasation of albumin, measured as the plasma-to-tissue clearance (E-alb) showed a significant increase after PAF (n = 7, P < 0.05). Conclusions:, The present study demonstrates that PAF induces plasma protein extravasation and decrease capillary selectivity of different sized plasma proteins. It also increases transcapillary fluid flux, and lowers Pif, indicating a role for PAF in the interstitium for generation of transcapillary transport of water and large molecules followed by formation of oedema. [source]


Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1

DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 6 2002
Jens Juul Holst
Abstract GLP-1 is a peptide hormone from the intestinal mucosa. It is secreted in response to meal ingestion and normally functions in the so-called ileal brake, that is, inhibition of upper gastrointestinal motility and secretion when nutrients are present in the distal small intestine. It also induces satiety and promotes tissue deposition of ingested glucose by stimulating insulin secretion. Thus, it is an essential incretin hormone. In addition, the hormone has been demonstrated to promote insulin biosynthesis and insulin gene expression and to have trophic effects on the beta cells. The trophic effects include proliferation of existing beta cells, maturation of new cells from duct progenitor cells and inhibition of apoptosis. Furthermore, glucagon secretion is inhibited. Because of these effects, the hormone effectively improves metabolism in patients with type 2 diabetes mellitus. Thus, continuous subcutaneous administration of the peptide for six weeks in patients with rather advanced disease greatly improved glucose profiles and lowered body weight, haemoglobin A1C, and free fatty acids (FFA). In addition, insulin sensitivity doubled and insulin responses to glucose were greatly improved. There were no side effects. Continuous administration is necessary because of rapid degradation by the enzyme dipeptidyl peptidase-IV. Alternative approaches include the use of analogues that are resistant to the actions of the enzyme, as well as inhibitors of the enzyme. Both approaches have shown remarkable efficacy in both experimental and clinical studies. The GLP-1-based therapy of type 2 diabetes, therefore, represents a new and attractive alternative. Copyright © 2002 John Wiley & Sons, Ltd. [source]


Incretins and other peptides in the treatment of diabetes

DIABETIC MEDICINE, Issue 3 2007
J. F. Todd
Abstract Glucagon-like peptide-1 (7-36) amide (GLP-1) is a gut hormone, released postprandially, which stimulates insulin secretion and insulin gene expression as well as pancreatic B-cell growth. Together with glucose-dependent insulinotropic polypeptide (GIP), it is responsible for the incretin effect which is the augmentation of insulin secretion following oral administration of glucose. Patients with Type 2 diabetes have greatly impaired or absent incretin-mediated insulin secretion which is mainly as a result of decreased secretion of GLP-1. However, the insulinotropic action of GLP-1 is preserved in patients with Type 2 diabetes, and this has encouraged attempts to treat Type 2 diabetic patients with GLP-1. GLP-1 also possesses a number of potential advantages over existing agents for the treatment of Type 2 diabetes. In addition to stimulating insulin secretion and promoting pancreatic B-cell mass, GLP-1 suppresses glucagon secretion, delays gastric emptying and inhibits food intake. Continuous intravenous and subcutaneous administration significantly improves glycaemic control and causes reductions in both HbA1c and body weight. However, GLP-1 is metabolized extremely rapidly in the circulation by the enzyme dipeptidyl peptidase IV (DPP-IV). This is the probable explanation for the short-lived effect of single doses of native GLP-1, making it an unlikely glucose-lowering agent. The DPP-IV resistant analogue, exenatide, has Food and Drug Administration (FDA) approval for the treatment of Type 2 diabetes and selective DPP-IV inhibitors are under development. Both approaches have demonstrated remarkable efficacy in animal models and human clinical studies. Both are well tolerated and appear to have advantages over current therapies for Type 2 diabetes, particularly in terms of the effects on pancreatic B-cell restoration and potential weight loss. [source]


No reactive hypoglycaemia in Type 2 diabetic patients after subcutaneous administration of GLP-1 and intravenous glucose

