Intravenous Bolus Dose Research Articles

Intraoperative blood glucose levels in nondiabetic patients undergoing elective major surgery under general anaesthesia receiving different crystalloid solutions for maintenance fluid.

Context:The study was undertaken to observe the effect of different maintenance-fluid regimen on intraoperative blood glucose levels in non-diabetic patients undergoing elective major non-cardiac surgery under general anesthesia.Aims:To know the intraoperative blood glucose levels.Settings and Design:Prospective randomized parallel group study.Subjects and Methods:Two hundred non-diabetic patients (100 in each group) aged between 18 years and 60 years were enrolled for this prospective randomized parallel group study. Group A patients received Ringer's lactate solution and Group B patients received 0.45% sodium chloride with 5% dextrose and 20 mmol/L potassium chloride as maintenance fluid. Capillary blood glucose (CBG) level was measured immediately before initiation of intravenous fluid therapy and thereafter hourly till the end of surgery. If at any time intraoperative CBG was found to be more than or equal to 150 mg/dL calculated dose of human soluble insulin was given as intravenous bolus equal to the amount of CBG/100 units.Statistical Analysis Used:For comparison of normally distributed variables independent sample t test was done. For rest of the data, i.e., CBG_0, CBG_4 and insulin consumption Mann-Whitney U test was employed.Results:63% patients in group B developed at least one episode of hyperglycemia CBG ≥ 150 mg/dL) but only 29% in the Group A did so. Insulin consumption was significantly higher in Group B than in Group A to maintain normoglycemia. The relative risk of becoming hyperglycemic in Group B patients is 2.172 (95% CI 1.544 to 3.057). Number needed to harm, i.e., hyperglycemia, in Group B is 2.941 (95% CI 2 to 5).Conclusions:We conclude that stress induced-hyperglycemic response in patients undergoing major non-cardiac surgery is common in non-diabetic population. Maintenance-fluid therapy by dextrose containing solution as opposed to Ringer's lactate solution increases the incidence of hyperglycemia. To achieve normoglycemia by intravenous bolus dose of human regular insulin, significantly higher doses are required in patients receiving dextrose containing saline as maintenance fluid.

MK-0448, a Specific Kv1.5 Inhibitor

Background— We evaluated the viability of I Kur as a target for maintenance of sinus rhythm in patients with a history of atrial fibrillation through the testing of MK-0448, a novel I Kur inhibitor. Methods and Results— In vitro MK-0448 studies demonstrated strong inhibition of I Kur with minimal off-target activity. In vivo MK-0448 studies in normal anesthetized dogs demonstrated significant prolongation of the atrial refractory period compared with vehicle controls without affecting the ventricular refractory period. In studies of a conscious dog heart failure model, sustained atrial fibrillation was terminated with bolus intravenous MK-0448 doses of 0.03 and 0.1 mg/kg. These data led to a 2-part first-in-human study: Part I evaluated safety and pharmacokinetics, and part II was an invasive electrophysiological study in healthy subjects. MK-0448 was well-tolerated with mild adverse experiences, most commonly irritation at the injection site. During the electrophysiological study, ascending doses of MK-0448 were administered, but no increases in atrial or ventricular refractoriness were detected, despite achieving plasma concentrations in excess of 2 μmol/L. Follow-up studies in normal anesthetized dogs designed to assess the influence of autonomic tone demonstrated that prolongation of atrial refractoriness with MK-0448 was markedly attenuated in the presence of vagal nerve simulation, suggesting that the effects of I Kur blockade on atrial repolarization may be negated by enhanced parasympathetic neural tone. Conclusions— The contribution of I Kur to human atrial electrophysiology is less prominent than in preclinical models and therefore is likely to be of limited therapeutic value for the prevention of atrial fibrillation.

