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Relevant Doses (relevant + dose)
Selected AbstractsDoes pethidine affect the cardiovascular and sedative effects of dexmedetomidine in dogs?JOURNAL OF SMALL ANIMAL PRACTICE, Issue 2 2009N. J. Grint Objectives: To investigate pethidine's effects on sedation and cardiovascular variables in dogs premedicated with dexmedetomidine. Methods: Sixty American Society of Anesthesiologists (ASA) I dogs were presented for routine neutering. Heart rate was measured at admission. Dogs were randomly assigned to one of the five groups to decide premedication; group D5+P (dexmedetomidine 5 ,g/kg plus pethidine 5 mg/kg), D10+P (dexmedetomidine 10 ,g/kg plus pethidine 5 mg/kg) with three control groups, D5 (dexmedetomidine 5 ,g/kg), D10 (dexmedetomidine 10 ,g/kg) or P (pethidine 5 mg/kg). Heart rate was measured at 3, 5, 10 and 20 minutes after preanaesthetic medication. Simple descriptive scores for sedation were assigned after 20 minutes. Anaesthesia was induced using propofol and maintained using isoflurane in oxygen. Heart rate was recorded throughout anaesthesia. Results: Sedation scores after preanaesthetic medication were significantly higher (P<0·001) in groups D5+P and D10+P compared with the other three groups. D5+P and D10+P groups tended to have lower heart rates in dogs at all time points after premedication compared with groups containing only pethidine or dexmedetomidine at the relevant dose. Clinical Significance: Greater sedation is achieved using combinations of dexmedetomidine and pethidine compared with each drug alone. Pethidine does not attenuate the alpha-2 adrenergic-induced bradycardia. [source] A comparison of the , -D-xyloside, odiparcil, to warfarin in a rat model of venous thrombosisJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2006J. R. TOOMEY Summary,Background:,A significant need exists for new chronic oral anticoagulation therapies to replace warfarin. Previous studies have shown that , -D-xylosides, which prime glycosaminoglycan (GAG) synthesis, have antithrombin and antithrombotic activity. In the following report, a new orally active , -D-xyloside (odiparcil) has been characterized in a rat model of venous thrombosis and its efficacy and bleeding liability compared to warfarin. Additionally, studies were conducted to investigate odiparcil's ex vivo antithrombin and antiplatelet activity, and also to explore the potential utility of protamine sulfate as a neutralizing agent. Methods and results:,In vivo thrombosis studies were conducted in a rat inferior vena cava model, and bleeding studies in a rat tail transection model. Following oral dosing, warfarin and odiparcil produced dose-related suppression of thrombus formation. A therapeutically relevant dose of warfarin in this model (international normalized ratio; INR 3.0) achieved ,65% inhibition of thrombus formation. Warfarin caused dose-related significant increases in bleeding indices. Odiparcil antithrombotic activity was limited by its mechanism to a maximum suppression of thrombus formation of 65,70%, and did not prolong bleeding indices. Additionally, odiparcil-induced heparin cofactor II (HCII)-dependent antithrombin activity was shown to be a function of dermatan sulfate-like GAG production. Other than thrombin-related effects, no odiparcil effects on platelet function were observed. In antidote studies, it was demonstrated that odiparcil-induced antithrombotic activity could be partially neutralized by protamine sulfate. Conclusions:,These experiments suggest that an antithrombotic approach based upon xyloside induction of circulating GAGs may have the potential to approximate the efficacy of warfarin and yet with a reduced risk to hemostasis. [source] Validation of Phage T7 Biological Dosimeter by Quantitative Polymerase Chain Reaction Using Short and Long Segments of Phage T7 DNA ,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 3 2003M. Hegedüs ABSTRACT Phage T7 can be used as a biological dosimeter; its reading, the biologically effective dose (BED), is proportional to the inactivation rate |ln (n/n0)|. For the measurement of DNA damage in phage T7 dosimeter, a quantitative polymerase chain reaction (QPCR) methodology has been developed using 555 and 3826 bp fragments of phage T7 DNA. Both optimized reactions are so robust that an equally good amplification was obtained when intact phage T7 was used in the reaction mixture. In the biologically relevant dose range a good correlation was obtained between the BED of the phage T7 dosimeter and the amount of ultraviolet (UV) photoproducts determined by QPCR with both fragments under the effect of five various UV sources. A significant decrease in the yield of photoproducts was detected by QPCR in isolated T7 DNA and in heated phage compared with intraphage DNA with all irradiation sources. Because the yield of photoproducts was the same in B, C and A conformational states of T7 DNA, a possible explanation for modulation of photoproduct frequency in intraphage T7 DNA is that the presence of bound phage proteins induces an alteration in DNA structure that can result in increased induction of photoproducts. [source] Can