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Plasma Half-life (plasma + half-life)
Selected AbstractsPharmacokinetics of detomidine administered to horses at rest and after maximal exerciseEQUINE VETERINARY JOURNAL, Issue 5 2009J. A. E. HUBBELL Summary Reason for performing study: Increased doses of detomidine are required to produce sedation in horses after maximal exercise compared to calm or resting horses. Objectives: To determine if the pharmacokinetics of detomidine in Thoroughbred horses are different when the drug is given during recuperation from a brief period of maximal exercise compared to administration at rest. Methods: Six Thoroughbred horses were preconditioned by exercising them on a treadmill. Each horse ran a simulated race at a treadmill speed that caused it to exercise at 120% of its maximal oxygen consumption. One minute after the end of exercise, horses were treated with detomidine. Each horse was treated with the same dose of detomidine on a second occasion a minimum of 14 days later while standing in a stocks. Samples of heparinised blood were obtained at various time points on both occasions. Plasma detomidine concentrations were determined by liquid chromatographymass spectrometry. The plasma concentration vs. time data were analysed by nonlinear regression analysis. Results: Median back-extrapolated time zero plasma concentration was significantly lower and median plasma half-life and median mean residence time were significantly longer when detomidine was administered after exercise compared to administration at rest. Median volume of distribution was significantly higher after exercise but median plasma clearance was not different between the 2 administrations. Conclusions and potential relevance: Detomidine i.v. is more widely distributed when administered to horses immediately after exercise compared to administration at rest resulting in lower peak plasma concentrations and a slower rate of elimination. The dose requirement to produce an equivalent effect may be higher in horses after exercise than in resting horses and less frequent subsequent doses may be required to produce a sustained effect. [source] The role of methadone in cancer pain treatment , a reviewINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 7 2009W. Leppert Summary Background:, Methadone is an opioid analgesic of step 3 of the World Health Organization (WHO) analgesic ladder. Aim and Methods:, To outline pharmacodynamics, pharmacokinetics, drug interactions, equianalgesic dose ratio with other opioids, dosing rules, adverse effects and methadone clinical studies in patients with cancer pain. A review of relevant literature on methadone use in cancer pain was conducted. Results:, Methadone is used in opioid rotation and administered to patients with cancer pain not responsive to morphine or other strong opioids when intractable opioid adverse effects appear. Methadone is considered as the first strong opioid analgesic and in patients with renal impairment. Methadone possesses different pharmacodynamics and pharmacokinetics in comparison to other opioids. The advantages of methadone include multimode analgesic activity, high oral and rectal bioavailability, long lasting analgesia, lack of active metabolites, excretion mainly with faeces, low cost and a weak immunosuppressive effect. The disadvantages include long and changeable plasma half-life, high bound to serum proteins, metabolism through P450 system, numerous drug interactions, lack of clear equianalgesic dose ratio to other opioids, QT interval prolongation, local reactions when administered subcutaneously. Conclusions:, Methadone is an important opioid analgesic at step 3 of the WHO analgesic ladder. Future controlled studies may focus on establishment of methadone equianalgesic dose ratio with other opioids and its role as the first strong opioid in comparative studies with analgesia, adverse effects and quality of life taken into consideration. [source] Effects of non-steroidal anti-inflammatory drugs on the pharmacokinetics and elimination of aciclovir in ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2005Hye-Sun Gwak This study aims to investigate the effect of commonly used non-steroidal anti-inflammatory drugs (NSAIDs) on the pharmacokinetics and the renal elimination of aciclovir in rats. Pharmacokinetic parameters were determined following an intravenous administration of aciclovir (5 mg kg,1) to rats in the presence and absence