Decline In Plasma Concentration Research Articles

Correlations between Milk and Plasma Levels of Amino and Carboxylic Acids in Dairy Cows

The objective of this study was to investigate the relationship between the concentrations of 19 amino acids, glucose, and seven carboxylic acids in the blood and milk of dairy cows and their correlations with established markers of ketosis. To that end, blood plasma and milk specimens were collected throughout lactation in two breeds of dairy cows of different milk yield. Plasma concentrations of glucose, pyruvate, lactate, α-aminobutyrate, β-hydroxybutyrate (BHBA), and most amino acids, except for glutamate and aspartate, were on average 9.9-fold higher than their respective milk levels. In contrast, glutamate, aspartate, and the Krebs cycle intermediates succinate, fumarate, malate, and citrate were on average 9.1-fold higher in milk than in plasma. For most metabolites, with the exception of BHBA and threonine, no significant correlations were observed between their levels in plasma and milk. Additionally, milk levels of acetone showed significant direct relationships with the glycine-to-alanine ratio and the BHBA concentration in plasma. The marked decline in plasma concentrations of glucose, pyruvate, lactate, and alanine in cows with plasma BHBA levels above the diagnostic cutoff point for subclinical ketosis suggests that these animals fail to meet their glucose demand and, as a consequence, rely increasingly on ketone bodies as a source of energy. The concomitant increase in plasma glycine may reflect not only the excessive depletion of protein reserves but also a potential deficiency of vitamin B6.

Pharmacokinetics and Pharmacodynamics of Edivoxetine (LY2216684), a Norepinephrine Reuptake Inhibitor, in Pediatric Patients with Attention-Deficit/ Hyperactivity Disorder

Edivoxetine (LY2216684) is a selective and potent norepinephrine reuptake inhibitor (NERI). The pharmacokinetics (PK) and pharmacodynamics (PD) of edivoxetine were assessed in children and adolescent patients with attention-deficit/hyperactivity disorder (ADHD) following single and once-daily oral doses of edivoxetine. During a phase 1 open-label safety, tolerability, and PK study, pediatric patients were administered edivoxetine at target doses of 0.05, 0.1, 0.2 and 0.3 mg/kg, and blood samples were collected to determine plasma concentrations of edivoxetine for PK assessments and plasma 3,4-dihydroxyphenylglycol (DHPG) concentrations for PD assessments. Edivoxetine plasma concentrations were measured using liquid chromatography with tandem mass spectrometric detection, and DHPG was measured using liquid chromatography with electrochemical detection. Edivoxetine PK was comparable between children and adolescents. The time to maximum concentration (t(max)) of edivoxetine was ∼2 hours, which was followed by a mono-exponential decline in plasma concentrations with a terminal elimination half-life (t(1/2)) of ∼6 hours. Dose-dependent increases in area under the edivoxetine plasma concentration versus time curve from zero to infinity (AUC(0-∞)) and maximum plasma concentration (C(max)) were observed, and there was no discernable difference in the apparent clearance (CL/F) or the apparent volume of distribution at steady state (V(ss)/F) across the dose range. In adolescents, edivoxetine caused a maximum decrease in plasma DHPG concentrations from baseline of ∼28%, most notably within 8 hours of edivoxetine administration. This initial study in pediatric patients with ADHD provides new information on the PK profile of edivoxetine, and exposures that decrease plasma DHPG consistent with the mechanism of action of a NERI. The PK and PD data inform edivoxetine pharmacology and can be used to develop comprehensive population PK and/or PK-PD models to guide dosing strategies.

Rhodiola crenulata root ameliorates derangements of glucose and lipid metabolism in a rat model of the metabolic syndrome and type 2 diabetes