Effect of propofol on oxidative stress status in erythrocytes from dogs under general anaesthesia

BackgroundAlterations of the normal redox balance might be attributed to increase of plasma free-radical concentration and a disruption of the antioxidant defense system. One of the adverse effects of general anaesthetics is the exogen sources of reactive oxygen radicals that are responsible for several diseases. The purposes of the current study were to evaluate the effect of propofol on oxidative stress and to compare the differences between propofol induction only and induction plus continuous infusion on antioxidant status in dogs.FindingsBeagle dogs were evaluated in the present study. The dogs were assigned randomly to receive three treatments in a crossover model. The three treatments were: group 1 (n = 9), 2% isoflurane; group 2 (n = 9), anaesthesia induced with an intravenous (IV) bolus dose of 6 mg/kg propofol and maintained with 1.5–2% isoflurane; group 3 (n = 9), total IV anaesthesia (induction with 6 mg/kg propofol, infusion with 0.6 mg/kg/min propofol). The results of this study show that dogs exposed to isoflurane had decreased antioxidant enzymes activities, whereas dogs injected with propofol had increased antioxidant enzymes activities.ConclusionsThe results of this study showed that an infusion dose of propofol has antioxidant effects in dogs. These effects may be beneficial to patients in whom free radicals play a role in oxidative stress, such as those with ischemia. Further studies are needed to evaluate whether these antioxidant effects of the anaesthetic are of clinical value.

Clevidipine: a review of its use in the management of acute hypertension.

Clevidipine: a review of its use in the management of acute hypertension.

Pharmacokinetics after a single intravenous dose of the opioid ketobemidone in neonates

Ketobemidone is often used as an alternative to morphine in children in the Scandinavian countries. In an earlier study, we have examined the pharmacokinetic properties in children in different age groups but have not focused on neonates. The aim of this clinical trial was to explore the pharmacokinetics of ketobemidone in neonates. Fifteen full-term neonates (eight females) from 37 gestational weeks at birth and scheduled for elective surgery were included in the trial. Their median age was 3 days (range 1-18 days). Ketobemidone hydrochloride was administered as a single intravenous bolus dose, and ketobemidone concentrations were measured by liquid chromatography-mass spectrometry over 10 h. Pharmacokinetic parameters were calculated with standard compartmental methods. The median (range) values for ketobemidone clearance, apparent volume of distribution, volume of central compartment, distribution half-life and elimination half-life were 0.46 (0.23-0.84) l/h/kg, 4.64 (3.50-7.31) l/kg, 1.71 (0.16-3.47) l/kg, 2.85 (1.04-10.78) min and 7.26 (3.5-11.3) h. Compared with our previous study in children older than 1 year of age, the elimination of ketobemidone appeared to be slower in full-term neonates. Despite a low pharmacokinetic variability of ketobemidone as observed in the present neonatal patient population, we recommend individualizing the dose of ketobemidone based on observations of analgesic efficacy.

The optimal dose of remifentanil for acceptable intubating conditions during propofol induction without neuromuscular blockade

Study ObjectiveTo determine the optimal remifentanil dose required to provide acceptable intubating conditions following induction of anesthesia with propofol without using neuromuscular blockade. DesignDose-response study. SettingOperating room of a university hospital. Patients50 ASA physical status 1 men, aged between 20 and 40 years, who were scheduled for general anesthesia. InterventionsIntubating conditions were evaluated according to the scoring system described by Viby-Mogensen et al. Successful intubation was defined as excellent or good. MeasurementsFor induction of anesthesia, an intravenous (IV) bolus dose of propofol 2.0 mg/kg was given over 30 seconds followed by the administration of predetermined IV remifentanil over 30 seconds; intubation was performed 90 seconds after completion of the remifentanil administration. The dose of remifentanil used for each patient was determined by the response of the previously tested patients, using the modified Dixon's up-and-down method (using 0.2 μg/kg as a step size). The first patient was tested with remifentanil 1.0 μg/kg. If intubation failed, the remifentanil dose was increased by 0.2 μg/kg; if intubation was successful, the dose was decreased by 0.2 μg/kg. Mean arterial pressure (MAP), heart rate (HR), and peripheral oxygen saturation were recorded during the study period. Main ResultsAccording to probit analysis, the effective dose of remifentanil in 50% (ED50) and 95% (ED95) of patients were 1.40 μg/kg and 2.40 μg/kg, respectively. Preintubation and postinduction HR and MAP values were lower than preinduction values (P < 0.001). ConclusionThe optimal bolus dose of remifentanil for acceptable intubating conditions was 2.40 μg/kg (95% confidence interval, 1.90-9.0 μg/kg) in 95% of patients during induction of anesthesia with propofol 2.0 mg/kg without neuromuscular blocking agents.