of ketoprofen or naproxen (25 mg kg,1). Compared with the control (given aciclovir alone), pre-treatment with ketoprofen or naproxen 30 min before aciclovir administration significantly altered the pharmacokinetics of aciclovir. Renal clearance of aciclovir was reduced by approximately two fold in the presence of ketoprofen or naproxen. Consequently, the systemic exposure (AUC) to aciclovir in the rats pre-treated with ketoprofen or naproxen was significantly (P < 0.05) higher than that from the control group given aciclovir alone. Furthermore, the mean terminal plasma half-life of aciclovir was enhanced by 4,5 fold by pre-treatment with ketoprofen or naproxen. These results suggest that NSAIDs, such as ketoprofen and naproxen, are effective in altering the pharmacokinetics of aciclovir by inhibiting the organic anion transporter-mediated tubular secretion of aciclovir. Therefore, concomitant use of ketoprofen or naproxen with aciclovir should require close monitoring for clinical consequence of potential drug interaction. [source] The promise and challenges of bioengineered recombinant clotting factorsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 8 2005S. W. PIPE Summary., The past 10 years of clinical experience have demonstrated the safety and efficacy of recombinant clotting factors. With the adoption of prophylactic strategies, there has been considerable progress in avoiding the complications of hemophilia. Now, insights from our understanding of clotting factor structure and function, mechanisms of hemophilia and inhibitors, gene therapy advances and a worldwide demand for clotting factor concentrates leave us on the brink of embracing targeted bioengineering strategies to further improve hemophilia therapeutics. The ability to bioengineer recombinant clotting factors with improved function holds promise to overcome some of the limitations in current treatment, the high costs of therapy and increase availability to a broader world hemophilia population. Most research has been directed at overcoming the inherent limitations of rFVIII expression and the inhibitor response. This includes techniques to improve rFVIII biosynthesis and secretion, functional activity, half-life and antigenicity/immunogenicity. Some of these proteins have already reached commercialization and have been utilized in gene therapy strategies, while others are being evaluated in pre-clinical studies. These novel proteins partnered with advances in gene transfer vector design and delivery may ultimately achieve persistent expression of FVIII leading to an effective long-term treatment strategy for hemophilia A. In addition, these novel FVIII proteins could be partnered with new advances in alternative recombinant protein production in transgenic animals yielding an affordable, more abundant supply of rFVIII. Novel rFIX proteins are being considered for gene therapy strategies whereas novel rVIIa proteins are being evaluated to improve the potency and extend their plasma half-life. This review will summarize the status of current recombinant clotting factors and the development and challenges of recombinant clotting factors bioengineered for improved function. [source] A multicenter pharmacokinetic study of the B-domain deleted recombinant factor VIII concentrate using different assays and standardsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 11 2003M. Morfini Summary., When the one-stage clotting assay is used in comparison with the chromogenic and immunological assays, plasma levels of factor (F)VIII are underestimated by 40,50% after infusion of B-domain deleted recombinant FVIII (BDD-rFVIII) in patients with hemophilia. A possible way to counteract the underestimation of FVIII levels by the one-stage assay is the adoption of a recombinant FVIII reference standard instead of a plasma standard. To evaluate the usefulness of such a standard [ReFacto® Laboratory Standard (RLS)], the pharmacokinetic parameters of a single dose of BDD-rFVIII (25 U kg,1) were evaluated in a multicenter study carried out in 18 patients with severe hemophilia A. The very low in vivo recovery, obtained with the combination of the one-stage assay and plasma reference standard, was increased up to the values obtained by the chromogenic assay when the results were expressed in terms of RLS. When the plasma standard was used, the one-stage/chromogenic ratio was 0.82 ± 0.12 for FVIII levels above 25 U dL,1 and 1.42 ± 0.99 for FVIII levels below 