Ethnopharmacological relevanceRhodiola species are traditionally used as tonics and stimulants to treat asthenia, suggesting their possible regulatory effect on energy metabolism. Clinical trials have demonstrated their glucose-lowering effect in type 2 diabetes. Aim of the studyTo examine the effects of Rhodiola on glucose and lipid metabolism in the metabolic syndrome and type 2 diabetes. Materials and methodsZucker diabetic fatty (ZDF) rats were treated with Rhodiola crenulata root (RCR) powder (100 and 500mg/kg, by gavage, once daily for 4 weeks). In addition, the effects of RCR on sucrose-induced acute hyperglycemia in mice and olive oil-induced hypertriglyceridemia in rats were also examined. Biochemical variables were determined enzymatically or by ELISA. ResultsIn ZDF rats, RCR treatment decreased the increased plasma insulin and triglyceride concentrations at baseline, the index of the homeostasis model assessment of insulin resistance (HOMA-IR) and excessive hepatic triglyceride accumulation. This treatment also inhibited abnormal increases in plasma glucose and insulin concentrations during oral glucose tolerance test. Furthermore, RCR reversed the increased adipose insulin resistance index, and accelerated the decline of plasma concentrations of non-esterified fatty acids after exogenous glucose stimulation. However, RCR minimally affected sucrose-induced acute hyperglycemia in mice and olive oil-induced acute hypertriglyceridemia in rats. ConclusionsThe present results demonstrate that RCR treatment improves metabolic derangements in animal model of the metabolic syndrome and type 2 diabetes. Our findings may provide new pharmacological basis of therapeutics for the adaptogenic plants to treat metabolic derangements-associated disorders, such as asthenia.

Biliary excretion and enterohepatic circulation of thienorphine and its glucuronide conjugate in rats

Thienorphine (TNP) is a new partial opioid agonist currently developed as a promising drug candidate with the intended clinical indication for the treatment of opioid dependence. The pharmacokinetic profile and biliary excretion of TNP and its glucuronide conjugate (TNP-Glu) were investigated after oral administration of TNP in rats. The concentrations of TNP and TNP-Glu were simultaneously quantified using a LC-MS/MS method. A double peak phenomenon was observed in TNP plasma concentration–time curves with the secondary peak appeared at 6–8h. A slower decline of plasma concentrations in the terminal phase was observed for TNP with T1/2 of 7.01h. TNP-Glu was the predominant component in rat plasma and bile. Its plasma level was about 10 times higher than TNP and the 24h accumulative bile excretion rate was 23%. Enterohepatic circulation of TNP and TNP-Glu was evaluated using a paired rat model. In bile-donor rats, no double-peak was detected and the elimination half life of TNP was significantly shortened (3.71h) when compared to intact rats (7.01h, P<0.05). Both TNP and TNP-Glu were detected in bile-recipient rats. Their exposures in recipient rats due to enterohepatic circulation were 15.6% and 42.6% for the parent drug and the metabolite, respectively. The deconjugation of the glucuronide conjugate and the reabsorption of free TNP were further confirmed in in situ perfused rat intestinal preparations. These results indicate that the enterohepatic circulation has a significant influence on the systemic exposure of the parent drug and its glucuronide conjugate, particularly on the terminal elimination of TNP, which may result in the prolonged retention of the drug in body.

Development of a liquid chromatography–tandem mass spectrometry method for measuring plasma and uterine tissue levels of indomethacin in rabbits treated with indomethacin-medicated Cu-IUDs

BackgroundSome side effects of copper intrauterine devices (Cu-IUDs) including increased uterine bleeding, pelvic infections and pain have been reported. The presence of indomethacin in such devices was found to be effective in relieving the symptoms. The aim of this study was to develop and validate a rapid and sensitive liquid chromatography–tandem mass spectrometric (LC-MS/MS) method for measuring plasma and uterine tissue levels of indomethacin in rabbits after insertion of indomethacin-medicated Cu-IUDs. Study DesignIndomethacin was extracted from rabbit plasma and uterine tissue by a simple protein precipitation using acetonitrile. Chromatographic separation was carried out on a Diamonsil C18 column (150×4.6 mm ID, 5 μm) with an isocratic mobile phase consisting of methanol, acetonitrile, water and formic acid (45:45:10:0.5, v/v/v/v). Mass spectrometric detection was achieved by a triple–quadrupole mass spectrometer equipped with an atmospheric pressure chemical ionization interface operating in positive ionization mode. Quantitation was performed using selective reaction monitoring mode. The LC-MS/MS method was validated with respect to selectivity, linearity, precision, accuracy, extraction recovery and stability, and then applied to the in vivo studies of indomethacin in rabbits treated with indomethacin-medicated Cu-IUDs. ResultsThe linear calibration curves of indomethacin in plasma and uterine tissue were obtained over the concentration range of 2.0–400 ng/mL and 4.0–800 ng/mL, respectively. The intra- and interday precision was less than 9.5%, and the relative error was within ±5.3%. After insertion of indomethacin-medicated Cu-IUDs in rabbits, indomethacin was rapidly absorbed, and peak plasma levels were reached in approximately 1 h. A multiphasic elimination pattern was observed, which was a rapid decline in plasma concentration during the first 100 h followed by a very slow clearance phase. The uterine indomethacin levels were significantly higher than simultaneous plasma levels. ConclusionsThe developed method proved to be rapid and sensitive, and was successfully applied to investigate the absorption and uterine distribution of indomethacin in rabbits after insertion of indomethacin-medicated Cu-IUDs.

