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Bolus Injection (bolus + injection)
Kinds of Bolus Injection Selected AbstractsCardio-respiratory reflexes evoked by phenylbiguanide in rats involve vagal afferents which are not sensitive to capsaicinACTA PHYSIOLOGICA, Issue 1 2010A. Dutta Abstract Aim:, Stimulation of pulmonary C fibre receptors by phenylbiguanide (PBG, 5-HT3 agonist) produces hypotension, bradycardia and tachypnoea or apnoea. However, tachypnoeic or apnoeic responses are not consistent. Therefore, this study was undertaken to delineate the actions of PBG on respiration and compared with those evoked by capsaicin (TRPV1 agonist). Methods:, Blood pressure, respiratory excursions and ECG were recorded in urethane anaesthetized adult rats. The effect of PBG or capsaicin was evaluated before and after ondansetron (5-HT3 antagonist), capsazepine (TRPV1 antagonist) or bilateral vagotomy. In addition, their effect on vagal afferent activity was also evaluated. Results:, Bolus injection of PBG produced concentration-dependent (0.1,100 ,g kg,1) hypotensive and bradycardiac responses, while there was tachypnoea at lower concentrations (0.1,3 ,g kg,1) and apnoea at higher concentrations (10,100 ,g kg,1). After vagotomy or after exposure to ondansetron both tachypnoeic and apnoeic responses were abolished along with cardiovascular responses. However, capsazepine (3 mg kg,1) did not block the PBG-induced reflex responses. Capsaicin (0.1,10 ,g kg,1), on the other hand, produced a concentration-dependent apnoea, hypotension and bradycardia but tachypnoea was not observed. Ondansetron failed to block the capsaicin-induced reflex response while bilateral vagotomy abolished bradycardiac and hypotensive responses and attenuated the apnoeic response. In another series, vagal afferent activity and cardio-respiratory changes evoked by PBG were blocked by ondansetron. However, capsaicin failed to activate the PBG-sensitive vagal afferents even though cardio-respiratory alterations were observed. Conclusions:, The present observations indicate that PBG produced tachypnoea at a lower concentration and apnoea at a higher concentration involving vagal afferents which are different from those excited by capsaicin. [source] Cardiac 17O MRI: Toward direct quantification of myocardial oxygen consumptionMAGNETIC RESONANCE IN MEDICINE, Issue 6 2010Kyle S. McCommis Abstract A new 17O-labeled blood contrast agent was injected intravenously in control dogs. Electrocardiogram (ECG)-triggered myocardial T1, imaging was performed to obtain spin-locking T1,-weighted myocardial signals for the detection of resultant metabolite H217O water in the heart. Bolus and slow injection methods of various doses of the 17O-labeled and 16O-labeled agents were carried out in order to evaluate the sensitivity of this method and determine the optimal injection method. Bolus injection provided approximately 1% signal reduction, whereas slow injection with larger amount of agent yielded 11.9 ± 0.6% signal reduction. Myocardial oxygen consumption rate was determined by a technique to quantify cerebral oxygenation consumption rate previously developed in 17O brain studies. With either injection method, myocardial oxygen consumption rate at rest was 5.0 , 5.6 ,mol/g/min. Therefore, it appears feasible to detect metabolically generated HO water in vivo in the heart, using the 17O-labeled blood tracer. Myocardial oxygen consumption rate can then be quantified in vivo, which may open new doors for the assessment of myocardial metabolism. Magn Reson Med 63:1442,1447, 2010. © 2010 Wiley-Liss, Inc. [source] Pharmacodynamics and pharmacokinetics of YM128, a GPIIb/IIIa antagonist prodrugDRUG DEVELOPMENT RESEARCH, Issue 3 2002Ken-ichi Suzuki Abstract We examined the biochemical properties of YM-57029 ({4-[4-(4-Carbamimidoylphenyl)-3-oxopiperazin-1-yl]piperidino}acetic acid monohydrochloride trihydrate) and the pharmacodynamics and pharmacokinetics of its prodrug, YM128 (Ethyl (Z)-(4-{4-[4-(N2 -hydroxycarbamimidoyl)phenyl]-3-oxopiperazin-1-yl}piperidino)acetate), an orally-active glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist. YM-57029 strongly inhibited aggregation of human platelets induced by various agonists, with IC50 values ranging from 3.6 to 51 nM. YM-57029 specifically inhibited fibrinogen binding to purified GPIIb/IIIa about 1,000-fold more potently than Arg-Gly-Asp-Ser (RGDS). Moreover, YM-57029 effectively inhibited an Arg-Gly-Asp (RGD) peptide binding to platelets, suggesting that YM-57029 competed with the RGD sequence of ligand. YM-57029 or YM128 dose-dependently inhibited ex vivo platelet aggregation after iv bolus injection or oral administration to beagle dogs and cynomolgus monkeys. However, YM128 exerted more potent and prolonged inhibitory effects on platelet aggregation than YM-57029 after oral administration to cynomolgus monkeys. Furthermore, YM-57029 prolonged template bleeding time at a dose that inhibited ex vivo platelet aggregation during cumulative iv infusion to cynomolgus monkeys. Metabolic and pharmacokinetic studies showed that YM128 effectively converted into YM-57029 in liver microsomes from humans as well as dogs and monkeys, and that bioavailabilities of YM128 in dogs and monkeys were 32.3 and 22.2%, respectively. These results suggest that YM128, a prodrug of YM-57029, may be a valuable GPIIb/IIIa antagonist with good bioavailability in humans. Drug Dev. Res. 55:149,161, 2002. © 2002 Wiley-Liss, Inc. [source] A randomized, double-blind trial demonstrating bioequivalence of the current recombinant activated factor VII formulation and a new robust 25°C stable formulationHAEMOPHILIA, Issue 5 2007B. V. BYSTED Summary., Recombinant activated factor VIIa (rFVIIa) is a well-established treatment for bleeding episodes in patients with congenital or acquired haemophilia A or B with inhibitors to factors VIII and IX and patients with FVII deficiency. The aim of this trial was to demonstrate bioequivalence between the currently marketed (rFVIIa/NovoSeven®) and a new rFVIIa formulation (VII25) stable at up to 25°C. Furthermore, short-term safety and tolerability of VII25 and pharmacokinetics of both formulations were investigated. In this