25 U dL,1. Using the RLS, the one-stage/chromogenic ratio increased to 1.01 ± 0.19 at FVIII levels above 25 U dL,1, as a consequence of a complete overlap of the two decays; however, at FVIII levels below 25 U dL,1, the one-stage/chromogenic ratio was still 1.6 ± 0.85. After the twelfth hour, FVIII concentrations obtained by chromogenic assay were always lower than those resulting from the one-stage clotting assay, independently of the standard used. Results obtained by chromogenic assay were not affected by the type of standard used. Compared with those obtained by the one-stage assay, higher values of clearance, lower volume of distribution area and shorter plasma half-life or mean residence time were obtained by chromogenic assay because of a shape change of the decay curve due to a shift to higher values in the first part (time interval 0,12 h) and to lower values in the second part of the decay curve (time interval 12,48 h). As a consequence, the slope of the decay curve obtained by means of chromogenic assay was steeper. In conclusion, the more homogeneous results of in vivo recovery and pharmacokinetic analysis, due to the decrease of discrepancy between the two methods when RLS was used, make the cheaper and more widely used one-stage assay preferable to the more expensive chromogenic assay, on condition that the ReFacto specific standard has used. [source] Pharmacokinetics of cimetidine in dogs after oral administration of cimetidine tabletsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2009G. LE TRAON Long-term oral treatment with cimetidine is recommended to reduce vomiting in dogs with chronic gastritis. Despite this, few studies have specifically examined the plasma disposition and pharmacokinetics of cimetidine in dogs, particularly following repeated oral administration. The pharmacokinetics of cimetidine following oral administration as tablets was investigated in healthy dogs. Cimetidine was absorbed rapidly post-treatment (tmax = 0.5 h). A mean absolute bioavailability of 75% was calculated following a single oral administration of 5 mg cimetidine/kg body weight. After intravenous administration, a plasma half-life of 1.6 h was calculated. Repeated oral administration at the recommended dose rate and regime (5 mg/kg body weight three times daily) for 30 consecutive days did not lead to any accumulation of cimetidine in plasma. Food intake concomitant with oral administration of cimetidine delayed (tmax = 2.25 h) and decreased the rate and extent of absorption (AUC) by about 40%. Cimetidine was well absorbed in fasted dogs. Administration of food decreased the bioavailability of cimetidine by 40%. Cimetidine does not accumulate over time in plasma when administered long term to dogs. [source] Isoxsuprine hydrochloride in the horse: a reviewJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2002R. S. ERKERT Isoxsuprine hydrochloride has been suggested for use in horses for treatment of navicular syndrome and laminitis. The drug has been shown to be a , -adrenoreceptor antagonist with , -adrenoreceptor agonistic properties, with both characteristics contributing to vasodilation and uterine relaxation. In addition, the drug is capable of decreasing blood viscosity and platelet aggregation. Studies have shown i.v. isoxsuprine to have a plasma half-life of <3 h with a large apparent volume of distribution. Cardiovascular effects resolve rapidly following i.v. administration, but are absent with oral dosing. Oral bioavailability is 2.2% with a high first pass effect. Isoxsuprine has an apparent affinity for melanin that may contribute to extended renal excretion. Clinical trials appear to support the use of isoxsuprine for treatment of navicular disease. However, poor bioavailability, lack of cardiovascular effects following oral administration, superficial support in clinical trials, and new evidence regarding the pathogenesis of navicular syndrome indicate that the use of isoxsuprine for treatment of navicular syndrome or laminitis is questionable at best. [source] Comparison of the effects of fasting morning, fasting evening and fed bedtime administration of tenatoprazole on intragastric pH in healthy volunteers: a randomized three-way crossover studyALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 8 2006A. B. R. THOMSON Background, The effectiveness of proton pump inhibitors is influenced by meals and administration time. Aim, To compare the effects on intragastric acidity of