A Much Sought-After Drug—Propofol Sedation for GI Endoscopy: Always Better but Who Cares?

Several hypnotic and analgesic strategies have beendevised for patients undergoing gastrointestinal (GI)endoscopy, ranging in a continuum from mild conscioussedation to general anesthesia.Endoscopic retrograde cholangiopancretography (ERCP)and endoscopic ultrasound (EUS) are particularly unpleas-ant diagnostic procedures for patients and more time con-suming than any other endoscopic procedure. Moreover,ERCP can be technically difficult and requires completepatient cooperation in order to be safely and successfullycompleted. Patients frequently are sedated for ERCP orEUS with intravenous bolus doses of benzodiazepines incombination with opioids, which are meant to improve thequality of sedation by providing analgesia. Deep sedation issometimes required.The introduction of propofol into clinical practice sig-nificantly changed the attitudes of both physicians andpatients towards sedation, with the result that propofolsedation for GI endoscopy has become common practiceworldwide. In recent years, propofol has been safely andeffectively used in advanced interventional endoscopicprocedures, such as ERCP and EUS, even for high-riskpatients [1]. Propofol is a hypnotic drug with rapid onsetand offset of action. Used as a single agent, it is commonlytitrated to attain deep sedation, whereas balanced propofolsedation (BPS), in which propofol use is associated withsmall doses of benzodiazepines and/or opioids, can besuccessfully titrated to attain moderate sedation.Several studies have shown that, when compared withconventional sedation, BPS with propofol, midazolam,and/or meperidine, yields higher physician and patientsatisfaction, better patient cooperation, and similar com-plication rates in patients undergoing therapeutic endo-scopic procedures. The total propofol dose may beexpected to be reduced by 50 % with BPS in comparisonwith propofol alone sedation.A critical advantage in dealing with BPS for moderatesedation is that it can be partially reverted, since antagonistsare available against both opioids and benzodiazepines.In the current issue of Digestive Diseases and Sciences,Tae Hoon Lee et al. [2] present the results of a randomizedprospective study comparing BPS (propofol, midazolam,and fentanyl) with propofol alone during moderate sedationfor ERCP and EUS. The authors demonstrate that propofolalone provides a shorter recovery time than BPS and iscomparably effective and safe. This paper is the naturalevolution of a previous study of the same authors in whichthey demonstrated a higher safety and efficacy of BPS incomparison with conventional sedation [3]. In this respect,Tae Hoon Lee et al. positively contribute to the knowledgeof sedation strategies for endoscopy.However, in another respect, they quietly and almostinadvertently hit a raw nerve in the ongoing debate aboutwho can/should provide propofol sedation. In both of theirstudies, sedation was provided by non-anesthesiologists,further adding to the body of literature indicating that theadministration of propofol by non-anesthesiologists may besafe and effective for selected patients undergoingadvanced endoscopic procedures.The subject of non-anesthesiologist administrationof propofol (NAAP), particularly for endoscopy, has

Ketamine Relieves Pain at End of Life

Ketamine Relieves Pain at End of Life

Su1616 The Inappropriate Prescription of Proton Pump Inhibitor Therapy in a Hospital Setting