single-centre, randomized, double-blind, two-way cross-over trial, healthy male subjects received one intravenous bolus injection of rFVIIa and one of VII25, both at 90 ,g kg,1, in a randomized order 2,3 weeks apart. Mean VII25/rFVIIa ratio for area under the plasma activity-time curve from time 0 to last quantifiable activity (primary bioequivalence endpoint), was 0.93, 90% confidence interval (CI) (0.89,0.96), within the predefined bioequivalence range (0.80,1.25). Secondary pharmacokinetic parameters were comparable between formulations. No serious adverse events were observed. Six mild or moderate treatment-emergent adverse events were reported in five subjects. Coagulation-related parameter profiles were similar between rFVIIa and VII25. No clinically abnormal changes were observed for laboratory parameters and no subjects developed FVIIa antibodies. This trial demonstrated bioequivalence between the currently available rFVIIa and VII25 stable at up to 25°C. VII25's ,user-friendly' formulation removes the inconvenience of storing/transporting at 2,8°C, and as the drug substance is the same, the activity and safety established for rFVIIa is maintained. [source] Subcutaneous lispro and intravenous regular insulin treatments are equally effective and safe for the treatment of mild and moderate diabetic ketoacidosis in adult patientsINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 4 2006H. Ö. Ersöz Summary In this prospective, randomised, open trial, we wanted to evaluate the efficacy and safety of hourly subcutaneous (SC) insulin lispro administration in the treatment of diabetic ketoacidosis (DKA) in comparison with intravenous (IV) regular insulin treatment. Twenty patients were enroled in the study. The patients were randomly assigned into two groups. Following a bolus injection of 0.15 U/kg IV regular insulin, group L received half of this dose as hourly SC insulin lispro while group R was treated conventionally with IV regular insulin infusion. At the end of treatment period, time that needed for normalisation of serum glucose, ,-hydroxybutyrate, blood pH and urine ketone levels were not different in groups L and R. There was no mortality or serious side effects in both groups. In this study, we revealed that treatment of mild and moderate DKA with SC insulin lispro is equally effective and safe in comparison with IV regular insulin. [source] Analgesic efficacy of subcutaneous local anaesthetic wound infiltration in bilateral knee arthroplasty: a randomised, placebo-controlled, double-blind trialACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 5 2010L. Ø. ANDERSEN Background: High-volume wound local infiltration analgesia is effective in knee arthroplasty, but the analgesic efficacy of subcutaneous wound infiltration has not been evaluated. Methods: In a randomised, double-blind, placebo-controlled trial in 16 patients undergoing bilateral knee arthroplasty with high-volume local infiltration analgesia in the deeper layers, saline or ropivacaine 2 mg/ml was infiltrated into the subcutaneous part of the wound in each knee along with the placement of multi-fenestrated catheters in the subcutaneous wound layers in both knees. Pain was assessed for 6 h post-operatively and for 3 h after a bolus injection given through the catheter 24 h post-operatively. Results: Visual analogue scale (VAS) pain scores were significantly lower from the knee infiltrated with ropivacaine compared with the knee infiltrated with saline in the subcutaneous layer of the wound, at rest (P<0.02), with flexion of the knee (P<0.04) and when the leg was straight and elevated (P<0.04). Twenty-four hours post-operatively, a decline in the VAS pain scores was observed in both groups, with no statistically significant difference between injection of ropivacaine or saline in the subcutaneously placed catheters (P>0.05). Conclusion: As part of a total wound infiltration analgesia intraoperative subcutaneous infiltration with ropivacaine in bilateral total knee arthroplasty is effective in early post-operative pain management, while a post-operative subcutaneous bolus administration through a multiholed catheter 24 h post-operatively did not show improved analgesia compared with the administration of saline. [source] Effect of nicotine on the pelvic afferent nerve activity and bladder pressure in ratsINTERNATIONAL JOURNAL OF UROLOGY, Issue 8 2009Hitoshi Kontani Objectives: To record afferent nerve activity and bladder pressure in anesthetized male rats and to investigate whether increased afferent nerve activity induced by nicotine is able to evoke reflex bladder contractions. Methods: Using continuous infusion cystometrography, bladder pressure was measured via a bladder cannula. Afferent activity was recorded in the uncut L6 dorsal root. Nicotine was injected intra-arterially through a cannula placed near the bifurcation of the internal iliac artery a few minutes after micturition. Results: Nicotine (0.15,1.5 µmol) evoked a marked elevation of afferent discharge without a simultaneous increase in bladder pressure. Bladder contractions appeared about 43 and 19 s after bolus injection of nicotine at 0.45 and 1.5 µmol, respectively. Firing rates of afferent nerves were reduced when the contraction appeared. Continuous infusion of nicotine at 0.75 µmol/min for 20 min evoked marked elevation of afferent discharge, which was maintained during infusion of nicotine and after it had been withdrawn. Repetitive contractions were observed thereafter and disappeared when the L6 dorsal roots were bilaterally resected. Conclusions: A transient increase in afferent discharges induced by bolus injection of nicotine was unable to evoke reflex bladder contraction. Repetitive bladder contractions after withdrawal of continuous nicotine infusion were induced in a reflex manner by the increased afferent activity. [source] Contrast-enhanced power Doppler sonography of ductal pancreatic adenocarcinomas: Correlation with digital subtraction angiography findingsJOURNAL OF CLINICAL ULTRASOUND, Issue 4 2004Chien-Hua Chen MD Abstract Purpose The purpose of this prospective study was to utilize contrast-enhanced power Doppler sonography to evaluate the enhancement characteristics of ductal pancreatic adenocarcinomas and