Assessing the Impact of Factors that Influence the Ketogenic Response to Varying Doses of Medium Chain Triglyceride (MCT) Oil.

Objectives, Design, Setting: The ketogenic effect of medium chain triglyceride (MCT) oil offers potential for Alzheimer's disease prevention and treatment. Limited literature suggests a linear B-hyroxybutyrate (BHB) response to increasing MCT doses. This pharmacokinetic study evaluates factors affecting BHB response in three subject groups. PARTICIPANTS: Healthy subjects without cognitive deficits <65years, similarly healthy subjects >=65years, and those with Alzheimer's Disease were assessed. INTERVENTION: Different doses (0g,14g, 28g, 42g) of MCT oil (99.3% C8:0) were administered, followed by fasting during the study period. MEASUREMENTS: BHB measured by finger prick sampling hourly for 5 hours after ingestion. Each subject attended four different days for each ascending dose. Data was also collected on body composition, BMI, waist/hip ratio, grip strength, gait speed, nutrient content of pre-study breakfast and side effects. RESULTS: Twenty-five participants: eight healthy; average age of 44yr (25-61), nine healthy; 79yr (65-90) and eight with AD; 78.6yr (57-86) respectively. Compiled data showed the expected linear dose response relationship. No group differences, with baseline corrected area under the blood vs. time curve (r2=0.98) and maximum concentrations (r2=0.97). However, there was notable individual variability in maximum BHB response (42g dose: 0.4 -2.1mM), and time to reach maximum BHB response both, within and between individuals. Variability was unrelated to age, sex, sarcopenic or AD status. Visceral fat, BMI, waist/hip ratio and pretest meal CHO and protein content all affected the BHB response (p<0.001). CONCLUSION: There was a large inter-individual variability, with phenotype effects identified. This highlights challenges in interpreting clinical responses to MCT intake.

Variations in tissue selectivity amongst insulin secretagogues: a systematic review.

AIM: Insulin secretagogues promote insulin release by binding to sulfonylurea receptors on pancreatic ß-cells (SUR1). However, these drugs also bind to receptor isoforms on cardiac myocytes (SUR2A) and vascular smooth muscle (SUR2B). Binding to SUR2A/SUR2B may inhibit ischaemic preconditioning, an endogenous protective mechanism enabling cardiac tissue to survive periods of ischaemia. This study was designed to identify insulin secretagogues that selectively bind to SUR1 when given at therapeutic doses. METHODS: Using accepted systematic review methods, three electronic databases were searched from inception to 13 June 2011. Original studies measuring the half-maximal inhibitory concentration (IC(50)) for an insulin secretagogue on K(ATP) channels using standard electrophysiological techniques were included. Steady-state concentrations (C(SS)) were estimated from the usual oral dose and clearance values for each drug. RESULTS: Data were extracted from 27 studies meeting all inclusion criteria. IC(50) values for SUR1 were below those for SUR2A/SUR2B for all insulin secretagogues and addition of C(SS) values identified three distinct patterns. The C(SS) for gliclazide, glipizide, mitiglinide and nateglinide lie between IC(50) values for SUR1 and SUR2A/SUR2B, suggesting that these drugs bind selectively to pancreatic receptors. The C(SS) for glimepiride and glyburide (glibenclamide) was above IC(50) values for all three isoforms, suggesting these drugs are non-selective. Tolbutamide and repaglinide may have partial pancreatic receptor selectivity because IC(50) values for SUR1 and SUR2A/SUR2B overlapped somewhat, with the C(SS) in the midst of these values. CONCLUSIONS: Insulin secretagogues display different tissue selectivity characteristics at therapeutic doses. This may translate into different levels of cardiovascular risk.

Pharmacokinetics of PSC 833 (valspodar) in its Cremophor EL formulation in rat.

Valspodar is a P-glycoprotein inhibitor widely used in preclinical and clinical studies for overcoming multidrug resistance. Despite this, the pharmacokinetics of valspodar in rat, a commonly used animal model, have not been reported. Here, we report on the pharmacokinetics of valspodar in Sprague-Dawley rats following intravenous and oral administration of its Cremophor EL formulation, which has been used for humans in clinical trials. After intravenous doses, valspodar displayed properties of slow clearance and a large volume of distribution. Its plasma unbound fraction was around 15% in the Cremophor EL formulation used in the study. After 10 mg kg(-1) orally it was rapidly absorbed with an average maximal plasma concentration of 1.48 mg l(-1) within approximately 2 h. The mean bioavailability of valspodar was 42.8%. In rat, valspodar showed properties of low hepatic extraction and wide distribution, similar to that of its structural analogue cyclosporine A.

Epoxyeicosatrienoic acid prevents postischemic electrocardiogram abnormalities in an isolated heart model.