BACKGROUNDS AND AIMS: Proton-pump inhibitor is more effective for gastric acid control in Asian than Western population possible because of high prevalence of poor metabolizing CYP2C19 genotype in Asian people. The aim of this study was to evaluate the effect of low dose intravenous (IV) bolus vs. standard recommended dose continuous IV infusion of omeprazole in Thai healthy volunteers with extensive metabolizing CYP2C19 genotype. METHODS: 8 healthy subjects (age 30±6yr, 5 F, BMI 24±3 kg/m2) with extensive metabolizing CYP2C19 genotype were randomized to receive either omeprazole 80mg IV bolus followed by 40 mg IV bolus every 12 hr or omeprazole 80mg IV bolus followed by 8mg/ hr continuous infusion for 48 hr. The gastric pH was monitored by a pH catheter with a data logger (DIGITRAPPER pH 400, Medtronic A/S) for 2 days during the omeprazole treatment peroids. The gastric pH sensor was positioned at 10 cm below the lower esophageal sphincter located by esophageal manometry. All subjects were allowed to consume 3 standard meals/day. RESULTS : The mean gastric pH for IV bolus was significantly lower than continuous infusion only on day 1 [6.2±1.0 vs. 7.1±0.6 (p 6 for IV bolus was also significantly lower compared to continuous infusion only on day 1(66.2±22.7% vs. 84.7±17.3%)(p 6 for the entire 48-hr study was significantly lower for IV bolus compared to continuous infusion (69.9±12.6% vs. 83.0±13.8%, p 24 had similar intragastric pH during both IV bolus and IV continuous infusion of omeprazole (IV bolus, BMI 24: 6.4±0.9 vs. 6.3±0.4) (continuous drip; 7.1±0.3 vs. 6.8±0.6)(p>0.05). CONCLUSION: Continuous IV infusion of standard recommended dose of omeprazole provided better gastric acid control compared to lower dose IV bolus only during the first day but not on the second day. Although the continuous IV infusion was more effective both standard dose continuous IV infusion and low dose IV bolus omeprazole was effective for gastric pH control in Thai healthy volunteers with extensive metabolizing CYP2C19 genotypes. The better gastric acid control compared to those reported in healthy volunteers in Western countries suggests the role of other factor(s), beside the CYP2C19 genotype, on gastric acid inhibition effect of IV omeprazole.

Su1615 Effect of Intravenous Proton-Pump Inhibitor (Omeprazole) on Intra-Gastric pH in Thai Healthy Volunteers With Extensive Metabolizing CYP2C19 Genotype: Comparison Between Intermittent Bolus (Low Dose) and Continuous Infusion (Standard Recommended Dose)

BACKGROUNDS AND AIMS: Proton-pump inhibitor is more effective for gastric acid control in Asian than Western population possible because of high prevalence of poor metabolizing CYP2C19 genotype in Asian people. The aim of this study was to evaluate the effect of low dose intravenous (IV) bolus vs. standard recommended dose continuous IV infusion of omeprazole in Thai healthy volunteers with extensive metabolizing CYP2C19 genotype. METHODS: 8 healthy subjects (age 30±6yr, 5 F, BMI 24±3 kg/m2) with extensive metabolizing CYP2C19 genotype were randomized to receive either omeprazole 80mg IV bolus followed by 40 mg IV bolus every 12 hr or omeprazole 80mg IV bolus followed by 8mg/ hr continuous infusion for 48 hr. The gastric pH was monitored by a pH catheter with a data logger (DIGITRAPPER pH 400, Medtronic A/S) for 2 days during the omeprazole treatment peroids. The gastric pH sensor was positioned at 10 cm below the lower esophageal sphincter located by esophageal manometry. All subjects were allowed to consume 3 standard meals/day. RESULTS : The mean gastric pH for IV bolus was significantly lower than continuous infusion only on day 1 [6.2±1.0 vs. 7.1±0.6 (p 6 for IV bolus was also significantly lower compared to continuous infusion only on day 1(66.2±22.7% vs. 84.7±17.3%)(p 6 for the entire 48-hr study was significantly lower for IV bolus compared to continuous infusion (69.9±12.6% vs. 83.0±13.8%, p 24 had similar intragastric pH during both IV bolus and IV continuous infusion of omeprazole (IV bolus, BMI 24: 6.4±0.9 vs. 6.3±0.4) (continuous drip; 7.1±0.3 vs. 6.8±0.6)(p>0.05). CONCLUSION: Continuous IV infusion of standard recommended dose of omeprazole provided better gastric acid control compared to lower dose IV bolus only during the first day but not on the second day. Although the continuous IV infusion was more effective both standard dose continuous IV infusion and low dose IV bolus omeprazole was effective for gastric pH control in Thai healthy volunteers with extensive metabolizing CYP2C19 genotypes. The better gastric acid control compared to those reported in healthy volunteers in Western countries suggests the role of other factor(s), beside the CYP2C19 genotype, on gastric acid inhibition effect of IV omeprazole.