correlate them with the tumor vascularity observed on digital subtraction angiography (DSA). Methods Twenty consecutive patients with ductal pancreatic adenocarcinoma underwent power Doppler sonography and DSA. Tumor vascularity was assessed using unenhanced and contrast-enhanced power Doppler sonography. The contrast agent Levovist was administered intravenously by bolus injection of a dose of 2.5 g at a concentration of 350 mg/mL; saline was administered immediately thereafter. The patients were asked to hold their breath for 30 seconds (for the period 15,45 seconds after saline injection) while the early phase of enhancement was studied; the delayed phase of enhancement was observed between 60 and 120 seconds after saline administration, while patients breathed gently. Results None of the 20 pancreatic carcinomas showed any color signals on power Doppler sonography before administration of the contrast medium. Seventeen (85%) of the 20 pancreatic carcinomas also showed no enhancement in the early and delayed phases of contrast-enhanced power Doppler sonography. However, in the early phase of contrast-enhanced power Doppler sonography; 1 lesion showed pronounced enhancement and 2 showed mild enhancement. On DSA, the 17 carcinomas showing no enhancement on power Doppler sonography were found to be hypovascular, whereas the remaining 3 carcinomas with contrast enhancement on power Doppler sonography were found to be hypervascular. Conclusions The enhancement characteristics of the ductal pancreatic adenocarcinomas correlated well with the tumor vascularity observed on DSA. However, further study is needed to determine the accuracy of contrast-enhanced sonography in the diagnosis of pancreatic masses. © 2004 Wiley Periodicals, Inc. J Clin Ultrasound 32:179,185, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jcu.20018 [source] Contrast media-enhanced power Doppler sonography for evaluation of hemangiomas and malignant tumors in the liverJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 1 2003AYDIN KARABACAKOGLU Abstract Aim: To evaluate the characterization of liver hemangiomas and malignant tumors using power Doppler sonography before and after intravenous injection of a sonocontrast agent. Methods: Forty-five patients with 57 liver tumors (22 hemangiomas, 24 metastases, 10 hepatocellular carcinomas (HCC) and one cholangiocellular carcinoma) were examined prospectively. The distribution (peripheral, central, mosaic) and extent (none, minimal, moderate and strong) of intratumoral flow pattern in each sonographic examination was subjectively classified. Results: The administration of the sonocontrast agent by bolus injection caused enhancement to gradually increase up to 2 min and lasted for 4,5 min. After injection of contrast agent, flow signals appeared or increased in 34 tumors. No signal enhancement was observed in 18 hemangiomas, four metastases and one HCC. The sensitivity and specificity of intratumoral vascularity for the detection of malignant liver tumors was 37.1 and 90.9% for unenhanced power Doppler sonography, and 85.7 and 81.8% for contrast-enhanced power Doppler sonography, respectively. Conclusion: Contrast-enhanced power Doppler sonography is superior to unenhanced power Doppler sonography in the demonstration of malignant tumor vascularity, and is helpful in differentiating between hemangiomas and malignant liver tumors. A specific flow pattern within the tumor is not established in primary and metastatic malignant tumors with contrast-enhanced power Doppler sonography. © 2003 Blackwell Publishing Asia Pty Ltd [source] A case of inability to belchJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 3 2001Michiko Tomizawa Abstract A 22-year-old man was unable to belch. He could sense intraesophageal gas, but had no chest pain. An upper gastrointestinal X-ray series and endoscopic examination showed no abnormalities. Esophageal manometry showed normal relaxation of both the upper and lower esophageal sphincters with primary peristalsis during deglutition. However, bolus injection of air into the middle esophagus failed to initiate the belch reflex. [source] Different mechanisms influencing permeation of PDGF-AA and PDGF-BB across the blood,brain barrierJOURNAL OF NEUROCHEMISTRY, Issue 1 2003Abba J. Kastin Abstract Platelet-derived growth factor (PDGF) exerts neurotrophic and neuromodulatory effects on the CNS. To determine the permeability of the blood,brain barrier (BBB) to PDGF, we examined the blood-to-brain influx of radioactively labeled PDGF isoforms (PDGF-AA and PDGF-BB) by multiple-time regression analysis after intravenous (i.v.) injection and by in-situ perfusion, and also determined the physicochemical characteristics which affect their permeation across the BBB, including lipophilicity (measured by octanol:buffer partition coefficient), hydrogen bonding (measured by differences in octanol : buffer and isooctane : buffer partition coefficients), serum protein binding (measured by capillary electrophoresis), and stability of PDGF in blood 10 min after i.v. injection (measured by HPLC). After i.v. bolus injection, neither 125I-PDGF-AA nor 125I-PDGF-BB crossed the BBB, their influx rates being similar to that of the vascular marker 99mTc-albumin. 125I-PDGF-AA degraded significantly faster in blood than 125I-PDGF-BB. PDGF-BB, however, was completely bound to a large protein in serum whereas PDGF-AA showed no binding. Thus, degradation might explain the poor blood-to-brain influx of PDGF-AA, whereas protein binding could explain the poor influx of circulating PDGF-BB. Despite their lack of permeation in the intact mouse, both 125I-PDGF-AA and 125I-PDGF-BB entered the brain by perfusion in blood-free buffer, and the significantly faster rate of 125I-PDGF-AA than 125I-PDGF-BB may be explained by the lower hydrogen bonding potential of 125I-PDGF-AA. Thus, the lack of significant distribution of PDGF from blood to brain is not because of the intrinsic barrier function of the BBB but probably because of degradation and protein binding. Information from these studies could be useful in the design of analogues for delivery of PDGF as a therapeutic agent. [source] Skeletal Growth Acceleration with Growth Hormone Secretagogues