times of dosing of tenatoprazole, a novel imidazopyridine-based proton pump inhibitor with a prolonged plasma half-life. Methods, This randomized three-period crossover study included 12 Helicobacter pylori -negative healthy subjects, who received tenatoprazole 40 mg either fasting at 7.00 am, fasting at 7.00 pm or fed at 9.30 pm for 7 days, with a 2-week washout between periods. Twenty-four hour intragastric pH was monitored on day 7 of each period. Results, On day 7, median 24-h pH was 4.7, 5.1 and 4.7 after breakfast, dinner and bedtime dosing, respectively (P = 0.11), whereas night-time pH was 4.2, 5.0 and 4.4 (P = 0.13). The mean 24-h percentage of time over pH 4 was 62, 72 and 64 after breakfast, dinner and bedtime dosing, respectively (N.S.), and 54, 68 and 56 during night-time (P = 0.06). Nocturnal acid breakthrough incidence decreased from 100% at baseline to 83%, 55% and 75% after 7.00 am, 7.00 pm and 9.30 pm dosing, respectively (P = 0.18), and its mean duration dropped from 6.2 to 2.8, 1.0 and 2.2 h, respectively (P < 0.05). Conclusion, Seven-day administration of tenatoprazole provides a prolonged duration of acid suppression, especially during the night-time, with little effect of food or time of dosing. [source] Registered nurse-administered propofol sedation for endoscopyALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2004S. C. Chen Summary Propofol has several attractive properties that render it a potential alternative sedative agent for endoscopy. Compared with meperidine and midazolam, it has an ultra-short onset of action, short plasma half-life, short time to achieve sedation, faster time to recovery and discharge, and results in higher patient satisfaction. Shorter times to achieve sedation enhance efficiency in the endoscopy unit. Multiple studies have documented the safe administration of propofol by non-anaesthesiologists. Administration by registered nurses is more cost-effective than administration by anaesthesiologists. However, the administration of propofol by a registered nurse supervised only by the endoscopist is controversial because the drug has the potential to produce sudden and severe respiratory depression. More information is needed on how training nurses and endoscopists should proceed to give propofol, as well as the optimal level of monitoring to ensure the safety of nurse-administered propofol. [source] Biological and Optical Properties of Fluorescent Nanoparticles Developed for Intravascular ImagingMICROSCOPY RESEARCH AND TECHNIQUE, Issue 9 2007Dino J. Ravnic Abstract Intravascular tracers in the blood circulation can provide a description of the flow field over time and space. To address the limitations of existing intravascular tracers, we have developed fluorescent nanoparticles capable of providing detailed information regarding the intravascular flow field. The nanoparticles were designed to maximize plasma half-life as well as minimize interactions with other blood components. The bioavailability of the particles in the blood circulation required nanoscale size and low surface charge density. Intravital imaging of nanoparticles in the microcirculation demonstrated that the fluorescence intensity of the nanoparticles was a major determinant of both temporal and spatial resolution of the flow field. We conclude that nanoparticles prepared with these physical and optical properties can provide an accurate description of the localized intravascular flow field. Microsc. Res. Tech., 2007. © 2007 Wiley-Liss, Inc. [source] Variability among nonsteroidal antiinflammatory drugs in risk of upper gastrointestinal bleedingARTHRITIS & RHEUMATISM, Issue 6 2010Elvira L. Massó González Objective Traditional nonsteroidal antiinflammatory drugs (NSAIDs) increase the risk of upper gastrointestinal (GI) bleeding/perforation, but the magnitude of this effect for coxibs in the general population and the degree of variability between individual NSAIDs is still under debate. This study was undertaken to assess the risk of upper GI bleeding/perforation among users of individual NSAIDs and to analyze the correlation between this risk and the degree of inhibition of whole blood cyclooxygenase 1 (COX-1) and COX-2 in vitro. Methods We conducted a systematic review of observational studies on NSAIDs and upper GI bleeding/perforation published between 2000 and 2008. We calculated pooled relative risk (RR) estimates of upper GI bleeding/perforation for individual NSAIDs. Additionally, we