Pharmacokinetics of Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Patients with Locally Advanced or Metastatic Solid Tumors: the Role of Alpha-1-Acid Glycoprotein Binding

In a phase I trial for patients with refractory solid tumors, hedgehog pathway inhibitor vismodegib (GDC-0449) showed little decline in plasma concentrations over 7 days after a single oral dose and nonlinearity with respect to dose and time after single and multiple dosing. We studied the role of GDC-0449 binding to plasma protein alpha-1-acid glycoprotein (AAG) to better understand these unusual pharmacokinetics. Sixty-eight patients received GDC-0449 at 150 (n = 41), 270 (n = 23), or 540 (n = 4) mg/d, with pharmacokinetic (PK) sampling at multiple time points. Total and unbound (dialyzed) GDC-0449 plasma concentrations were assessed by liquid chromatography/tandem mass spectrometry, binding kinetics by surface plasmon resonance-based microsensor, and AAG levels by ELISA. A linear relationship between total GDC-0449 and AAG plasma concentrations was observed across dose groups (R(2) = 0.73). In several patients, GDC-0449 levels varied with fluctuations in AAG levels over time. Steady-state, unbound GDC-0449 levels were less than 1% of total, independent of dose or total plasma concentration. In vitro, GDC-0449 binds AAG strongly and reversibly (K(D) = 13 μmol/L) and human serum albumin less strongly (K(D) = 120 μmol/L). Simulations from a derived mechanistic PK model suggest that GDC-0449 pharmacokinetics are mediated by AAG binding, solubility-limited absorption, and slow metabolic elimination. GDC-0449 levels strongly correlated with AAG levels, showing parallel fluctuations of AAG and total drug over time and consistently low, unbound drug levels, different from previously reported AAG-binding drugs. This PK profile is due to high-affinity, reversible binding to AAG and binding to albumin, in addition to solubility-limited absorption and slow metabolic elimination properties.

Toloxatone pharmacokinetics in the plasma and cerebrospinal fluid of the rabbit.

The pharmacokinetics of toloxatone (5 and 10 mg kg-1, i.v.) was studied in anaesthetized rabbits. There was a biexponential decline in plasma concentration with time. No differences were observed in the pharmacokinetic parameters with the increase of the dose. The terminal half-life was short (47.4 +/- 2.8 and 41.5 +/- 4.2 min for 5 and 10 mg kg-1, respectively). The total clearance was 79 +/- 18 mL min-1 after a dose of 5 mg kg-1 and 106 +/- 40 mL min-1 after a dose of 10 mg kg-1. The volume of distribution was 5.8 +/- 2.8 (5 mg kg-1) and 5.4 +/- 1.8 L (10 mg kg-1). The average percentage of toloxatone bound to plasma protein was 30% and was not affected by concentrations within the investigated range. In cerebrospinal fluid (CSF), the highest concentrations of toloxatone were obtained within 15 min after the end of the injection. The CSF level of toloxatone was equal to that of plasma unbound toloxatone and declined at a rate similar to toloxatone in plasma. These results suggest that the toloxatone passage through the blood-brain barrier may be completed by passive diffusion. In addition, the unbound plasma concentration would accurately reflect the toloxatone concentration in CSF and could be a useful tool for drug monitoring.

The relation between blood levels and urinary excretion of amphetamine under controlled acidic and under fluctuating urinary pH values using [14C] amphetamine.

Abstract Plasma, blood cell and urine levels of amphetamine were determined after the oral administration of S-(+)-[14C]amphetamine sulphate to two subjects under conditions of controlled acidic and fluctuating urinary pH. The decline in plasma concentration of the drug was more rapid under the controlled acidic conditions than under conditions of fluctuating urinary pH. Under controlled conditions, the concentration time profiles of drug and metabolite in urine or plasma (as opposed to body levels), were suitable for kinetic analysis. The apparent rate of urinary excretion of amphetamine was proportional to its plasma concentration only under the controlled acidic urinary conditions. Amphetamine was cleared from blood more rapidly than could be accounted for by glomerular filtration under acid conditions, but when urinary pH fluctuated, clearance of the drug could be accounted for by this route.