in Transgenic Growth Retarded Rats: Pattern-Dependent Effects and Mechanisms of DesensitizationJOURNAL OF NEUROENDOCRINOLOGY, Issue 6 2001T. Wells Abstract The transgenic growth retarded (Tgr) rat is the first genetic model of growth hormone (GH) deficiency whose growth can be accelerated with exogenous GH secretagogues (GHSs). In this study, we have demonstrated that GHS-receptor (GHS-R) mRNA expression in the arcuate nucleus of Tgr rats was not significantly different to that in wild-type littermates. We have confirmed that GHS-induced elevation in body weight gain was accompanied by acceleration of skeletal growth, and that the effects of the GHS, GHRP-6, were both dose- and pattern-dependent. The growth response with continuous infusion of GHRP-6 was transient, accompanied by suppression of GH and corticosterone responses to bolus injection of GHRP-6. This desensitization occurred without downregulation of arcuate GHS-R mRNA expression, but was accompanied by elevated periventricular somatostatin mRNA expression. In contrast, pulsatile (3-hourly) infusion of GHRP-6 produced sustained growth and GH responses, which were accompanied by suppression of corticosterone responses and elevated arcuate GH-releasing factor (GRF) mRNA expression. Skeletal growth was further accelerated by coinfusion of GRF, but significant depletion of pituitary GH stores suggested that this growth rate may not be sustainable. These experiments confirm the importance of the Tgr rat for investigating the growth promoting potential of the GHSs in the context of GH-deficient dwarfism, and suggest that elevated somatostatin expression may mediate the suppression of the GRF-GH and hypothalamo-pituitary-adrenal axes following continuous GHRP-6 treatment. [source] Volume of distribution at steady state for a linear pharmacokinetic system with peripheral eliminationJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 6 2004Leonid M. Berezhkovskiy Abstract The problem of finding the steady-state volume of distribution Vss for a linear pharmacokinetic system with peripheral drug elimination is considered. A commonly used equation Vss,=,(D/AUC)*MRT is applicable only for the systems with central (plasma) drug elimination. The following equation, Vss,=,(D/AUC)*MRTint, was obtained, where AUC is the commonly calculated area under the time curve of the total drug concentration in plasma after intravenous (iv) administration of bolus drug dose, D, and MRTint is the intrinsic mean residence time, which is the average time the drug spends in the body (system) after entering the systemic circulation (plasma). The value of MRTint cannot be found from a drug plasma concentration profile after an iv bolus drug input if a peripheral drug exit occurs. The obtained equation does not contain the assumption of an immediate equilibrium of protein and tissue binding in plasma and organs, and thus incorporates the rates of all possible reactions. If drug exits the system only through central compartment (plasma) and there is an instant equilibrium between bound and unbound drug fractions in plasma, then MRTint becomes equal to MRT,=,AUMC/AUC, which is calculated using the time course of the total drug concentration in plasma after an iv bolus injection. Thus, the obtained equation coincides with the traditional one, Vss,=,(D/AUC)*MRT, if the assumptions for validity of this equation are met. Experimental methods for determining the steady-state volume of distribution and MRTint, as well as the problem of determining whether peripheral drug elimination occurs, are considered. The equation for calculation of the tissue,plasma partition coefficient with the account of peripheral elimination is obtained. The difference between traditionally calculated Vss,=,(D/AUC)*MRT and the true value given by (D/AUC)*MRTint is discussed. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1628,1640, 2004 [source] Milk Fat Globule EGF Factor 8 Attenuates Sepsis-Induced Apoptosis and Organ Injury in Alcohol-Intoxicated RatsALCOHOLISM, Issue 9 2010Rongqian Wu Background:, Despite advances in our understanding of excessive alcohol-intake-related tissue injury and modernization of the management of septic patients, high morbidity and mortality caused by infectious diseases in alcohol abusers remain a prominent challenge. Our previous studies have shown that milk fat globule epidermal growth factor-factor VIII (MFG-E8), a protein required to opsonize apoptotic cells for phagocytosis, is protective in inflammation. However, it remains unknown whether MFG-E8 ameliorates sepsis-induced apoptosis and organ injury in alcohol-intoxicated rats. The purpose of this study was to determine whether recombinant murine MFG-E8 (rmMFG-E8) attenuates organ injury after acute alcohol exposure and subsequent sepsis. Methods:, Acute alcohol intoxication was induced in male adult rats by a bolus injection of intravenous alcohol at 1.75 g/kg BW, followed by an intravenous infusion of 300 mg/kg BW/h of alcohol for 10 hours. Sepsis was induced at the end of 10-hour alcohol infusion by cecal ligation and puncture (CLP). rmMFG-E8 or vehicle (normal saline) was administered intravenously 3 times (i.e., at the beginning of alcohol injection, the beginning of CLP, and 10 hours post-CLP) at a dose of 20 ,g/kg BW each. Blood and tissue samples were collected 20 hours after CLP in alcoholic animals for various measurements. Results:, Acute alcohol exposure per se did not affect the production of MFG-E8; however, it primed the animal and enhanced sepsis-induced MFG-E8 downregulation in the spleen. Administration of rmMFG-E8 reduces alcohol/sepsis-induced apoptosis in the spleen, lungs, and liver. In addition, administration of rmMFG-E8 after alcohol exposure and subsequent sepsis decreases circulating levels of TNF-, and interleukin-6 and attenuates organ injury. Conclusions:, rmMFG-E8 attenuates sepsis-induced apoptosis and organ injury in alcohol-intoxicated rats. [source] The influence of lithium on the antidiuretic effect of desmopressinJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 9 2002Torbjörn Callréus ABSTRACT The objective of this study was to investigate the graded influence from lithium on the antidiuretic effects of desmopressin. Eight