verified whether the degree of inhibition of whole blood COX-1 and COX-2 in vitro by average circulating concentrations predicted the RR of upper GI bleeding/perforation. Results The RR of upper GI bleeding/perforation was 4.50 (95% confidence interval [95% CI] 3.82,5.31) for traditional NSAIDs and 1.88 (95% CI 0.96,3.71) for coxibs. RRs lower than that for NSAIDs overall were observed for ibuprofen (2.69 [95% CI 2.17,3.33]), rofecoxib (2.12 [95% CI 1.59,2.84]), aceclofenac (1.44 [95% CI 0.65,3.2]), and celecoxib (1.42 [95% CI 0.85,2.37]), while higher RRs were observed for ketorolac (14.54 [95% CI 5.87,36.04]) and piroxicam (9.94 [95% CI 5.99,16.50). Estimated RRs were 5.63 (95% CI 3.83,8.28) for naproxen, 5.57 (95% CI 3.94,7.87) for ketoprofen, 5.40 (95% CI 4.16,7.00) for indomethacin, 4.15 (95% CI 2.59,6.64) for meloxicam, and 3.98 (95% CI 3.36,4.72) for diclofenac. The degree of inhibition of whole blood COX-1 did not significantly correlate with RR of upper GI bleeding/perforation associated with individual NSAIDs (r2 = 0.34, P = 0.058), but a profound and coincident inhibition (>80%) of both COX isozymes was associated with higher risk. NSAIDs with a long plasma half-life and with a slow-release formulation were associated with a greater risk than NSAIDs with a short half-life. Conclusion The results of our analysis demonstrate that risk of upper GI bleeding/perforation varies between individual NSAIDs at the doses commonly used in the general population. Drugs that have a long half-life or slow-release formulation and/or are associated with profound and coincident inhibition of both COX isozymes are associated with a greater risk of upper GI bleeding/perforation. [source] Intestinal absorption characteristics of ketoprofen in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2006Jun-Shik Choi Abstract The present study aims to investigate the intestinal absorption characteristics of ketoprofen in rats. The pharmacokinetic profile of ketoprofen was evaluated following a single p.o. administration of ketoprofen (1 mg/kg) to rats in the absence and presence of benzoic acid or lactic acid (2 and 10 mg/kg), the substrates of monocarboxylic acid transporters. The pharmacokinetic profiles of ketoprofen (1 mg/kg) were significantly altered by the concurrent use of benzoic acid or lactic acid (10 mg/kg), compared with the control (given ketoprofen alone). The Cmax and AUC of ketoprofen in the presence of benzoic acid or lactic acid (10 mg/kg) were significantly (p<0.05) lower than those from the control group, while there was no significant change in Tmax and the terminal plasma half-life (T1/2) of ketoprofen. These results suggest that ketoprofen shares a common transport pathway with benzoic acid and lactic acid during the intestinal absorption in rats. Copyright © 2005 John Wiley & Sons, Ltd. [source] Inhibition of allergen-induced wheal and flare reactions by levocetirizine and desloratadineBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2008Nelly Frossard What is already known about this subject ,,The reproducible and standardized histamine-induced wheal and flare model helps identify the objective effectiveness of antihistamines in humans, as well as their differences in onset and duration of action. ,,Some of the newest antihistamines have already been compared in a head-to-head setting using this model. However, their objective action at inhibiting the allergen-induced wheal and flare response has not been reported yet. What this study adds ,,The time,response study presented here shows the objective activity of two of the newest generation of antihistamines, levocetirizine and desloratadine, at inhibiting the allergen-induced wheal and flare response in a randomized, cross over, placebo-controlled trial. ,,This model is interesting to the clinical setting since allergic subjects are recruited, and the response to allergen involves mast cell degranulation and release of numerous vasoactive and pro-inflammatory mediators additionally to histamine. ,,In addition, this study reports receptor occupancy for both antihistamines at therapeutic dosage, leading to analysis of potential differences in activity. ,,This study clearly shows the potential anti-inflammatory properties of desloratadine and levocetirizine in their skin activity when allergen is the challenging agent as occurs in the clinical situation. Aims To evaluate the inhibitory activity of the new-generation antihistamines levocetirizine