Bioavailability of isradipine in young and old rats: Effect of mode of administration

The bioavailability of isradipine has been examined in 7- and 52-week-old rats after oral (12.5 mg kg-1) or intravenous (2.5 mg kg-1) doses as a solution and administration of various doses (1.8-85.5 mg kg-1) in the diet. Serial plasma samples were obtained from each rat and the drug concentration was determined by radioimmunoassay. Absorption from the dose given by gavage was rapid but when administered in a drug diet mixture, isradipine appeared in the plasma slowly and in a manner reflecting the feeding pattern. Its absolute bioavailability from the drug-diet mixture averaged 3% over the dose range tested. By gavage its bioavailability was enhanced to 5% of dose with peak plasma values approximately 7 times higher than from a comparable dose in the diet. The low oral bioavailability of isradipine in the rat was most likely due to extensive first-pass metabolism. The decline in plasma concentrations was biexponential, with a mean terminal half-life of 3.6-3.7 h after oral or intravenous dosing. The pharmacokinetic characteristics of isradipine examined were independent of the age of the rat, except that its volume of distribution decreased with age. The older rats also showed a greater inter-animal variability in isradipine bioavailability from the drug-diet mixture.

Abstract B211: Pralatrexate pharmacokinetics with intravenous administration to oncology patients

Abstract Pralatrexate is a rationally designed antifolate with high affinity for reduced folate carrier-1 (RFC-1) and folyl poly-glutamyl synthetase (FPGS), resulting in efficient uptake and retention in cancer cells. Pralatrexate is being developed for various indications, including peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma, non-small cell lung cancer (NSCLC), and bladder cancer. Pralatrexate is a 1:1 racemic mixture of R- and S- diastereomers. Here we summarize the pharmacokinetics (PK) of pralatrexate from 3 Phase 1–2 studies. Pralatrexate was administered weekly or bi-weekly by IV push over 3–5 minutes (n=44) or as a 60-minute infusion (n=10) at doses ranging from 30–325 mg/m2. Serial plasma and urine samples, collected for up to 72 hours after dosing, were analyzed using a validated chiral LC-MS/MS method (lower limit of quantitation: 0.5 ng/ml). PK parameters were estimated by noncompartmental PK analysis. Clinical covariates were captured at screening to explore relationships with pralatrexate PK. The final PK results were based on 54 patients; 10 with relapsed/refractory PTCL (PDX-008), 38 with advanced NSCLC (PDX-007), and 6 with advanced solid tumors and concurrent docetaxel administration (PDX-99-083). The PK population was predominantlyWhite (81%) and balanced by gender (52% female). Age ranged from 24 to 77 (mean 60) years, body weight from 43–127 (77) kg, and estimated creatinine clearance from 53 to 130 (89) mL/min. Patients had adequate hepatic and hematologic function. Both pralatrexate diastereomers showed a similar multiphasic decline in plasma concentrations with a slow terminal phase (t½term = 12∓18h, PDX-008), likely reflecting the return from deep intracellular compartments. There was no evidence of PK nonlinearities in the dose range of 30–325 mg/m2. On a weekly or biweekly administration schedule, there was no significant drug accumulation in plasma over the first 2–6 doses. Other than expected changes in Cmax and Tmax, there were no apparent differences in PK between IV administration over 3–5 minutes and 60-minute infusion. Mean (COV) values (n=41−54) for total body clearance, renal clearance and volume of distribution at steady-state were 495 mL/min (57%), 125 mL/min (71%) and 106 L (121%) for the S-diastereomer and 218 mL/min (44%), 74 mL/min (60%) and 36 L (78%) for the R-diastereomer, respectively. These results suggest net renal tubular secretion, low hepatic extraction, and limited tissue distribution for both diastereomers. Consistent with approximately 30% contribution of renal excretion to overall drug elimination, creatinine clearance and age accounted for only 10% of the observed variability in total body clearance. In conclusion, this analysis suggests that pralatrexate PK is linear and dose-proportional across the dose range tested, with no accumulation with repeated dosing. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B211.

Role of Subcutaneous Abdominal Fat on Cardiac Function and Proinflammatory Cytokines in Premenopausal Obese Women

The role of surgically removing subcutaneous fat by abdominoplasty on circulating inflammatory markers and myocardial dysfunction, evaluated by myocardial performance index (MPI), were investigated. Twenty volunteers submitted to the abdominoplasty (abdominoplasty group), and other 28 women treated by hypocaloric diet (diet group) were evaluated. Echocardiographic parameters of MPI, circulating levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, were performed at baseline and 2 months later. Compared with nonobese women, obese women had increased concentrations of TNF-alpha (P < 0.01), IL-6 (P < 0.01), and higher MPI (P < 0.02), indicating ventricular dysfunction. Subcutaneous fat concentrations of TNF-alpha and IL-6 were related to MPI impairment. After 60 days, waist-to hip ratio was significantly reduced in the abdominoplasty group. Anthropometric changes were accompanied by a significant decline in plasma concentrations of TNF-alpha and IL-6 levels as well as by significant improvements of MPI in abdominoplasty group compared with diet group. Abdominoplasty may represent a safe method for ameliorating cardiac function in obese women.