experimental paradigms and animal models be used to discover clinically effective medications for alcoholism?ADDICTION BIOLOGY, Issue 4 2005Mark Egli Evaluating medications in animal laboratory paradigms can reveal whether the compound is effective in an established alcoholism model, at clinically relevant doses and exposure conditions, when administered orally (or transdermally) and without serious limiting side effects. Positive outcomes constitute a possible discovery for relevance to alcoholism and, under favorable marketing conditions, encourage further development. Medication testing using animal models of alcoholism might also guide clinical testing by discriminating clinically effective from clinically ineffective compounds. This ability rests on whether there are tests or, more reasonably, batteries of tests having this discriminative ability. The present paper examines this possibility. Effects of naltrexone and acamprosate in animal paradigms which model behavioral aspects of alcoholism are reviewed and compared with the effects of compounds which have limited effects in alcoholics. It is not clear at present whether any single paradigm or combination of paradigms differentiates clinically effective from clinically limited compounds. Steps are suggested to improve the use of preclinical laboratory tests to predict which compounds are likely to be effective medications for reducing drinking and sustaining abstinence in human alcoholics. [source] Alcohol and Cognitive Function: Assessment in Everyday Life and Laboratory Settings Using Mobile PhonesALCOHOLISM, Issue 12 2009Brian Tiplady Background:, Mobile phone (cellphone) technology makes it practicable to assess cognitive function in a natural setting. We assessed this method and compared impairment of performance due to alcohol in everyday life with measurements made in the laboratory. Methods:, Thirty-eight volunteers (20 male, aged 18,54 years) took part in the everyday study, completing assessments twice a day for 14 days following requests sent by text messages to the mobile phone. Twenty-six of them (12 male, aged 19,54) took part in a subsequent two-period crossover lab study comparing alcohol with no alcohol (placebo). Results:, Everyday entries with 5 or more units of alcohol consumed in the past 6 hours (inferred mean blood alcohol concentration 95 ml/100 ml) showed higher scores for errors in tests of attention and working memory compared with entries with no alcohol consumed that day. Response times were impaired for only 1 test, sustained attention to response. The laboratory comparison of alcohol (mean blood alcohol concentration 124 mg/100 ml) with placebo showed impairment to both reaction time and error scores for all tests. A similar degree of subjective drunkenness was reported in both settings. Conclusions:, We found that mobile phones allowed practical research on cognitive performance in an everyday life setting. Alcohol impaired function in both laboratory and everyday life settings at relevant doses of alcohol. [source] Effects of hyperoncotic or hypertonic,hyperoncotic solutions on polymorphonuclear neutrophil count, elastase- and superoxide-anion production: a randomized controlled clinical trial in patients undergoing elective coronary artery bypass graftingACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 7 2007G. P. Molter Background:, Hypertonic,hyperoncotic solutions may be an effective treatment for systemic inflammatory response syndrome (SIRS). With regard to the immunomodulatory effects of these drugs, previous studies demonstrated controversial results. Therefore, the present study investigated the influence of different hyperoncotic and hypertonic,hyperoncotic solutions on polymorphonuclear neutrophil leukocyte (PMNL) count, elastase and superoxide-anion production in patients undergoing elective coronary artery bypass grafting (CABG) with cardiopulmonary bypass. Methods:, Fifty patients scheduled for elective CABG with cardiopulmonary bypass were randomly assigned to five groups: (i) NaCl 0.9%, 750 ml/m2 body surface area (BSA); (ii) hydroxyethylic starch 10%, 250 ml/m2 BSA and NaCl 0.9%, 400 ml/m2 BSA; (iii) dextran 10%, 250 ml/m2 BSA and NaCl 0.9%, 300 ml/m2 BSA; (iv) hypertonic sodium chloride 7.2%/hyperoncotic hydroxyethylic starch 10%, 150 ml/m2 BSA; and (v) hypertonic sodium chloride 7.2%/hyperoncotic dextran 10%, 150 ml/m2 BSA. Blood samples were drawn from arterial, central venous and coronary artery sinus catheters peri-operatively. PMNL count, superoxide-anion production and elastase were recorded. Results:, PMNL counts and elastase activity increased in all groups after reperfusion. Superoxide-anion production showed only minor changes. Between groups, no significant differences were demonstrated. Conclusions:, Infusion of clinically relevant doses of hypertonic,hyperoncotic solution did not affect PMNL count, elastase- or superoxide-anion production during elective CABG with cardiopulmonary bypass. [source] Levosimendan has an inhibitory effect on platelet functionAMERICAN JOURNAL OF HEMATOLOGY, Issue 1 2008at Kaptan Levosimendan enhances cardiac contractility by increasing myocyte sensitivity to calcium, and