DIABETIC MEDICINE, Issue 2 2001
T. Vilsbřll
SUMMARY Aims It has previously been shown that intravenous and subcutaneous administration of glucagon-like peptide (GLP)-1 concomitant with intravenous glucose results in reactive hypoglycaemia in healthy subjects. Since GLP-1 is also effective in Type 2 diabetic patients and is presently being evaluated as a therapeutic agent in this disease, it is important to investigate whether GLP-1 can cause hypoglycaemia in such patients. Methods Eight Type 2 diabetic patients (age 54 (49,67) years; body mass index 31 (27,38) kg/m2; HbA1c 9.4 (7.0,12.5)%) and seven matched non-diabetic subjects (HbA1c 5.5 (5.2,5.8)%, fasting plasma glucose 5.4 (5.0,5.7) mmol/l) were given a subcutaneous injection of 1.5 nmol GLP-1/kg body weight (maximally tolerated dose), and 15 min later, plasma glucose (PG) was raised to 15 mmol/l with an intravenous glucose bolus. Results Hypoglycaemia with a PG at or below 2.5 mmol/l was seen in five of the seven healthy subjects after 60,70 min, but PG spontaneously increased again, reaching 3.7 (3.3,4.0) mmol/l at 90 min. In the patients, PG fell slowly and stabilized at 8.6 (4.2,12.1) mmol/l after 80 min. In both groups, glucagon levels initially decreased, but later increased, exceeding basal levels in healthy subjects, in spite of persistent, high concentrations of GLP-1 (P < 0.02). Conclusions Subcutaneous GLP-1 plus intravenous glucose induced reactive hypoglycaemia in healthy subjects, but not in Type 2 diabetic patients. Therefore, a GLP-1-based therapy would not be expected to be associated with an increased risk of hypoglycaemia in Type 2 diabetes mellitus. [source]


Subcutaneous histamine versus botulinum toxin type A in migraine prophylaxis: a randomized, double-blind study

EUROPEAN JOURNAL OF NEUROLOGY, Issue 1 2009
R. O. Millán-Guerrero
Objectives:, To compare the efficacy and tolerability of the subcutaneous administration of histamine and botulinum toxin type A (BoNTA) in migraine prophylaxis. Background:, Histamine has a selective affinity for H3 receptors and it may specifically inhibit the neurogenic edema response involved in migraine pathophysiology. Methods:, One hundred patients with migraine were selected in a 12-week double-blind controlled clinical trial to evaluate the efficacy of subcutaneous administration of histamine (1,10 ng twice a week) n = 50, compared with administration of 50 U of BoNTA (one injection cycle) n = 50. Results:, The data collected during the 4th week of treatment revealed a significant decrease in all parameters studied, in histamine and BoNTA (P < 0.001). After 4 weeks of treatment, but one injection cycle of 50 U BoNTA had only a 40-day period of efficacy. Conclusions:, This randomized study demonstrated that both histamine and BoNTA are similarly effective and well tolerated in reducing or eliminating headache in migraine prophylaxis. Low doses of histamine applied subcutaneously may represent a novel and effective therapeutic alternative in migraine patients and lay the clinical and pharmacological groundwork for the use of H3 agonist in migraine prophylaxis. [source]


Subcutaneous histamine versus sodium valproate in migraine prophylaxis: a randomized, controlled, double-blind study