Body composition determines direct FFA storage pattern in overweight women

Direct FFA storage in adipose tissue is a recently appreciated pathway for postabsorptive lipid storage. We evaluated the effect of body fat distribution on direct FFA storage in women with different obesity phenotypes. Twenty-eight women [10 upper body overweight/obese (UBO; WHR >0.85, BMI >28 kg/m(2)), 11 lower body overweight/obese (LBO; WHR <0.80, BMI >28 kg/m(2)), and 7 lean (BMI <25 kg/m(2))] received an intravenous bolus dose of [9,10-(3)H]palmitate- and [1-(14)C]triolein-labeled VLDL tracer followed by upper body subcutaneous (UBSQ) and lower body subcutaneous (LBSQ) fat biopsies. Regional fat mass was assessed by combining DEXA and CT scanning. We report greater fractional storage of FFA in UBSQ fat in UBO women compared with lean women (P < 0.01). The LBO women had greater storage per 10(6) fat cells in LBSQ adipocytes compared with UBSQ adipocytes (P = 0.04), whereas the other groups had comparable storage in UBSQ and LBSQ adipocytes. Fractional FFA storage was significantly associated with fractional VLDL-TG storage in both UBSQ (P < 0.01) and LBSQ (P = 0.03) adipose tissue. In conclusion, UBO women store a greater proportion of FFA in the UBSQ depot compared with lean women. In addition, LBO women store FFA more efficiently in LBSQ fat cells compared with UBSQ fat cells, which may play a role in development of their LBO phenotype. Finally, direct FFA storage and VLDL-TG fatty acid storage are correlated, indicating they may share a common rate-limiting pathway for fatty acid storage in adipose tissue.

Use of intravenous bolus doses of ketamine for acute refractory pain

BackgroundKetamine is used in palliative care to help relieve refractory pain that does not respond to conventional opioids or adjuvant analgesics. It is commonly administered via subcutaneous or the oral...

Multidose optimization simulation of erythropoietin treatment in preterm infants

Preterm infants commonly develop anemia requiring red blood cell transfusions (RBCTx). Although an alternative therapy is recombinant human erythropoietin (Epo), it is not widely employed. To provide a rigorous scientific basis supporting the latter approach, a model-based simulation analysis of endogenous erythropoiesis was developed. The pharmacodynamic/pharmacokinetic (PK/PD) model identified an optimal Epo dosing algorithm in preterm infants that demonstrated maximal efficacy when Epo was dosed frequently during the early weeks of life (when phlebotomy loss is greatest). Model-based simulations employing optimized Epo dosing predicted that 13 of the 27 (46%) infants would avoid RBCTx ("good responders"). Importantly, simulation results identified five subject-specific covariate factors predictive of good Epo response. This simulation study provides a basis for possibly eliminating RBCTx in infants who can be selected for optimized Epo therapy. Epo PD hemoglobin production parameters were determined in 27 preterm infants studied intensively during the first 28 d of life. Model-derived Epo PD parameters were combined with PK parameters derived from the literature to simulate an optimized intravenous Epo bolus dosing schedule. The goal of this simulated optimized schedule was to eliminate RBCTx, as prescribed per current guidelines, in as many preterm infants as possible.