healthy male subjects participated in this open, randomised cross-over study with two periods comprising 6 days each. For each subject, one of the study days (6th day) was preceded by a period of lithium treatment. On the study days the subjects were orally water loaded to achieve a state of overhydration with a high urine flow rate. When a steady-state diuresis was achieved after approximately 2 h, 0.396 ,g of desmopressin was administered intravenously as a bolus injection. An indirect-response model, where desmopressin was assumed to inhibit the elimination of response, was fitted to the urine osmolarity data. The effects of the independent variables, Uflow (baseline) (baseline urine flow rate), R0 (baseline osmolarity) and serum lithium concentration, on IC50 (concentration producing 50% of the maximum inhibition) could be expressed by multiple linear regression. In conclusion, we found that an indirect-response model can be a useful tool in investigating and describing the pharmacodynamic interaction between drugs, in this particular case, between lithium and desmopressin. [source] Uptake and Dispersion of Metformin in the Isolated Perfused Rat LiverJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2000CHEN-HSI CHOU Although metformin is a widely used oral antihyperglycaemic, the exact mechanisms of its cellular uptake and action remain obscure. In this study the hepatic extraction and disposition kinetics of metformin were investigated by use of an isolated in-situ rat liver preparation. The liver was perfused in single-pass mode with protein-free Krebs bicarbonate medium at a flow rate of 20mLmin,1. During constant infusion with 1 mgL,1 metformin hydrochloride the hepatic uptake of metformin approached equilibrium within 10 min. The steady-state availability, F, determined from the ratio of outflow concentration to input concentration, was 0.99±0.02 (mean±s.d., n=4). The outflow profile of metformin resulting from a bolus injection of 25 ,g into the portal vein, had a sharp peak then a slower declining terminal phase. The mean transit time (MTT; 49.5±14.5, n = 6) and normalized variance (CV2; 4.13±0.05) of the hepatic transit times of metformin were estimated by numerical integration from the statistical moments of the outflow data. The volume of distribution of metformin in the liver (1.58±0.28 mL (g liver),1) was estimated from its MTT. The volume of distribution is greater than the water space of liver, indicating that metformin enters the hepatic aqueous space and becomes distributed among cellular components. The magnitude of CV2 for metformin is greater than for the vascular marker sucrose, suggesting that distribution of metformin into hepatic tissue is not instantaneous. In conclusion, hepatic uptake of metformin is rate-limited by a permeability barrier. Although metformin is accumulated in the liver, the organ does not extract it. [source] Melatonin and its precursor, L -tryptophan: influence on pancreatic amylase secretion in vivo and in vitroJOURNAL OF PINEAL RESEARCH, Issue 3 2004Jolanta Jaworek Abstract:, Melatonin, considered as a main pineal product, may be also synthetized in the gastrointestinal tract from l -tryptophan. Melatonin has been recently shown to affect insulin release and its receptors have been characterized in the pancreas however, the effects of melatonin on the pancreatic enzyme secretion have not been examined. The aim of this study was to investigate the effects of melatonin or l -tryptophan on amylase secretion in vivo in anaesthetized rats with pancreato-biliary fistulas, and in vitro using isolated pancreatic acini. Melatonin (1, 5 or 25 mg/kg) or l -tryptophan (10, 50 or 250 mg/kg) given to the rats as a intraperitoneal (i.p.) bolus injection produced significant and dose-dependent increases in pancreatic amylase secretion under basal conditions or following stimulation of enzyme secretion by diversion of bile-pancreatic juice. This was accompanied by a dose-dependent rise in melatonin plasma level. Stimulation of pancreatic enzyme secretion caused by melatonin or l -tryptophan was completely abolished by vagotomy, deactivation of sensory nerves with capsaicin or pretreatment with CCK1 receptor antagonists (tarazepide or l -364,718). Pretreatment with luzindole, an antagonist of melatonin MT2 receptor failed to affect melatonin- or l -tryptophan-induced amylase secretion. Administration of melatonin (1, 5 or 25 mg/kg i.p.) or l -tryptophan (10, 50 or 250 mg/kg i.p.) to the rats resulted in the dose-dependent increase of cholecystokinin (CCK) plasma immunoreactivity. Enzyme secretion from isolated pancreatic acini was not significantly affected by melatonin or l -tryptophan used at doses of10,8,10,5 m. We conclude that exogenous melatonin, as well as that produced endogenously from l -tryptophan, stimulates pancreatic enzyme secretion in vivo while increasing CCK release. Stimulatory effect of melatonin or l -tryptophan on the exocrine pancreas involves vagal sensory nerves and the CCK release by these substances. [source] Ex vivo inhibition of thrombus formation by an anti-glycoprotein VI Fab fragment in non-human primates without modification of glycoprotein VI expressionJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 6 2008P. OHLMANN Summary.,Objectives:,Glycoprotein (GP)VI is an attractive target for the development of new antithrombotic drugs. Its deficiency protects animals in several models of thrombosis, arterial stenosis and ischemia-,reperfusion while inducing no major bleeding tendency. The Fab fragment of one anti-GPVI monoclonal antibody (9O12.2) inhibits all GPVI functions in vitro. The aim of this study was to determine the ex vivo effects of 9O12.2 Fab on hemostasis, coagulation and thrombosis in non-human primates. Methods and results:,Blood samples were collected from cynomolgus monkeys before and after (30, 90 and 150 min, 1 and 7 days) a bolus injection of 9O12.2 Fab (4 mg kg,1) or vehicle. Platelet counts and coagulation tests (prothrombin time, activated partial thromboplastin time) were not modified following Fab injection. The PFA-100 closure time increased during the first hours and returned to initial values on day + 1. Platelet-bound Fab was detected from 30 min to 24 