EUROPEAN JOURNAL OF NEUROLOGY, Issue 10 2007
R. O. Millán-Guerrero
Histamine has a selective affinity for H3-receptors and it may specifically inhibit the neurogenic edema response involved in migraine pathophysiology. The objective of this study was to evaluate the therapeutic potential of subcutaneous administration of histamine in migraine prophylaxis, compared with oral administration of sodium valproate, in an open clinical trial. Ninety-two patients with migraine were selected under criteria established by the International Headache Society and enrolled in a 12-week double-blind controlled clinical trial to evaluate the efficacy of subcutaneous administration of histamine (1,10 ng twice a week; n = 46) compared with oral administration of sodium valproate (500 mg daily dose; n = 46). The variables studied were headache intensity, frequency, duration, analgesic intake and migraine disability assessment (MIDAS). Two-tailed Student's t - test was used to compare means and the Mann,Whitney U and anova tests were used. The data collected during the 4th, 8th and 12th weeks of treatment revealed that histamine caused a significantly greater reduction (P < 0.001) in intensity and duration of migraine attacks as well as in analgesic intake. No difference was detected in the frequency of attacks or in MIDAS. The present study provides evidence of the superior efficacy of histamine applied subcutaneously in migraine prophylaxis when compared with sodium valproate taken orally. Subcutaneously applied histamine may represent a novel and effective therapeutic alternative in resistant migraine patients. [source]


Genetic basis for the psychostimulant effects of nicotine: a quantitative trait locus analysis in AcB/BcA recombinant congenic mice

GENES, BRAIN AND BEHAVIOR, Issue 7 2005
K. J. Gill
Genetic differences in sensitivity to nicotine have been reported in both animals and humans. The present study utilized a novel methodology to map genes involved in regulating both the psychostimulant and depressant effects of nicotine in the AcB/BcA recombinant congenic strains (RCS) of mice. Locomotor activity was measured in a computerized open-field apparatus following subcutaneous administration of saline (days 1 and 2) or nicotine on day 3. The phenotypic measures obtained from this experimental design included total basal locomotor activity, as well as total nicotine activity, nicotine difference scores, nicotine percent change and nicotine regression residual scores. The results indicated that the C57BL/6J (B6) were insensitive to nicotine over the entire dose,response curve (0.1, 0.2, 0.4 and 0.8 mg/kg). However, the 0.8-mg/kg dose of nicotine produced a significant decrease in the locomotor activity in the A/J strain and a wide and continuous range of both locomotor excitation and depression among the AcB/BcA RCS. Single-locus association analysis in the AcB RCS identified quantitative trait loci (QTL) for the psychostimulant effects of nicotine on chromosomes 11, 12, 13, 14 and 17 and one QTL for nicotine-induced depression on chromosome 11. In the BcA RCS, nicotine-induced locomotor activation was associated with seven putative regions on chromosomes 2, 7, 8, 13, 14, 16 and 17. There were no overlapping QTL and no genetic correlations between saline- and nicotine-related phenotypes in the AcB/BcA RCS. A number of putative candidate genes were in proximity to regions identified with nicotine sensitivity, including the ,2 subunit of the nicotinic acetylcholine receptor and the dopamine D3 receptor. [source]


Evaluation of newly developed combination therapy of intra-arterial 5-fluorouracil and systemic pegylated interferon ,-2b for advanced hepatocellular carcinoma with portal venous invasion: preliminary results

HEPATOLOGY RESEARCH, Issue 2 2009
Kazuhiro Kasai
Aim:, Prognosis is extremely poor for advanced hepatocellular carcinoma (HCC) in patients with portal invasion. The present study evaluated the efficacy of combined intra-arterial 5-fluorouracil (5-FU) and systemic pegylated interferon (PEG-IFN),-2b in patients with advanced HCC. Methods:, The subjects comprised nine HCC patients with portal vein thrombosis treated using subcutaneous administration of PEG-IFN,-2b (50,100 µg on day 1 of every week, for 4 weeks) and intra-arterial infusion of 5-FU (250 mg/day for 5 h on days 1,5 of every week, for 4 weeks). For four patients with hepatitis C virus (HCV) infection, oral administration of ribavirin (400,800 mg/day) was added. At the end of every cycle, response to therapy was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Results:, Partial response (PR) was observed in seven of nine patients, with stable or progressive disease in the remaining two patients. Tumors were resectable in three patients displaying PR after treatment. Tumor markers decreased significantly after therapy. Serum HCV-RNA titers were markedly decreased and became undetectable in all patients with HCV infection. National Cancer Institute,Common Toxicity Criteria: version 3.0 (NCI-CTC) grade 3 thrombocytopenia was seen in one case at the end of treatment, but was resolved with cessation of treatment. Other adverse effects were manageable. Conclusion:, Combination therapy with intra-arterial 5-FU and systemic PEG-IFN,-2b may be useful as a palliative treatment for patients with advanced HCC. A prospective controlled trial using a larger population of patients with advanced HCC is needed to evaluate this new combination therapy. [source]