Does Increased Levetiracetam Clearance&gt; during Pregnancy Require Planned Intervention?

Pharmacokinetics of Levetiracetam During Pregnancy, Delivery, in the Neonatal Period, and Lactation. Tomson T, Palm R, Källén K, Ben-Menachem E, Söderfeldt B, Danielsson B, Johansson R, Luef G, Ohman I. Epilepsia 2007;48:1111–1116. PURPOSE: To study pharmacokinetics of levetiracetam (LEV) during pregnancy, delivery, lactation, and in the neonatal period. METHODS: Fourteen women with epilepsy receiving LEV treatment during pregnancy and lactation contributed with 15 pregnancies to this prospective study in which LEV concentrations in plasma and breast milk were determined. Trough maternal plasma samples were collected each trimester, and at baseline after delivery. Blood samples were obtained at delivery from mothers, from the umbilical cord, and from newborns during 2 days after delivery. LEV concentration was also determined in breast milk and in plasma collected from 11 of the mothers and their suckling infants after birth. RESULTS: The umbilical cord/maternal plasma concentration ratios ranged from 0.56 to 2.0 (mean 1.15, n = 13). LEV plasma concentrations in the neonates declined with an estimated half-life of 18 h (n = 13). The mean milk/maternal plasma concentration ratio was 1.05 (range, 0.78–1.55, n = 11). The infant dose of LEV was estimated to 2.4 mg/kg/day, equivalent to 7.9% of the weight-normalized maternal dose. Plasma concentrations in breastfed were approximately 13% of the mother's plasma levels. Maternal plasma concentrations during third trimester were only 40% of baseline concentrations outside pregnancy (p &lt; 0.001, n = 7). CONCLUSIONS: Our observations suggest considerable transplacental transport of LEV and fairly slow elimination in the neonate. Plasma concentrations of LEV in nursed infants are low despite an extensive transfer of LEV into breast milk. Pregnancy appears to enhance the elimination of LEV resulting in marked decline in plasma concentration, which suggests that therapeutic monitoring may be of value.

Pharmacokinetics of Levetiracetam during Pregnancy, Delivery, in the Neonatal Period, and Lactation

To study pharmacokinetics of levetiracetam (LEV) during pregnancy, delivery, lactation, and in the neonatal period. Fourteen women with epilepsy receiving LEV treatment during pregnancy and lactation contributed with 15 pregnancies to this prospective study in which LEV concentrations in plasma and breast milk were determined. Trough maternal plasma samples were collected each trimester, and at baseline after delivery. Blood samples were obtained at delivery from mothers, from the umbilical cord, and from newborns during 2 days after delivery. LEV concentration was also determined in breast milk and in plasma collected from 11 of the mothers and their suckling infants after birth. The umbilical cord/maternal plasma concentration ratios ranged from 0.56-2.0 (mean 1.15, n=13). LEV plasma concentrations in the neonates declined with an estimated half-life of 18 h (n=13). The mean milk/maternal plasma concentration ratio was 1.05 (range, 0.78-1.55, n=11). The infant dose of LEV was estimated to 2.4 mg/kg/day, equivalent to 7.9% of the weight-normalized maternal dose. Plasma concentrations in breastfed were approximately 13% of the mother's plasma levels. Maternal plasma concentrations during third trimester were only 40% of baseline concentrations outside pregnancy (p<0.001, n=7) Our observations suggest considerable transplacental transport of LEV and fairly slow elimination in the neonate. Plasma concentrations of LEV in nursed infants are low despite an extensive transfer of LEV into breast milk. Pregnancy appears to enhance the elimination of LEV resulting in marked decline in plasma concentration, which suggests that therapeutic monitoring may be of value.