Pre-clinical pharmacokinetics of the acridine antitumour candidate AC04 and its 1-oxo-metabolite plasma profile

This work aimed to investigate plasma pharmacokinetics and tissue distribution of a new acridine derivative 5-acridin-9-ylmethylene-3-(4-methyl-benzyl)-thiazolidine-2,4-dione (AC04) and its 1-oxo-AC04 metabolite disposition in Wistar rats.After a single AC04 1.5 mg/kg intravenous (i.v.) bolus dose, blood samples were taken up to 120 h. Plasma samples were deproteinization, and AC04 and metabolite were quantified by validated liquid chromatography in tandem with mass spectrometry method. Protein binding was determined by ultrafiltration. AC04 tissue disposition was evaluated after i.v. bolus dose.Individual AC04 concentration–time profiles were best fitted by a two-compartment model showing CLtot of 3.4 ± 3.4 L/h/kg, VdSS of 137.9 ± 91.4 L/kg, AUC0–∞ of 788 ± 483 ng·h/mL and a t1/2 of 45.5 ± 31.5 h. Protein binding was 98.1 ± 1.6%. AC04 showed higher penetration into the lung, spleen and liver, with AUC0–96 of 798,443, 263,211 and 303,722 ng·h/mL, respectively. The 1-oxo-AC04 metabolite represented 10% of AC04 plasma concentration, showing a t1/2 of 23.2 ± 10.4 h.These results suggest that, despite the small free plasma fraction, AC04 penetrates extensively reaching high concentrations in most tissues residing for a long time, which is important for its activity on solid tumours. All results combined indicate that AC04 is potentially a good antitumour candidate.

Pharmacokinetics and tissue and tumor exposure of CP-31398, a p53-stabilizing agent, in rats

CP-31398 (N0-[2-[(E)-2-(4-methoxyphenyl)ethenyl] quinazolin-4-yl]-N,N-dimethylpropane-1,3-diamine hydrochloride) is one of the new class of agents that can stabilize the DNA-binding domain of p53 and thereby maintain the activity of p53 as a tumor suppressor and transcription factor. Through its activity as a p53 stabilizer, CP-31398 demonstrates significant cancer preventive and therapeutic activity in several in vivo animal models. The objective of the current study was to describe the pharmacokinetic profile and tissue distribution of this novel agent following intravenous or oral (gavage and dietary) administration. CP-31398 was administered to male CD and F344 rats as a single intravenous bolus dose or by daily oral gavage dosing. Male F344 rats also received drug as an ad libitum dietary supplement. Plasma, liver, skin, colon, and colon tumor samples were collected after oral dosing. Concentrations of CP-31398 in plasma and tissue samples were analyzed using LC–MS/MS, and the resultant data were subjected to a non-compartmental pharmacokinetic analysis. Bioavailability (12–32%), elimination half-life (14–20 h), clearance (4.2–4.8 l/h/kg), and volume of distribution (70–82 l/kg) were determined. Tissue levels of CP-31398 after oral (gavage or diet) administration were several orders of magnitude higher than were corresponding plasma concentrations; CP-31398 levels were especially high in colon and liver. Levels of CP-31398 in tissues were higher after gavage dosing than after dietary administration. CP-31398 is bioavailable and has a relatively long elimination half-life, which supports the achievement of plasma steady-state levels with a once daily dosing regimen. CP-31398 exhibits a dramatically high volume of distribution, which is consistent with its tissue concentrations being much higher than corresponding plasma levels. It is accumulated in colon tumor tissues, albeit at lower concentrations than found in liver, skin, and colon.

Pharmacokinetics and pharmacodynamics of intravenous medetomidine in the horse

ObjectiveTo describe the pharmacodynamics and pharmacokinetics following an intravenous (IV) bolus dose of medetomidine in the horse. Study designProspective experimental trial. AnimalsEight, mature healthy horses age 11.7 ± 4.6 (mean ± SD) years, weighing 557 ± 54 kg. MethodsMedetomidine (10 μg kg−1) was administered IV. Blood was sampled at fixed time points from before drug administration to 48 hours post administration. Behavioral, physiological and biochemical data were obtained at predetermined time points from 0 minutes to 24 hours post administration. An algometer was also used to measure threshold responses to noxious stimuli. Medetomidine concentrations were determined by liquid chromatography-Mass Spectrometry and used for calculation of pharmacokinetic parameters using noncompartmental and compartmental analysis. ResultsPharmacokinetic analysis estimated that medetomidine peaked (8.86 ± 3.87 ng mL−1) at 6.4 ± 2.7 minutes following administration and was last detected at 165 ± 77 minutes post administration. Medetomidine had a clearance of 39.6 ± 14.6 mL kg−1 minute−1 and a volume of distribution of 1854 ± 565 mL kg−1. The elimination half-life was 29.1 ± 12.5 minutes. Glucose concentration reached a maximum of 176 ± 46 mg dL−1 approximately 1 hour post administration. Decreased heart rate, respiratory rate, borborygmi, packed cell volume, and total protein concentration were observed following administration. Horses lowered their heads from 107 ± 12 to 20 ± 10 cm within 10 minutes of drug administration and gradually returned to normal. Horse mobility decreased after drug administration. An increased mechanical threshold was present from 10 to 45 minutes and horses were less responsive to sound.Conclusion and clinical relevance Behavioral and physiological effects following intravenous administration positively correlate with pharmacokinetic profiles from plasma medetomidine concentrations. Glucose concentration gradually transiently increased following medetomidine administration. The analgesic effect of the drug appeared to have a very short duration.