h after Fab injection without GPVI depletion at any time. Collagen-induced platelet aggregation was selectively and fully inhibited at 30 min. Thrombus formation on collagen in flowing whole blood (1500 s,1) was delayed and decreased, and collagen-induced or tissue factor-induced thrombin generation in platelet-rich plasma was profoundly inhibited. Conclusion:,The anti-GPVI 9O12.2 Fab inhibits thrombus formation ex vivo in non-human primates with a composite effect on platelet activation and thrombin generation in the absence of GPVI depletion. [source] Spatiotemporal control of vascular endothelial growth factor delivery from injectable hydrogels enhances angiogenesisJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 3 2007E. A. SILVA Summary. Therapeutic angiogenesis with vascular endothelial growth factor (VEGF) delivery may provide a new approach for the treatment of ischemic diseases, but current strategies to deliver VEGF rely on either bolus delivery or systemic administration, resulting in limited clinical utility, because of the short half-life of VEGF in vivo and its resultant low and transient levels at sites of ischemia. We hypothesize that an injectable hydrogel system can be utilized to provide temporal control and appropriate spatial biodistribution of VEGF in ischemic hindlimbs. A sustained local delivery of relatively low amounts of bioactive VEGF (3 ,g) with this system led to physiologic levels of bioactive VEGF in ischemic murine (ApoE,/,) hindlimbs for 15 days after injection of the gel, as contrasted with complete VEGF deprivation after 72 h with bolus injection. The gel delivery system resulted in significantly greater angiogenesis in these limbs as compared to bolus (266 vs. 161 blood vessels mm,2). Laser Doppler perfusion imaging showed return of tissue perfusion to normal levels by day 28 with the gel system, whereas normal levels of perfusion were never achieved with saline delivery of VEGF or in control mice. The system described in this article could represent an attractive new generation of therapeutic delivery vehicle for treatment of cardiovascular diseases, as it combines long-term in vivo therapeutic benefit (localized bioactive VEGF for 1,2 weeks) with minimally invasive delivery. [source] Single-dose dexmedetomidine attenuates airway and circulatory reflexes during extubationACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 8 2005G. Guler Background:, The alpha agonist dexmedetomidine, a sedative and analgesic, reduces heart rate and blood pressure dose-dependently. We investigated whether it also has the ability to attenuate airway and circulatory reflexes during emergence from anaesthesia. Methods:, Sixty ASA I,III patients received a standard anaesthetic. Five minutes before the end of surgery, they were randomly allocated to receive either dexmedetomidine 0.5 µg/kg (Group D) (n = 30) or saline placebo (Group P) (n = 30) intravenously (i.v.) over 60 s in a double-blind design. The blinded anaesthetist awoke all the patients, and the number of coughs per patient was continuously monitored for 15 min after extubation; coughing was evaluated on a 4-point scale. Any laryngospasm, bronchospasm or desaturation was recorded. Heart rate (HR) and systolic and diastolic blood pressure (SAP, DAP) were measured before, during and after tracheal extubation. The time from tracheal extubation and emergence from anaesthesia were recorded. Results:, Median coughing scores were 1 (1,3) in Group D and 2 (1,4) in Group P (P < 0.05), but there were no differences between the groups in the incidence of breath holding or desaturation. HR, SAP and DAP increased at extubation in both groups (P < 0.05), but the increase was less significant with dexmedetomidine. The time from tracheal extubation and emergence from anaesthesia were similar in both groups. Conclusion:, These findings suggest that a single-dose bolus injection of dexmedetomidine before tracheal extubation attenuates airway-circulatory reflexes during extubation. [source] Initial steroid bolus injection promotes vigorous CD8+ alloreactive responses toward early graft acceptance immediately after liver transplantation in humansLIVER TRANSPLANTATION, Issue 9 2007Hiroto Egawa We have found that steroid bolus withdrawal prior to graft reperfusion increased the incidence of acute cellular rejection (ACR). This study aims to clarify how initial steroid bolus (ISB) injection at reperfusion influences the kinetics of CD8+ alloreactive immune responses immediately after living donor liver transplantation (LDLT). A total of 49 hepatitis C virus (HCV)-infected recipients were classified into 3 groups according to hierarchical clustering by preoperative CD8+CD45 isoforms. The naive T cell proportion was considerably higher in Group I than in Groups II and III, whereas Group II recipients had the highest effector memory (EM) T cells and Group III the highest effector T cells. The frequency of ACR was significantly higher in recipients without ISB than in those with ISB. In particular, the ACR rates were the highest in Group II without ISB. Following ISB, the proportion of effector T cells was promptly upregulated within 6 hours after graft reperfusion, simultaneously with the upregulation of CD27,CD28, subsets, interferon-gamma (IFN-,), tumor necrosis factor-alpha and perforin expression, which significantly correlated with increasing interleukin (IL)-12 receptor beta 1 cells. These were then downregulated to below preoperative levels by tacrolimus (Tac) administered at 24 hours. These changes did not occur in the absence of ISB. In Group II without ISB, the downregulation of IL-12R,1+ cells was the greatest, consistent with the highest rates of ACR and mortality (60%). In conclusion, ISB must be done in place, especially in Group II with preexisting high EM T cells, to enable the development of early allograft acceptance. Liver Transpl 13:1262,1271, 2007, © 2007 AASLD. [source] The MRI-measured arterial input function resulting from a bolus injection of Gd-DTPA in a rat model of stroke slightly underestimates that of Gd-[14C]DTPA and marginally overestimates the blood-to-brain influx rate constant determined by Patlak plotsMAGNETIC RESONANCE IN MEDICINE, Issue 6 2010Tavarekere