Pharmacokinetics and Therapeutic Drug Monitoring of Newer Antiepileptic Drugs During Pregnancy and the Puerperium

The treatment of epilepsy in pregnancy is particularly challenging in that the fetal and maternal risks associated with maternal seizures need to be balanced against the potential teratogenic effects of antiepileptic drugs (AEDs). Pregnancy is known to affect the pharmacokinetics of older-generation AEDs. Understanding such alterations is important in the effort to optimise drug therapy since they may affect seizure control as well as fetal drug exposure. Therapeutic drug monitoring has therefore been recommended to control for changes in the disposition of the older-generation AEDs during pregnancy. Much less is known about gestation-induced alterations in the pharmacokinetics of the newer AEDs that have been introduced in the last 15 years. Lamotrigine is by far the most extensively studied of the newer AEDs. Pronounced alterations have been reported in the apparent clearance of lamotrigine, with an increase of >300% from baseline in late pregnancy in some patients on monotherapy, most likely due to enhanced metabolism. The available data suggest that the corresponding decline in plasma concentrations can be associated with loss of seizure control. More limited data indicate that a similar decline in plasma concentrations of the active monohydroxy derivative of oxcarbazepine may occur in late pregnancy. Preliminary experience also suggests that a significant fall in plasma concentrations of levetiracetam may occur during pregnancy. No systematic information is available on the pharmacokinetics during pregnancy of other newer AEDs (e.g. gabapentin, pregabalin, tiagabine, topiramate or zonisamide). Given the importance of maintaining optimal treatment of epilepsy during pregnancy, therapeutic drug monitoring appears to be justified for lamotrigine and oxcarbazepine in particular. Systematic studies of the effects of pregnancy on the pharmacokinetics of the other newer-generation AEDs are urgently needed.

METABOLISM OF [14C]GEMOPATRILAT AFTER ORAL ADMINISTRATION TO RATS, DOGS, AND HUMANS

This study describes the pharmacokinetic parameters of gemopatrilat, a potent vasopeptidase inhibitor, in humans and the comparative biotransformation of the compound in rats, dogs, and humans after administration of a single oral dose of [14C]gemopatrilat. Gemopatrilat was rapidly absorbed in humans with an oral bioavailability of 49%. Within 5 h after dose, the mean concentrations of gemopatrilat were less than 1% of the mean Cmax values. The total area under the first-moment time curve extrapolated to infinity [AUC(INF)] value for gemopatrilat was only 2% of the AUC(INF) of radioactivity in plasma. Gemopatrilat showed a large apparent steady-state volume of distribution (2500 liters) and a prolonged terminal-phase decline in plasma concentration. These results are consistent with the idea that the free sulfhydryl group of gemopatrilat forms reversible disulfide linkages with plasma and tissue proteins and is thus eliminated from the body at a very slow rate. Approximately half of the drug-related radioactivity in 1-h plasma samples from rat, dog, and human was reduced chemically with dithiothreitol to gemopatrilat, suggesting that disulfide linkage occurred in all species. In addition, metabolites formed through S-methylation and amide hydrolysis were also detected in rat, dog, and human plasma. No gemopatrilat was detected in urine and fecal samples from all three species, indicating that the compound is extensively metabolized in vivo. The major metabolites identified in human urine and feces were also present in rat and dog. These data suggest that the metabolism of gemopatrilat in all three species were qualitatively very similar.

Etoricoxib in acute pain associated with dental surgery: A randomized, double-blind, placebo- and active comparator-controlled dose-ranging study