Pharmacokinetics, metabolism and excretion of 14C-monoethyl phthalate (MEP) and 14C-diethyl phthalate (DEP) after single oral and IV administration in the juvenile dog

The pharmacokinetics, metabolism and excretion of monoethyl phthalate (MEP) and diethyl phthalate (DEP) were compared after intravenous or oral administration of [14C]MEP or [14C]DEP in juvenile beagle dogs. Four male juvenile beagle dogs were treated with a single oral or bolus intravenous dose of either [14C]MEP or [14C]DEP (164 μg/kg).The absorption, metabolism, excretion and pharmacokinetics of [14C]MEP and [14C]DEP were nearly identical. [14C]DEP was rapidly and nearly completely metabolized to [14C]MEP following either intravenous or oral administration. [14C]MEP and[14C]DEP were rapidly absorbed, the elimination half-life was estimated to be 1 hour. Approximately 90%–96% of the dose was excreted in urine with 2%–3% of the dose in faeces. MEP accounted for the majority of the dose in plasma and urine; in addition, three minor metabolites (M1, M2 and M3) were detected. The minor metabolites were neither phthalic acid nor glucuronide/sulfate conjugates.The nearly identical metabolism and pharmacokinetics of MEP and DEP in juvenile dogs justifies the use of DEP toxicity data in the risk assessment of MEP exposure.

The use of dermal fibroblasts as a predictive tool of the toll-like receptor 4 response pathway and its development in Holstein heifers

The innate immune system comprises the host's first line of defense against invading pathogens, and variation in the magnitude of this response between animals has been shown to affect susceptibility to mastitis. The toll-like receptor (TLR) family of proteins initiates the response to invading bacteria, specifically with TLR4 recognizing lipopolysaccharide (LPS) of gram-negative microbes. The underlying genetic variation in the TLR4 pathway leading to differential response is not well understood; therefore, the objective of this work was to determine the efficacy in which the response to LPS by dermal fibroblasts could be used to predict the actual systemic response of that animal to an intravenous endotoxin challenge. To accomplish this, dermal fibroblasts were isolated from 15 Holstein heifers at 5, 11, and 16mo of age and exposed to either LPS or IL-1β; then, the production of IL-8 in medium was quantified by ELISA. Animals were ranked based upon the magnitude of the fibroblast IL-8 response, and 8 heifers were selected [4 low responders (LR) and 4 high responders (HR)] for challenge with an intravenous bolus dose (0.5μg/kg of body weight) of LPS. Overall, between-animal variation in fibroblast IL-8 production following LPS or IL-1β was high, indicating appreciable differences in the TLR4 pathway of the animals. Ranking of the fibroblast responses was consistent across the 3 sampling times for each animal; however, the absolute response increased, and the age at which the fibroblasts were obtained was consistent with the potential for age-related changes in cell function to affect immune function processes. Following systemic LPS challenge, HR heifers had higher plasma concentrations of tumor necrosis factor-α and IL-8 than LR heifers. However, LR heifers had a stronger febrile response than HR heifers. The use of dermal fibroblasts under laboratory conditions appears to represent a practical model for predicting the innate immune response in vivo and could act as an important tool in mapping genetic differences of the TLR4 pathway.