induces vasodilatation. Although studies have evaluated the efficacy of levosimendan in heart failure, it is not clear whether it might produce functional influence on platelet response. In this study, the effect of levosimendan on platelet aggregation was investigated. Platelet function tests were performed in 12 healthy male volunteers. Three concentrations of levosimendan solution were prepared that would result in 10, 25, and 45 ng/ml levosimendan concentrations in the blood similar to that observed after clinical therapeutic intravenous application of 0.05,0.1 ,g/kg/min. Each concentration of levosimendan solution and a control diluent without levosimendan were incubated with whole blood at 37°C. After incubation for 15 min, aggregation responses were evaluated with adenosine diphosphate (ADP) (5 and 10 ,M) and collagen (2 and 5 ,g/ml) in platelet-rich plasma. Preincubation with all dilutions of levosimendan inhibited aggregation of platelets induced by ADP and collagen significantly. Levosimendan also inhibited significantly the secondary wave of platelet aggregation induced by ADP. The results showed that there was a relationship between levosimendan concentration and inhibition of platelet aggregation. In conclusion, this study with an in vitro model showed that levosimendan had a significant inhibitory effect on platelets in clinically relevant doses. Am. J. Hematol., 2008. © 2007 Wiley-Liss, Inc. [source] Pharmacokinetics and protein binding of the selective neuronal nitric oxide synthase inhibitor 7-nitroindazoleBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2000Mark A. Bush Abstract Utilization of nitric oxide (NO) synthase (NOS) inhibitors to probe the role of NO in various central nervous system processes requires use of an inhibitor selective for neuronal NOS, and is facilitated by knowledge of the pharmacokinetics of the inhibitor. The present project was undertaken to elucidate the disposition of the selective neuronal NOS inhibitor 7-nitroindazole (7-NI). A simple, specific HPLC assay was developed with requisite sensitivity to quantitate 7-NI in serum after administration of pharmacologically relevant doses. Further experiments were performed to assess the effects of administered dose on 7-NI disposition. 7-NI displayed marked nonlinearity, consistent with saturable elimination, when administered by ip injection in peanut oil. The nonlinearity was related to total dose, but not to the concentration of 7-NI in the vehicle. Binding of 7-NI in rat serum was concentration-independent and does not contribute to the nonlinearity. Various formulations for iv administration of this water-insoluble compound were evaluated; the optimal vehicle, from the standpoint of 7-NI solubility, appeared to inhibit the clearance of 7-NI from the systemic circulation. Considering the nonlinear disposition of 7-NI, knowledge of the pharmacokinetics of this inhibitor is requisite to designing administration protocols to achieve the desired magnitude and duration of NOS inhibition. Copyright © 2000 John Wiley & Sons, Ltd. [source] Oral administration of a tri-therapy for central pattern generator activation in paraplegic mice: Proof-of-concept of efficacyBIOTECHNOLOGY JOURNAL, Issue 4 2010Pierre A. Guertin Dr. Abstract Spinal cord injury (SCI) is a neurological condition, for which no cure exists, typically leading to an immediate and irreversible loss of sensory and voluntary motor functions accompanied by significant health problems. We conducted proof-of-concept experiments aimed at assessing efficacy upon oral administration of a novel combination therapy for central pattern generator (CPG) activation and corresponding locomotor movement generation in completely paraplegic animals. Co-administration orally (by gavage) of buspirone, levodopa and carbidopa was found to dose-dependently induce episodes of steady weight-bearing stepping in low-thoracic (Th9/10) spinal cord-transected (Tx) mice (with no other form of assistance or training). Robust hindlimb stepping with weight-bearing capabilities was induced with the tri-therapy but not with clinically relevant doses of these compounds administered separately. These results provide evidence suggesting that this drug combination may be ideally suited to constitute a first-in-class therapy (CPG activator) for locomotor activity induction in chronic SCI individuals, given that efficacy was shown using commercially available brain-permeable small molecules, already known as safe for the treatment of various neurological indications. [source] Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRIBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2008C-L Chin Background and purpose: Activation of cannabinoid CB1 and/or CB2 receptors mediates analgesic effects across a broad spectrum of preclinical pain models. Selective activation of CB2 receptors may produce analgesia without the undesirable psychotropic side effects associated with modulation of CB1 receptors. To address selectivity in vivo, we describe non-invasive, non-ionizing, functional data that distinguish CB1 from CB2 receptor neural activity using pharmacological MRI (phMRI) in awake rats. Experimental