Iatrogenic calcinosis cutis following nadroparin injection

INTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 10 2005
Simonetta Giorgini MD
Accumulation of calcium in the skin is usually classified as a group of disorders referred to as calcinosis cutis. We report the case of a patient who developed iatrogenic calcinosis at the site of subcutaneous administration of low-molecular-weight heparins (LMWH) as nadroparin. This is usually used for the prevention of deep venous thrombosis, especially following renal transplantation. The role of calcium content in nadroparin is discussed. [source]


Oestrogenic activity of isobutylparaben in vitro and in vivo

JOURNAL OF APPLIED TOXICOLOGY, Issue 4 2002
P. D. Darbre
Abstract The alkyl esters of p -hydroxybenzoic acid (parabens) are used widely as preservatives in foods, pharmaceuticals and cosmetics to which the human population is exposed. Recent studies have reported that methylparaben, ethylparaben, n -propylparaben and n -butylparaben all possess oestrogenic activity in several in vitro assays and in animal models in vivo. This study reports on the oestrogenic activity of isobutylparaben in a panel of assays in vitro and in vivo. Isobutylparaben was able to displace [3H]oestradiol from cytosolic oestrogen receptor , of MCF7 human breast cancer cells by 81% at 100 000-fold molar excess. Using a clonal line of MCF7 cells containing a stably transfected oestrogen-responsive ERE-CAT reporter gene, CAT gene expression could be increased by isobutylparaben such that the magnitude of the response was the same at 10,5 M isobutylparaben as with 10,8 M 17,-oestradiol. Isobutylparaben could also increase expression of the endogenous oestrogen-responsive pS2 gene in MCF7 cells and maximal expression at 10,5 M isobutylparaben could be inhibited with the anti-oestrogen ICI 182 780. The proliferation of two oestrogen-dependent human breast cancer cell lines MCF7 and ZR-75-1 could be increased with isobutylparaben such that at concentrations of 10,5 M the proliferation response was of the same magnitude as with 10,8 M 17,-oestradiol. Evidence for oestrogen receptor mediation of proliferation effects was provided by the inability of isobutylparaben to influence the growth of oestrogen-unresponsive MDA-MB-231 human breast cancer cells and by the ability of the anti-oestrogen ICI 182 780 to inhibit the isobutylparaben effects on MCF7 cell growth. The proliferation response to 10,10 M 17,-oestradiol was not antagonized with isobutylparaben at any concentration from 10,9 M to 10,4 M in either MCF7 or ZR-75-1 cells. Finally, subcutaneous administration of isobutylparaben was able to increase the uterine weight in the immature mouse after three daily doses of 1.2 or 12.0 mg per mouse. Previous work using linear-alkyl-chain parabens has shown that oestrogenic activity increases with alkyl chain length from methylparaben to n -butylparaben. The results here show that branching of the alkyl chain to isobutylparaben increases oestrogenic activity beyond that of the equivalent length linear alkyl chain in n -butylparaben. Copyright © 2002 John Wiley & Sons, Ltd. [source]


A study on the effect of the duration of subcutaneous heparin injection on bruising and pain