N. Nagaraja Abstract The hypothesis that the arterial input function (AIF) of gadolinium-diethylenetriaminepentaacetic acid injected by intravenous bolus and measured by the change in the T1 -relaxation rate (,R1; R1 = 1/T1) of superior sagittal sinus blood (AIF-I) approximates the AIF of 14C-labeled gadolinium-diethylenetriaminepentaacetic acid measured in arterial blood (reference AIF) was tested in a rat stroke model (n = 13). Contrary to the hypothesis, the initial part of the ,R1 -time curve was underestimated, and the area under the normalized curve for AIF-I was about 15% lower than that for the reference AIF. Hypothetical AIFs for gadolinium-diethylenetriaminepentaacetic acid were derived from the reference AIF values and averaged to obtain a cohort-averaged AIF. Influx rate constants (Ki) and proton distribution volumes at zero time (Vp + Vo) were estimated with Patlak plots of AIF-I, hypothetical AIFs, and cohort-averaged AIFs and tissue ,R1 data. For the regions of interest, the Kis estimated with AIF-I were slightly but not significantly higher than those obtained with hypothetical AIFs and cohort-averaged AIF. In contrast, Vp + Vo was significantly higher when calculated with AIF-I. Similar estimates of Ki and Vp + Vo were obtained with hypothetical AIFs and cohort-averaged AIF. In summary, AIF-I underestimated the reference AIF; this shortcoming had little effect on the Ki calculated by Patlak plot but produced a significant overestimation of Vp + Vo. Magn Reson Med 63:1502,1509, 2010. © 2010 Wiley-Liss, Inc. [source] 17O relaxation time and NMR sensitivity of cerebral water and their field dependenceMAGNETIC RESONANCE IN MEDICINE, Issue 4 2001Xiao-Hong Zhu Abstract 17O spin relaxation times and sensitivity of detection were measured for natural abundance H217O in the rat brain at 4.7 and 9.4 Tesla. The relaxation times were found to be magnetic field independent (T2 = 3.03 ± 0.08 ms, T = 1.79 ± 0.04 ms, and T1 = 4.47 ± 0.14 ms at 4.7T (N = 5); T2 = 3.03 ± 0.09 ms, T = 1.80 ± 0.06 ms, and T1 = 4.84 ± 0.18 ms at 9.4T (N = 5)), consistent with the concept that the dominant relaxation mechanism is the quadrupolar interaction for this nucleus. The 17O NMR sensitivity was more than fourfold higher at 9.4T than at 4.7T, for both the rat brain and a sodium chloride solution. With this sensitivity gain, it was possible to obtain localized 17O spectra with an excellent signal-to-noise ratio (SNR) within 15 s of data acquisition despite the relatively low gyromagnetic ratio of this nucleus. Such a 15-s 2D 17O-MRS imaging data set obtained for natural abundance H217O in the rat brain yielded an SNR greater than 40:1 for a ,16,l voxel. This approach was employed to measure cerebral blood flow using a bolus injection of H217O via one internal carotid artery. These results demonstrate the ability of 17O-MRS imaging to reliably map the H217O dynamics in the brain tissue, and its potential for determining tissue blood flow and oxygen consumption rate changes in vivo. Magn Reson Med 45:543,549, 2001. © 2001 Wiley-Liss, Inc. [source] Real-Time Contrast Imaging: A New Method to Monitor Capillary Recruitment in Human Forearm Skeletal MuscleMICROCIRCULATION, Issue 3 2008Alexandra H. Mulder ABSTRACT Objective: Muscle capillary perfusion can be measured by contrast-enhanced ultrasound. We examined whether a less time-consuming ultrasound technique, called "real-time imaging," could be used to measure capillary recruitment in human forearm skeletal muscle. Methods: We measured microvascular blood volume and microvascular flow velocity using bolus injections of contrast microbubbles after forearm muscle exercise and a two-hour infusion of insulin into the brachial artery (both associated with capillary recruitment) and after sodium nitroprusside infusion (no changes in flow distribution). Results: After an intravenous bolus injection of the contrast agent, the steady-state concentration of contrast agent in forearm muscle lasted long enough (approximately 190 seconds) for the duration of the measurements (which take 70,80 seconds), rendering the continuous infusion of microbubbles unnecessary. Microvascular blood-volume measurements showed a good short-time reproducibility and a good reproducibility after repositioning of the forearm. Reproducibility of microvascular flow velocity was too low. Exercise and insulin infusion both increased microvascular blood volume, consistent with capillary recruitment. Sodium nitroprusside had no effect. Conclusion: Real-time contrast imaging, after bolus injections of an ultrasound contrast agent, provides reliable information about capillary recruitment in human forearm skeletal muscle, and may offer a valuable tool in studying human (patho)physiology. [source] Severe intoxication after an intentional overdose of amlodipineACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 8 2003L. Rasmussen Intoxication with 280 mg of amlodipine caused severe hypotension, third-degree heart block and hyperkalaemia in a 36-year-old female patient. The patient was initially treated with fluids, dopamine, calcium chloride, and epinephrine without effect. The patient was then given a bolus injection of insulin and glucose as a temporary mean to treat the hyperkalaemia. We observed a rise in blood pressure (BP) after insulin was given and the BP was subsequently responsive to epinephrine. A possible positive inotropic effect of insulin therapy in patients with calcium channel blocker intoxication is in accordance with previous findings. In conclusion, it is suggested that hyperinsulinaemia-euglycaemia therapy may be considered as a first-line therapy in calcium channel blocker intoxication. [source] Safety and Efficacy of Intrathecal Baclofen Infusion by Implantable Pump for the Treatment of Severe Spinal Spasticity: A Spanish Multicenter StudyNEUROMODULATION, Issue 4 2000J Vidal MD Objective. To assess long-term efficacy, safety and functional benefit of intrathecal baclofen for severe spinal spasticity. Materials and Methods. This prospective multicenter study was performed in two stages: the first one consisted of an intrathecal bolus injection of baclofen, and the second of a continuous intrathecal baclofen infusion by means of an implantable