and desloratadine at their therapeutic doses on the allergen-induced wheal and flare reaction at 1.5 h, 4 h, 7 h, 12 h and 24 h postdose, and to measure their plasma and skin concentrations. Methods A double-blind, randomized, cross-over, placebo-controlled study in 18 allergic subjects was carried out. The time,response of the wheal and flare reaction areas under the curve (AUC) were compared by anova. Results Both antihistamines significantly (P < 0.001) inhibited the allergen-induced wheal and flare reactions compared with placebo. Levocetirizine was significantly more potent than desloratadine. Mean ± SEM wheal AUC(0,24 h) was 506.4 ± 81.0 with levocetirizine and 995.5 ± 81.0 mm2 h with desloratadine as compared with placebo (1318.5 ± 361.0 mm2 h). Flare AUC(0,24 h) was 5927.3 ± 1686.5 and 15838.2 ± 1686.5 mm2 h, respectively [P < 0.001 for both compared with placebo (22508.2 ± 7437.1 mm2 h)]. Levocetirizine showed significant inhibition of wheal and flare already at 1.5 h postdose compared with placebo (P , 0.001); desloratadine achieved a significant effect only after 4 h. The mean total plasma concentration at 12 h and 24 h after intake was higher for levocetirizine (58.1 ± 13.4 and 20.0 ± 8.1 ng ml,1, respectively) as compared with desloratadine (0.82 ± 0.24 and 0.45 ± 0.16 ng ml,1). Similarly, higher mean unbound skin concentrations were observed for levocetirizine 24 h after intake (1.80 ng g,1) than for desloratadine (0.07 ng g,1). This was associated with greater receptor occupancy for levocetirizine (54%) than desloratadine (34%) at 24 h. Conclusions Levocetirizine suppressed the cutaneous allergic reactions with a higher potency than desloratadine, which correlated with its high receptor occupancy. Receptor occupancy rather than drug affinity or plasma half-life is more representative of antihistamine potency. [source] Haemodynamic action of B-type natriuretic peptide substantially outlasts its plasma half-life in conscious dogsCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2003Colleen J Thomas Summary 1.,The objective of the present study was to determine the plasma half-life of B-type natriuretic peptide (BNP) in conscious dogs after intravenous administration and to compare this with its haemodynamic effects. In six chronically instrumented dogs, plasma BNP concentrations were measured under basal conditions, during a constant infusion of canine BNP-32 (10 pmol/kg per min; 25 min) to steady state and at nominated time points up to 75 min after stopping the infusion. Concomitant, continuous measurements of mean arterial blood pressure (MAP), heart rate (HR), central venous pressure (CVP) and mesenteric blood flow (MBF) were obtained. 2.,Baseline plasma BNP levels were 15.0 ± 2.3 fmol/mL and rose approximately 10-fold to 159 ± 23 fmol/mL after 20,25 min BNP infusion. When the infusion was turned off, plasma BNP levels declined in a biphasic manner, with an initial half-life of 1.57 ± 0.14 min and a terminal half-life of 301 ± 85 min. The metabolic clearance rate of BNP was 2.29 ± 0.34 L/min. 3.,The infusion of BNP reduced MAP (approximately 10%), CVP (approximately 65%) and MBF (approximately 25%), whereas haematocrit (approximately 4%) and mesenteric vascular resistance (MVR) increased (approximately 40%; all P < 0.05). Plasma BNP levels returned to baseline by 20 min after BNP infusion had been stopped, whereas none of the haemodynamic variables returned to normal by this time. Mean arterial pressure returned to resting levels within 10,15 min after plasma BNP returned to normal. However, CVP, haematocrit and MBF remained substantially below baseline values for more than 20 min after circulating BNP levels had returned to pre-infusion levels. Of these, only mesenteric vascular changes were returned to baseline within 60 min of plasma BNP levels normalizing. 4.,These results demonstrate that the removal of BNP from the canine circulation is rapid, similar to observations made regarding the metabolism of circulating atrial natriuretic peptide in dogs. The half-life of BNP in dogs was shorter than that in rats, sheep or humans. However, the haemodynamic actions of BNP substantially outlasted its plasma half-life. Whether this disparity in plasma level and haemodynamic activity of BNP reflects long-lasting activation of second messenger systems or slow recovery from the hydraulic changes at the capillary level, reflected in the haematocrit and CVP, remains to be answered. [source] | ||||||||||