JOURNAL OF CLINICAL NURSING, Issue 3 2008
Ayten Zaybak PhD
Aim., This study was carried out to determine the effect of injection duration on bruising and pain following the administration of the subcutaneous injection of heparin. Background., Although different methods to prevent bruising and pain following the subcutaneous injection of heparin have been widely studied and described, the effect of injection duration on the occurrence of bruising and pain is little documented. Design., This study was designed as within-subject, quasi-experimental research. Method., The sample for the study consisted of 50 patients to whom subcutaneous heparin was administered. Heparin was injected over 10 seconds on the right abdominal site and 30 seconds on the left abdominal site. Injections areas were assessed for the presence of bruising at 48 and 72 hours after each injection. Dimensions of the bruising on the heparin applied areas were measured using transparent millimetric measuring paper. The visual analog scale (VAS) was used to measure pain intensity and a stop-watch was used to time the pain period. Data were analysed using chi-square test, Mann,Whitney U, Wilcoxon signed ranks tests and correlation. Results., The percentage of bruising occurrence was 64% with the injection of 10 seconds duration and 42% in the 30-second injection. It was determined that the size of the bruising was smaller in the 30-second injection. Pain intensity and pain period were statistically significantly lower for the 30-second injection than for the 10-second injection. Conclusions., It was determined that injection duration had an effect on bruising and pain following the subcutaneous administration of heparin. This study should be repeated on a larger sample. Relevance to clinical practice., When administering subcutaneous heparin injections, it is important to extend the duration of the injection. [source]


Administration of enoxaparin by continuous infusion in a naturalistic setting: analysis of renal function and safety,

JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2005
S. L. Kane-Gill Pharm D MSc
Summary Study objective:, To describe the clinical use and safety of continuous infusion (CI) enoxaparin in a naturalistic setting and to evaluate the influence of renal function on enoxaparin elimination. Design:, Retrospective medical record review. Setting:, 1000-bed tertiary care teaching centre. Patients:, Hospitalized patients that received enoxaparin by CI during a 2-year period. Interventions:, None. Measurements:, Specific details of dosage and monitoring were collected. Adverse drug reactions (ADR) were recorded. Creatinine clearance (CrCl) was calculated using Cockroft and Gault and Brater equations. A population pharmacokinetic analysis was performed using the non-linear mixed effect model (NONMEM). For patients located in the intensive care unit (ICU) and ward, POSTHOC pharmacokinetic parameter estimates were evaluated using the Wilcoxon rank-sum. Pearson correlation coefficient was calculated to determine the association between renal function and anti-Xa clearance. Main results:, Sixty-seven patients received enoxaparin by CI of which 61·2% were in the ward and 38·8% in the ICU. The average initial rate and duration of infusion were 5·2 mg/h and 5·6 days, respectively. The number of anti-Xa concentration measurements averaged five per patient. Nine patients experienced an ADR. The most frequent ADR was gastrointestinal bleeding (n = 4). Among the 67 patients, 48 had available anti-Xa concentrations and were included in the NONMEM model. The anti-Xa CL and volume of distribution for ICU and ward patients averaged 0·64 ± 0·34 L/h, 10·6 ± 1·55 L and 1·01 ± 0·39 L/h, 9·08 ± 1·17 L, respectively. CrCl was not a significant covariate when included in the NONMEM model, and the association between CrCl and anti-Xa clearance was not significant (R2 = 0·0005; P = 0·8916). Conclusions:, This study is the first to report the use and safety of prolonged CI enoxaparin. Pharmacokinetic parameters of enoxaparin differ in ICU vs. ward patients. Overall, we found the safety of CI to be comparable to subcutaneous administration. Also, we found no effect of renal function on enoxaparin elimination. [source]