Intravenous pharmacokinetics, oral bioavailability, dose proportionality and in situ permeability of anti-malarial lumefantrine in rats

BackgroundDespite the wide spread use of lumefantrine, there is no study reporting the detailed preclinical pharmacokinetics of lumefantrine. For the development of newer anti-malarial combination(s) and selection of better partner drugs, it is long felt need to understand the detailed preclinical pharmacokinetics of lumefantrine in preclinical experimental animal species. The focus of present study is to report bioavailability, pharmacokinetics, dose linearity and permeability of lumefantrine in rats.MethodsA single dose of 10, 20 or 40 mg/kg of lumefantrine was given orally to male rats (N = 5 per dose level) to evaluate dose proportionality. In another study, a single intravenous bolus dose of lumefantrine was given to rats (N = 4) at 0.5 mg/kg dose following administration through the lateral tail vein in order to obtain the absolute oral bioavailability and clearance parameters. Blood samples were drawn at predetermined intervals and the concentration of lumefantrine and its metabolite desbutyl-lumefantrine in plasma were determined by partially validated LC-MS/MS method. In-situ permeability study was carried in anaesthetized rats. The concentration of lumefantrine in permeability samples was determined using RP-HPLC.ResultsFor nominal doses increasing in a 1:2:4 proportion, the Cmax and AUC0-∞ values increased in the proportions of 1:0.6:1.5 and 1:0.8:1.8, respectively. For lumefantrine nominal doses increasing in a 1:2:4 proportion, the Cmax and the AUC0-t values for desbutyl-lumefantrine increased in the proportions of 1:1.45:2.57 and 1:1.08:1.87, respectively. After intravenous administration the clearance (Cl) and volume of distribution (Vd) of lumefantrine in rats were 0.03 (± 0.02) L/h/kg and 2.40 (± 0.67) L/kg, respectively. Absolute oral bioavailability of lumefantrine across the tested doses ranged between 4.97% and 11.98%. Lumefantrine showed high permeability (4.37 × 10-5 cm/s) in permeability study.ConclusionsThe pharmacokinetic parameters of lumefantrine and its metabolite desbutyl-lumefantrine were successfully determined in rats for the first time. Lumefantrine displayed similar pharmacokinetics in the rat as in humans, with multiphasic disposition, low clearance, and a large volume of distribution resulting in a long terminal elimination half-life. The absolute oral bioavailability of lumefantrine was found to be dose dependent. Lumefantrine displayed high permeability in the in-situ permeability study.

Pharmacokinetics of TH-302: a hypoxically activated prodrug of bromo-isophosphoramide mustard in mice, rats, dogs and monkeys

To characterize the pharmacokinetics of the prodrug, TH-302, and its active metabolite, bromo-IPM (Br-IPM), in nonclinical species. TH-302 was administered in single oral, intraperitoneal and intravenous bolus doses to mice, rats, dogs and monkeys as well as in acute and chronic safety studies in rats and dogs as a 30-min intravenous infusion given once a week for 3 weeks. Assessments were made using liquid chromatography-tandem mass spectrometry. TH-302 was extensively distributed with high systemic clearance exceeding hepatic plasma flow in all species studied, resulting in half-lives ranging between 8 min (mice) and over 4 h (rats). In rats, TH-302 exhibited linear kinetics following intravenous administration and good oral bioavailability. In acute and chronic safety studies, there was no accumulation of TH-302 following once weekly dosing for 3 weeks in the rat and dog. Br-IPM plasma concentrations were a small fraction of the TH-302 plasma concentrations with significantly smaller percentages present in dogs than in rats. Allometric scaling predicted that the systemic clearance and steady-state volume of distribution in humans would be 38.8 l/h/m(2) and 34.3 l/m(2), respectively, resulting in a terminal elimination half-life of about 36 min. These values were similar to those observed in patients with solid tumors (27.1 l/h/m(2), 23.5 l/m(2) and 47 min). TH-302 exhibited good safety, efficacy and pharmacokinetic properties in nonclinical species, translating into favorable properties in humans.