Background: Patients experiencing acute pain after surgery, including dental surgery, often require analgesia. Ideally, the chosen analgesic should have a rapid onset and sustained effect. Etoricoxib is a new cyclooxygenase-2-selective inhibitor that has demonstrated analgesic efficacy in the treatment of acute pain with a rapid onset and long-lasting pain relief. Objective: The goal of this study was to determine the analgesic effect of single oral doses of etoricoxib 60, 120, 180, and 240 mg compared with placebo in the treatment of pain after dental surgery. Ibuprofen was used as an active control. Methods: This was a randomized, double-blind, parallel-group, single-dose, placebo- and active comparator-controlled study performed at a single center. It consisted of 3 visits (prestudy, treatment, and poststudy). Eligible patients were aged ≥16 years with moderate or severe pain after surgical extraction of ≥2 third molars, of which ≥1 was an impacted mandibular molar. Patients were assessed over 24 hours and reported pain intensity and pain relied at 14 predefined time points. Plasma samples for a pharmacokinetic/pharmacodynamic analysis were collected from a subset of patients at baseline and the 14 predefined time points. The end points included total pain relief over 8 hours (TOPAR8, the primary end point), sum of pain intensity difference over 8 hours, patient's global evaluation of treatment, median time to onset of pain relief (2-stopwatch method), peak pain relief, and duration of analgesic effect (median time to use of rescue medication). Adverse events were collected up to 14 days postdose. Results: Three hundred ninety-eight (63.1% women, 36.9% men; mean age, 21.1 years; 72.1% white, 27.9% other; mean number of third molars removed, 3.5; 65.2% experiencing moderate pain) were randomly allocated to receive etoricoxib 60 mg (n = 75), etoricoxib 120 mg (n = 76), etoricoxib 180 mg (n = 74), etoricoxib 240 mg (n = 76), ibuprofen 400 mg (n = 48), and placebo (n = 49). All active treatments had significantly greater overall analgesic effect (TOPAR8) compared with placebo ( P ≤ 0.001). Patients who received etoricoxib 120 and 180 mg had significantly higher TOPAR8 scores than those who received etoricoxib 60 mg ( P ≤ 0.001) and ibuprofen ( P < 0.05 etoricoxib 120 mg; P ≤ 0.001 etoricoxib 180 mg). Least-squares mean TOPAR8 scores for etoricoxib 60, 120, 180, and 240 mg, ibuprofen, and placebo were 16.0, 22.0, 23.5, 20.7, 18.6, and 5.2, respectively. The median time to onset of analgesia was 24 minutes for etoricoxib 120, 180, and 240 mg, and 30 minutes for etoricoxib 60 mg and ibuprofen. There were no significant differences in the onset of analgesia between etoricoxib 120, 180, and 240 mg and ibuprofen. The duration of analgesic effect was >24 hours for etoricoxib 120, 180, and 240 mg, and 12.1 hours for etoricoxib 60 mg. The duration of effect was significantly longer with all 4 etoricoxib doses compared with ibuprofen (10.1 hours; P < 0.05 etoricoxib 60 mg; P ≤ 0.001 etoricoxib 120, 180, and 240 mg) and compared with placebo (2.1 hours; P ≤ 0.001). In the pharmacokinetic/pharmacodynamic analysis (n ≈ 120), there was a linear relationship between plasma etoricoxib concentrations and pain relief scores up to the maximum observed concentration, followed by a decline in plasma concentrations with persistent analgesia. The most common adverse events were postextraction alveolitis and nausea. Conclusions: In this dose-ranging study, etoricoxib 120 mg was determined to be the minimum dose that had maximal efficacy in patients with moderate to severe acute pain associated with dental surgery. Both etoricoxib and ibuprofen were generally well tolerated.

Phase I Clinical Trial of the Farnesyltransferase Inhibitor BMS-214662 Given as a 1-Hour Intravenous Infusion in Patients with Advanced Solid Tumors

BMS-214662 is a nonsedating benzodiazepine derivative that exhibits broad spectrum cytotoxicity against human solid tumor cell lines and potently inhibits farnesylation of the H-ras and K-ras oncogenic proteins. This report describes the initial Phase I clinical trial of the compound. The main objective of the study was to determine the dose-limiting toxicities and the maximum tolerated dose of BMS-214662 when administered as a single dose i.v. over 1 h every 21 days to patients with advanced solid tumors. Patients with advanced solid tumors and adequate organ function were eligible for the study. The dose was escalated according to a modified Fibonacci schedule after evaluating groups of at least three patients for toxicity during the first cycle of therapy at each dose level. Pharmacokinetic and pharmacodynamic studies were performed after administration of the two initial doses. The dose of BMS-214662 was escalated from 36 to 225 mg/m(2) through 5 intermediate dose levels in a total of 44 patients. Dose-limiting toxicities occurred in 3 of the 13 (23%) patients during the first cycle of treatment with 225 mg/m(2), consisting of grade 3 nausea/vomiting in 2 patients and grade 3 diarrhea in another patient. In addition, four of these patients experienced reversible grade 3 transaminitis, which was not considered to be dose-limiting. At the recommended dose for Phase II studies, 200 mg/m(2), the most common side effects were reversible transaminitis, nausea, and vomiting. Although there were no objective responses, one patient with pancreatic cancer continues to receive treatment more than 3.5 years after entering the study. BMS-214662 exhibited linear pharmacokinetics and had a mean biological half-life of 1.55 +/- 0.27 h and a total body clearance of 21.8 +/- 10.8 liters/h/m(2), with a low apparent volume of distribution at steady state (31.5 +/- 12.9 liters/m(2)). In patients treated with the recommended Phase II dose, the mean maximum plasma concentration of the drug was 6.57 +/- 2.94 microg/ml, and farnesyltransferase activity in peripheral blood mononuclear cells decreased to a nadir of 10.5 +/- 6.4% of baseline at the end of the infusion but fully recovered within 24 h. BMS-214662 can be delivered safely as a single 1-h i.v. infusion at a dose that results in pronounced inhibition of farnesyltransferase activity in peripheral blood mononuclear cells. However, the duration of enzyme inhibition was transient, recovering in parallel with the decline in plasma concentrations of this rapidly eliminated drug. Because indications of anticancer activity were observed in several patients, further optimization of the administration schedule for this promising new compound is warranted.