Pathological Role of Aquaporin-2 in Impaired Water Excretion and Hyponatremia

JOURNAL OF NEUROENDOCRINOLOGY, Issue 4 2004
S. Ishikawa
Abstract In the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), inappropriately elevated secretion of vasopressin can result in a reduction of antidiuretic efficacy: a phenomenon known as ,vasopressin escape'. We compared experimental SIADH with 1-deamino-8- d -arginine vasopressin (dDAVP)-excess rats, where both groups received continuous subcutaneous administration of dDAVP by osmotic minipump but the SIADH rats also received a liquid diet that induced hyponatraemia. The SIADH rats, but not the dDAVP excess rats, showed a marked attenuation of urinary concentrating ability. Vasopressin V2 receptor binding capacity and mRNA expression were similar between the two groups, but the SIADH rats showed a diminished up-regulation of aquaporin-2 (AQP-2) mRNA and protein expression. These findings indicate the presence of tonicity-response regions in the AQP-2 promoter gene, and that either hypervolemia or hypotonicity may attenuate the postreceptor signalling of vasopressin in renal collecting duct cells in SIADH rats. [source]


New potent hGH-RH analogues with increased resistance to enzymatic degradation

JOURNAL OF PEPTIDE SCIENCE, Issue 7 2002
Professor Jan Izdebski
Abstract Four hGH-RH analogues containing homoarginine (Har) and/or D -Arg were obtained by solid-phase methodology using Boc-chemistry. To introduce Har residues, a Lys(Fmoc) protected Lys derivative was incorporated in the appropriate positions (11, 12, 20, 21 or 29); after assembly of the peptide chain the Fmoc group was removed and the peptide-resin was guanidinylated by treatment with N, N,-bis(tert -butoxycarbonyl)- S -methylisothiourea. The peptides were cleaved from the resin by treatment with liquid HF, and the products were purified by RP-HPLC. The peptides were subjected to digestion by trypsin, and the course of the reaction was followed by HPLC and ESI-MS. It was found that peptide bonds formed by the carboxyl group of Har are completely stable to trypsin. The course of cleavage at Lys or Arg residues depends on the position of Har in the sequence. All the analogues investigated stimulate the release of GH in rats after subcutaneous administration, and were about 50,100 times as potent as rGH-RH itself. The analogues had no effect on PRL, LH and FSH levels. Copyright © 2002 European Peptide Society and John Wiley & Sons, Ltd. [source]


Influence of subcutaneous administration of recombinant TNF-, on ligature-induced periodontitis in rats

JOURNAL OF PERIODONTAL RESEARCH, Issue 2 2003
Rok Ga
Proinflammatory cytokine tumor necrosis factor alpha (TNF-,) was found in inflamed periodontal tissues and many studies pointed to its significant role in development of periodontal disease. In this study, the influence of subcutaneously administered recombinant human TNF-, (rhTNF-,) on inflammatory reaction and periodontal breakdown in rats was analyzed during experimental periodontitis, induced by placing silk ligatures around the maxillary right second molar tooth. The rats were divided into two groups with five animals in each; the first group was infused subcutaneously with rhTNF-, via osmotic pumps for 2 weeks and the second group was infused with phosphate-buffered saline (PBS) in the same manner. Inflammatory reaction and periodontal breakdown was evaluated morphometrically on hematoxylin and eosin stained sections. Serum ionized calcium and inorganic phosphates were monitored colorimetrically. Serum calcium and phosphate levels were similar in rats receiving rhTNF-, and PBS. Ligation resulted in accelerated periodontal breakdown, while subcutaneous rhTNF-, administration by itself had no significant effect. Combined effect of subcutaneous rhTNF-, administration and ligation resulted in a significantly greater inflammatory reaction and periodontal breakdown then either treatment alone. We concluded that the subcutaneous administration of rhTNF-, accelerates the progression of experimental periodontitis in rats. [source]