pump. The sample consisted of 72 adult patients with severe spinal spasticity. Sixty-four were implanted and followed for 36 months. Muscular tone, spasms, and functional scales were evaluated before and periodically after administration of the drug, with a follow-up period of 36 months. Results. A very significant decrease in tone and spasms was observed in all cases (p < 0.001). Tolerance appeared during the first 12 months, increasing doses from a mean initial dose of 83.2 ,g (range 25,200 ,g) to a mean final dose of 270 ,g (range 25,800 ,g). Later on, efficacy remained stable, except in cases of mechanical problems of the infusion system. [source] Therapeutic efficacy of 5-fluorouracil-loaded microspheres on rat glioma: a magnetic resonance imaging studyNMR IN BIOMEDICINE, Issue 6 2001L. Lemaire Abstract The aim of this work was to assess the therapeutic efficacy of an intratumoral bolus injection of 5-fluorouracil (FU) compared to that of drug loaded in biodegradable microspheres, for the treatment of brain tumour. Experiments were carried out using a fast-growing C6-glioma rat model. The therapeutic protocols were performed 12 days after the injection of glioma cells. At this stage, the tumours were installed and the mean volume was 13,±,2,µl as measured by proton magnetic resonance (MR) imaging. This technique was used for the follow-up of the tumour volume with respect to time and therapy. In terms of rat survival, both therapies induced a significant 50% increase in animal life span (p,<,0.05) compared to animals receiving no drug or unloaded microspheres. Whilst no cure was observed, analysis of the MR images showed that the local and sustained delivery of FU slowed the tumour development in the vicinity of the microspheres by a factor of 3, compared with the bolus intratumoral injection. Copyright © 2001 John Wiley & Sons, Ltd. [source] Successful uses of magnesium sulfate for torsades de pointes in children with long QT syndromePEDIATRICS INTERNATIONAL, Issue 2 2006KENJI HOSHINO Abstract Background: Administration of magnesium sulfate (MgSO4) is an effective and safe treatment for torsades de pointes (TdP) associated with acquired long QT syndrome (LQTS) in adults. As for children, there are few reports focusing on it. The authors discuss the efficacy of MgSO4 for TdP in children with congenital and acquired LQTS. The authors also discuss the optimal administration dosage and serum magnesium (SMg) concentration during MgSO4 therapy. Methods: The authors studied seven consecutive LQTS children undergoing MgSO4 therapy for TdP. Of the seven children, five were congenital LQTS and two were acquired LQTS. A bolus injection of MgSO4 was given intravenously over 1,2 min followed by continuous infusion for the next 2,7 days. Results: Of the seven patients, six responded completely to the initial bolus. The bolus dosage was 5.9 ± 3.8 mg/kg (range, 2.3,12 mg/kg) in these six, and the other remaining one (neonate with congenital LQTS) required a total of 30 mg/kg until complete abolishment. The continuous infusion was given at rates of 0.3,1.0 mg/kg per h and patients did not show recurrence of TdP. The SMg concentration was 3.9 ± 1.0 mg/dL (2.9,5.4 mg/dL) immediately after bolus injection. The mean corrected QT (QTc) interval before and after bolus injection did not show significant difference. Conclusion: Intravenous infusion of MgSO4 was effective for TdP in children with LQTS, and MgSO4 abolished TdP without shortening the QTc interval. The optimal bolus dosage, infusion rates and SMg concentration were 3,12 mg/kg, 0.5,1.0 mg/kg per h and 3,5 mg/dL, respectively. [source] WST11, A Novel Water-soluble Bacteriochlorophyll Derivative; Cellular Uptake, Pharmacokinetics, Biodistribution and Vascular-targeted Photodynamic Activity Using Melanoma Tumors as a Model,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 2 2005Ohad Mazor ABSTRACT WST11 is a novel negatively charged water-soluble palladiumbacteriochlorophyll derivative that was developed for vascular-targeted photodynamic therapy (VTP) in our laboratory. The in vitro results suggest that WST11 cellular uptake, clearance and phototoxicity are mediated by serum albumin trafficking. In vivo, WST11 was found to clear rapidly from the circulation (t1/2= 1.65 min) after intravenous bolus injection in the mouse, whereas a longer clearance time (t1/2= 7.5 min) was noted in rats after 20 min of infusion. The biodistribution of WST11 in mouse tissues indicates hepatic clearance (t1/2= 20 min), with minor (kidney, lung and spleen) or no intermediary accumulation in other tissues. As soon as 1 h after injection, WST11 had nearly cleared from the body of the mouse, except for a temporal accumulation in the lungs from which it cleared within 40 min. On the basis of these results, we set the VTP protocol for a short illumination period (5 min), delivered immediately after WST11 injection. On subjecting M2R melanoma xenografts to WST11-VTP, we achieved 100% tumor flattening at all doses and a 70% cure with 9 mg/kg and a light exposure dose of 100 mW/cm2. These results provide direct evidence that WST11 is an effective agent for VTP and provide guidelines for further development of new candidates. [source] The effect of pre-emptive use of minimal dose fentanyl on fentanyl-induced coughingANAESTHESIA, Issue 1 2010K.-C. Hung Summary We performed a randomised, double-blind study to evaluate the effect of the pre-emptive use of minimal dose intravenous fentanyl (25 ,g) on the incidence of cough caused by a larger bolus of intravenous fentanyl. Six hundred patients were randomly assigned to one of three groups to receive either 0.5 ml saline 0.9% 1 min before administration of fentanyl 150 ,g (3 ml), or pre-emptive fentanyl 25 ,g (0.5 ml) 1 min before administration of fentanyl 125 ,g or 150 ,g. The incidence of fentanyl-induced cough was significantly lower in both pre-emptive groups (7 (3.5%) for 125 ,g fentanyl and 15 (7.5%) for 150 ,g fentanyl) than in the saline group (37 (18.5%); p = 0.001). We conclude that pre-emptive use of fentanyl 25 ,g, administered 1 min before bolus injection of fentanyl (125 or 150 ,g), can effectively suppress fentanyl-induced cough. [source] | |||||||||||||||||||||||||||||||