approach: Using a high field (7 T) MRI scanner, we examined and quantified the effects of non-selective CB1/CB2 (A-834735) and selective CB2 (AM1241) agonists on neural activity in awake rats. Pharmacological specificity was determined using selective CB1 (rimonabant) or CB2 (AM630) antagonists. Behavioural studies, plasma and brain exposures were used as benchmarks for activity in vivo. Key results: The non-selective CB1/CB2 agonist produced a dose-related, region-specific activation of brain structures that agrees well with published autoradiographic CB1 receptor density binding maps. Pretreatment with a CB1 antagonist but not with a CB2 antagonist, abolished these activation patterns, suggesting an effect mediated by CB1 receptors alone. In contrast, no significant changes in brain activity were found with relevant doses of the CB2 selective agonist. Conclusion and implications: These results provide the first clear evidence for quantifying in vivo functional selectivity between CB1 and CB2 receptors using phMRI. Further, as the presence of CB2 receptors in the brain remains controversial, our data suggest that if CB2 receptors are expressed, they are not functional under normal physiological conditions. British Journal of Pharmacology (2008) 153, 367,379; doi:10.1038/sj.bjp.0707506; published online 29 October 2007 [source] Oligonucleotide N3,,P5, Phosphoramidates and Thio -Phoshoramidates as Potential Therapeutic AgentsCHEMISTRY & BIODIVERSITY, Issue 3 2010Sergei Abstract Nucleic acids analogues, i.e., oligonucleotide N3,,P5, phosphoramidates and N3,,P5, thio -phosphoramidates, containing 3,-amino-3,-deoxy nucleosides with various 2,-substituents were synthesized and extensively studied. These compounds resist nuclease hydrolysis and form stable duplexes with complementary native phosphodiester DNA and, particularly, RNA strands. An increase in duplexes' melting temperature, ,Tm, relative to their phosphodiester counterparts, reaches 2.2,4.0° per modified nucleoside. 2,-OH- (RNA-like), 2,- O -Me-, and 2,- ribo -F-nucleoside substitutions result in the highest degree of duplex stabilization. Moreover, under close to physiological salt and pH conditions, the 2,-deoxy- and 2,-fluoro-phosphoramidate compounds form extremely stable triple-stranded complexes with either single- or double-stranded phosphodiester DNA oligonucleotides. Melting temperature, Tm, of these triplexes exceeds Tm values for the isosequential phosphodiester counterparts by up to 35°. 2,-Deoxy-N3,,P5, phosphoramidates adopt RNA-like C3,- endo or N -type nucleoside sugar-ring conformations and hence can be used as stable RNA mimetics. Duplexes formed by 2,-deoxy phosphoramidates with complementary RNA strands are not substrates for RNase H-mediated cleavage in vitro. Oligonucleotide phosphoramidates and especially thio -phosphoramidates conjugated with lipid groups are cell-permeable and demonstrate high biological target specific activity in vitro. In vivo, these compounds show good bioavailability and efficient biodistribution to all major organs, while exerting acceptable toxicity at therapeutically relevant doses. Short oligonucleotide N3,,P5, thio -phosphoramidate conjugated to 5,-palmitoyl group, designated as GRN163L (Imetelstat), was recently introduced as a potent human telomerase inhibitor. GRN163L is not an antisense agent; it is a direct competitive inhibitor of human telomerase, which directly binds to the active site of the enzyme and thus inhibits its activity. This compound is currently in multiple Phase-I and Phase-I/II clinical trials as potential broad-spectrum anticancer agent. [source] Concentration Of Egg White Lysozyme In The Serum Of Healthy Subjects After Oral AdministrationCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2002Seiichi Hashida SUMMARY 1. While the egg white lysozyme preparation ER0068 (Neuzym®; Eisai, Tokyo, Japan) is widely used clinically, no studies have been performed on its pharmacokinetic properties at clinically relevant doses. In the present study, we used a highly sensitive two-site enzyme immunoassay in order to determine the pharmacokinetic properties of egg white lysozyme after oral administration of two doses within the clinical range, paying particular attention to the effects of food intake. 2. A total of 22 healthy male subjects aged 20,45 years participated in the study. All subjects had been screened for egg white allergy and non-specific lysozyme inhibitors in their serum. Subjects who received 90 mg ER0068 after an overnight fast reached a maximum serum concentration of 1700 pg/mL within 1 h, compared with non-detectable levels in untreated controls. In a second experiment, subjects received 30 and 90 mg ER0068 after an overnight fast and 90 mg in the non-fasted state and exhibited maximum serum levels of 37, 360 and 49 pg/mL, respectively. Egg white lysozyme concentrations in serum returned to undetectable levels after a maximum of 48 h. 3. We conclude that clinically relevant concentrations of egg white lysozyme are absorbed in significant amounts, despite its high molecular weight. However, food intake considerably reduces the amount of enzyme absorbed. [source] | |||||||||||||