Effect of chitosan on the intranasal absorption of salmon calcitonin in sheep

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2005
Michael Hinchcliffe
The effects of a chitosan-based delivery system on the pharmacokinetics of intranasally administered salmon calcitonin (sCT) were investigated in a sheep model. In particular, the feasibility of producing a formulation with a comparable or improved bioavailability and/or less variability than the currently marketed nasal product (Miacalcin nasal spray, Novartis Pharmaceuticals) was assessed. A comparator (control) formulation comprising sCT solution was also tested. Sheep (n = 6) were dosed intranasally according to a randomized crossover design. The intranasal sCT dose was 1100 IU (equivalent to approximately 17 IU kg,1). After completion of the nasal dosing legs, five of the sheep received 300 IU sCT (equivalent to approximately 5 IU kg,1) by subcutaneous injection to estimate relative bioavailability. After intranasal or subcutaneous dosing, serial blood samples were taken and plasma separated by centrifugation before measuring sCT concentrations by ELISA. Pharmacokinetic (non-compartmental) and statistical (analysis of variance or non-parametric alternative) analyses were performed. No systemic or local adverse effects were observed following intranasal or subcutaneous administration of sCT. The mean relative bioavailability of sCT from the chitosan solution was improved twofold compared with Miacalcin nasal spray and threefold compared with sCT control solution. Inter-animal variability in sCT absorption appeared to be lower with use of the chitosan-based solution compared with the control solution or commercial product. Based on the reported sheep data, a chitosan delivery system could offer the potential to significantly improve the intranasal absorption of sCT and reduce the variability in absorption. In the clinical setting, this may allow relatively lower doses of the drug to be given intranasally and/or lead to improvements in the efficacy or quality of intranasal therapy. [source]


Pharmacokinetic characterization of 14C-vascular endothelial growth factor controlled release microspheres using a rat model

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2002
Tae-Kyoung Kim
The objectives of this study were to characterize the pharmacokinetics of vascular endothelial growth factor (VEGF) in poly(lactic-co-glycolic) acid (PLGA) microspheres using a rat model, and to develop a pharmacokinetic model for this controlled release formulation. 14C-VEGF was encapsulated using a solid-in-oil-in-water emulsification method. The microspheres were administered subcutaneously to rats and the pharmacokinetic parameters were compared with those of protein solutions. Intravenous administration of protein solutions resulted in short half-lives and subcutaneous administration resulted in rapid clearance from the subcutaneous tissue, with high plasma concentrations as expressed by rapid absorption and elimination. The subcutaneous administration of the VEGF microspheres produced low plasma concentrations and high subcutaneous concentrations over a period of 7 weeks. The area under the curve (AUC), the time required to achieve the maximum concentration (tmax), the maximum concentration (Cmax) in blood samples and the elimination rate constant (kel) values at the subcutaneous tissue site were selected to compare the pharmacokinetic characterization of VEGF microspheres with that of protein solutions. The in-vivo release profiles of the proteins were slower than the in-vitro release profiles and they followed the same trend as the in-vitro and in-vivo PLGA degradation rates. The PLGA microsphere degradation was the determinant step for VEGF release from the microspheres and its absorption at the subcutaneous site. Microspheres appear to be an attractive system for the localized rate-controlled delivery of VEGF. 14C-Methylation via reductive alkylation of VEGF did not affect its mitogenic activity, however approximately 25% activity was lost following release from PLGA microspheres. This loss of activity may be due to degradation in an acidic environment as a result of PLGA degradation. [source]


A novel and simple type of liposome carrier for recombinant interleukin-2

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2001
Eri Kanaoka
The strong interaction between recombinant interleukin-2 (IL-2) and liposome was characterized and its possible application to drug-delivery control considered. The liposomes were prepared with egg phosphatidylcholine, distearoyl-phosphatidylglycerol (DSPG), dipalmitoyl-phosphatidylcholine, dipalmitoyl-phosphatidylglycerol or distearoyl-phosphatidylcholine (DSPC). Small and hydrophobic liposomes were selected, which were composed of saturated and long-fatty-acid-chain phospholipids. When the composition and the mixture ratio of IL-2 and the liposome were optimized, more than 95% of the lyophilized IL-2 (Imunace, 350000, JRU) was adsorbed consistently onto the DSPC-DSPG liposome (molar ratio, 10:1; 25 ,mol mL,1; 30 nm in size). Merely mixing IL-2 lyophilized with liposome suspension is convenient pharmaceutically. After intravenous administration to mice, liposomal IL-2 was eliminated half as slowly from the systemic circulation as free IL-2, with more than 13 and 18 times more IL-2 being delivered to the liver and spleen, respectively. After subcutaneous administration of liposomal IL-2 to mice, the mean residence time of IL-2 in the systemic circulation was 8 times that of free IL-2. These results show that IL-2 consistently adsorbs onto the surface of liposomes after optimization of its composition and mixing ratio. Intravenous and subcutaneous administration to mice demonstrates the gradual release of IL-2. Further trials are warranted using these liposomes. [source]