Pharmacokinetics of single and multiple escalating doses of dapoxetine in healthy volunteers

Objective To characterize the pharmacokinetics and safety of single and multiple doses of dapoxetine, a novel agent under development for the treatment of premature ejaculation, a urogenital disorder. Methods: This was a randomized, double-blind, placebo-controlled, single and multiple dose study in 77 healthy male volunteers. Dapoxetine was administered orally as a single dose of 60, 100, 140, or 160 mg or once-daily for 6 days at 80, 100, or 120 mg. Pharmacokinetic parameters were determined by non-compartmental methods. Safety was evaluated by physical exam; laboratory, vital signs and ECG measurements; and monitoring of adverse events. Results: Dapoxetine was quickly absorbed with peak plasma concentrations occurring at ~1.5 h after dosing followed by a rapid decline in plasma concentrations. Cmax and AUC increased proportionally up to 100 mg. Dapoxetine had a terminal half-life of ~18 h. Single- and multiple-dose pharmacokinetics were comparable. No serious adverse events were reported, and there were no clinically relevant changes in any clinical laboratory tests, vital signs, or ECG. Nausea, the most common adverse event, was mild or moderate. Conclusions: Following oral administration, dapoxetine was rapidly absorbed; a fast decline in plasma concentrations followed. Dapoxetine was well tolerated following single and multiple doses to healthy volunteers. Clinical Pharmacology & Therapeutics (2004) 75, P32–P32; doi: 10.1016/j.clpt.2003.11.123

Pharmacokinetics and pharmacodynamics of clemastine in healthy horses

Clemastine is an H1 antagonist used in certain allergic disorders in humans and tentatively also in horses, although the pharmacology of the drug in this species has not yet been investigated. In the present study we determined basic pharmacokinetic parameters and compared the effect of the drug measured as inhibition of histamine-induced cutaneous wheal formation in six horses. The most prominent feature of drug disposition after intravenous dose of 50 microg/kg bw was a very rapid initial decline in plasma concentration, followed by a terminal phase with a half-life of 5.4 h. The volume of distribution was large, Vss = 3.8 L/kg, and the total body clearance 0.79 L/h kg. Notably, oral bioavailability was only 3.4%. There was a strong relationship between plasma concentrations and effect. The effect maximum (measured as reduction in histamine-induced cutaneous wheal formation) was 65% (compared with controls where saline was injected) and the effect duration after i.v. dose was approximately 5 h. The effect after oral dose of 200 microg/kg was minor. The results indicate that clemastine is not appropriate for oral administration to horses because of low bioavailability. When using repeated i.v. administration, the drug has to be administered at least three to four times daily to maintain therapeutic plasma concentrations because of the short half-life. However, if sufficient plasma concentrations are maintained the drug is efficacious in reducing histamine-induced wheal formations.

Plasma concentrations of atrial and brain natriuretic peptides in a case with hypertensive encephalopathy

Hemodynamic mechanism for brain edema formation in patients with hypertensive encephalopathy is unclear. Potential roles of natriuretic peptides in the pathogenesis of hypertensive encephalopathy are discussed. A 32-year-old man presented with slight left hemiparesis. He was slightly confused, and his blood pressure was extremely high. Cranial plain computerized tomography scans revealed diffuse brain edema mainly in the supratentorial white matter region. Blood examination revealed that plasma concentrations of atrial and brain natriuretic peptides were significantly high. His left hemiparesis disappeared within a day, but he tended to be agitated. His altered mental status, however, resolved with control of blood pressure. Serial magnetic resonance imagings demonstrated that the magnitude of brain edema was attenuated in proportion to decline in plasma concentrations of natriuretic peptides. This case suggests that significant elevation of plasma concentrations of natriuretic peptides may contribute to an acute rise in blood pressure, and that these peptides potentially play an important role in development of brain edema in hypertensive encephalopathy. [Neurol Res 2002; 24: 627-630]