Improvement of Subcutaneous Bioavailability of Insulin by Sulphobutyl Ether ,-Cyclodextrin in Rats

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2000
KEIICHI TOKIHIRO
The objective of this study was to examine and compare how hydrophilic ,-cyclodextrin derivatives (,-CyDs) improve the bioavailability of insulin following subcutaneous injection of insulin solution in rats. When insulin solutions in the absence of ,-CyDs were injected into the dorsal subcutaneous tissues of rats, the absolute bioavailability of insulin calculated from plasma immunoreactive insulin (IRI) levels was approximately 50%. When maltosyl-,-cyclodextrin was added to the solutions, there was no change in the plasma IRI levels and hypoglycaemia compared with those of the insulin-alone solution. Dimethyl-,-cyclodextrin decreased the bioavailability of insulin, although it increased the maximal concentration of IRI in plasma and the capillary permeability of the fluorescein isothiocyanatedextran 40, a non-degraded permeation marker. When insulin solutions containing sulphobutyl ether-,-cyclodextrin with a degree of substitution of the sulphobutyl group of 3,9 (SBE4-,-CyD) were injected, the IRI level rapidly increased and maintained higher IRI levels for at least 8h. The bioavailability of the insulin/SBE4-,-CyD system was about twice that of insulin alone and approached 96%. The enhancing effects of SBE4-,-CyD may be in part due to the inhibitory effects of SBE4-,-CyDs on the enzymatic degradation and/or the adsorption of insulin onto the subcutaneous tissue at the injection site, although this does not apparently facilitate capillary permeability. These results suggest that SBE4-,-CyD in aqueous insulin injection for subcutaneous administration is useful for improving the bioavailability and the hence the pharmacological effects of insulin. [source]


Melatonin enhances the rewarding properties of morphine: involvement of the nitric oxidergic pathway

JOURNAL OF PINEAL RESEARCH, Issue 4 2007
Noushin Yahyavi-Firouz-Abadi
Abstract:, Melatonin has different interactions with opioids including the enhancement of the analgesic effects of morphine and also reversal of tolerance and dependence to morphine. The present study assessed the effect of melatonin on morphine reward in mice using a conditioned place preference (CPP) paradigm. Our data showed that subcutaneous administration of morphine (1,7.5 mg/kg) significantly increased the time spent in the drug-paired compartment in a dose-dependent manner. Intraperitoneal (i.p.) administration of melatonin (1,40 mg/kg) alone did not induce either CPP or conditioned place aversion (CPA), while the combination of melatonin (5,20 mg/kg) and sub-effective dose of morphine (0.5 mg/kg) led to rewarding effect. We further investigated the involvement of the nitric oxidergic pathway in the enhancing effect of melatonin on morphine CPP, by a general nitric oxide synthase inhibitor, NG -nitro- l -arginine methyl ester (l -NAME). l -NAME (1 and 5 mg/kg, i.p.) alone or in combination with morphine (0.5 mg/kg) did not show any significant CPP or CPA. Co-administration of l -NAME (5 mg/kg) with an ineffective combination of melatonin (1 mg/kg) plus morphine (0.5 mg/kg) produced significant CPP that may imply the similarity of action of melatonin and l -NAME and involvement of the nitric oxidergic pathway in this regard. Our results indicate that pretreatment of animals with melatonin enhances the rewarding properties of morphine via a mechanism which may involve the nitric oxidergic pathway. [source]