Cytochrome P450 epoxygenases metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs) which are in turn converted to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). The main objective of this study was to investigate the protective effects of EETs following ischemic injury using an ex vivo electrocardiogram (EKG) model. Hearts from C57Bl/6, transgenic mice with cardiomyocyte-specific overexpression of CYP2J2 (Tr) and wildtype (WT) littermates were excised and perfused with constant pressure in a Langendorff apparatus. Electrodes were placed superficially at the right atrium and left ventricle to assess EKG waveforms. In ischemic reperfusion experiments hearts were subjected to 20 min of global no-flow ischemia followed by 20 min of reperfusion (R20). The EKG from C57Bl/6 hearts perfused with 1 microM 14,15-EET showed less QT prolongation (QTc) and ST elevation (STE) (QTc=41+/-3, STE=2.3+/-0.3; R20: QTc=42+/-2 ms, STE=1.2+/-0.2mv) than control hearts (QTc=36+/-2, STE=2.3+/-0.2; R20: QTc=53+/-3 ms; STE=3.6+/-0.4mv). Similar results of reduced QT prolongation and ST elevation were observed in EKG recording from CYP2J2 Tr mice (QTc=35+/-1, STE=1.9+/-0.1; R20: QTc=38+/-4 ms, STE=1.3+/-0.2mv) compared to WT hearts. The putative epoxygenase inhibitor MS-PPOH (50 microM) and EET antagonist 14,15-EEZE (10 microM) both abolished the cardioprotective response, implicating EETs in this process. In addition, separate exposure to the K(ATP) channel blockers glibenclamide (1 microM) and HMR1098 (10 microM), or the PKA protein inhibitor H89 (50 nM) during reperfusion abolished the improved repolarization in both the models. Consistent with a role of PKA, CYP2J2 Tr mice had an enhanced activation of the PKAalpha regulatory II subunit in plasma membrane following IR injury. The present data demonstrate that EETs can enhance the recovery of ventricular repolarization following ischemia, potentially by facilitating activation of K(+) channels and PKA-dependent signaling.

Suppression of drug-metabolizing enzymes and efflux transporters in the intestine of endotoxin-treated rats.

Infection and inflammation impose a suppression in the expression and activity of several drug transporters and drug-metabolizing enzymes in liver. In the intestine, cytochrome P450 3A (CYP3A), P-glycoprotein (PGP/mdr1), and the multidrug resistance-associated protein 2 (MRP2) are important barriers to the absorption of many clinically important drugs; thus, the expression and activity of these proteins were examined in inflammation. Transport and metabolism were determined in jejunum segments isolated at 24 h from endotoxin-treated or control rats (n = 8) mounted in Ussing chambers. Transport and metabolism of (3)H-digoxin, 5-carboxyfluorescein (5-CF), amiodarone (AM), and 7-benzyloxyquinoline (7-BQ) were measured for 90 min in the presence and absence of inhibitors. Reverse transcription-polymerase chain reaction was used to measure mRNA levels. As compared with controls, levels of mdr1a and mrp2 mRNA were significantly decreased by approximately 50% in the jejunum of LPS-treated rats. Corresponding reductions in the basolateral-->apical efflux of digoxin, AM, and 5-CF were observed, resulting in significant increases in the apical-->basolateral absorption of these compounds. Intestinal CYP3A mRNA levels and CYP3A-mediated metabolism of 7-BQ and AM were also decreased by approximately 50 to 70% (p < 0.05) in the LPS group. Mannitol permeability and lactate dehydrogenase release were not altered. These studies indicate that endotoxin-induced inflammation imposes a reduction in the intestinal expression and activity of PGP, mrp2, and CYP3A in rats, which elicits corresponding changes in the intestinal transport and metabolism of their substrates. Hence, infection and inflammatory diseases may impose variability in drug bioavailability through alterations in the intestinal expression and activity of drug transporters and metabolic enzymes.

High-performance liquid chromatography assay of amiodarone in rat plasma.

PURPOSE: A high-performance liquid chromatographic method is described for the determination of amiodarone in rat plasma. METHODS: After liquid-liquid extraction, the separation of amiodarone from internal standard and endogenous components was accomplished using reversed phase chromatography. The mobile phase, a combination of monobasic potassium phosphate, methanol and acetonitrile, was run isocratically through a C(8) analytical column. The UV detection was at 254 nm for ethopropazine, the internal standard, and subsequently changed to 242 nm for amiodarone detection. RESULTS: Analytical run time was less than 13 min. Mean recovery was 75% and 82% for lower (0.5 microg/ml) and higher concentrations (5 microg/ml), respectively. The assay exhibited excellent linear relationships between peak height ratios and plasma concentrations; quantitation limit was at least 0.035 microg/ml, based on 100 microl of rat plasma. Accuracy and precision were <17% over the concentration range of 0.035 to 5 microg/ml. CONCLUSION. The assay was applied successfully to the measurement of amiodarone plasma concentrations in rats given the drug orally.

Enhancement of dissolution of ethopropazine using solid dispersions prepared with phospholipid and/or polyethylene glycol.

The purpose of this study was to improve the dissolution properties of a poorly water soluble and bioavailable drug, ethopropazine HCl (ET), by incorporating the drug in three different types of solid dispersion systems. Solid dispersions of ET were prepared using 1:1 (w/w) ratios of (1) phospholipid (1,2 dimyristoyl-sn-glycerophosphocholine) (DMPC), (2) polyethylene glycol 8000 (PEG8000), and (3) a novel combination of both DMPC and PEG8000. Using the solvent method of preparation, ET and DMPC and/or PEG were dissolved in chloroform, and solvent subsequently was evaporated using nitrogen gas. The resulting solid dispersion(s) was passed through a 60-mesh sieve. Characterization of ET/DMPC solid dispersion was performed by differential scanning calorimetry (DSC) and X-ray diffractometry studies. Dissolution studies conducted in phosphate buffered saline (PBS) (pH 7.4, 37 degrees C +/- 0.5 degrees C) using the USP type II (paddle) dissolution apparatus showed significant increases in the dissolution rate of ET with all the solid dispersions in this study. Specifically, within the first 5 min (D5), solid dispersions containing ET/DMPC (1:1) showed an eightfold increase in dissolution; in combination with DMPC and PEG8000 (1:1), there was an approximately sixfold increase; and a fourfold increase was observed with PEG8000 (1:1). Complete dissolution of all solid dispersions occurred within 60 min (D60) of the run. Storage of the ET/DMPC sample for over 4.5 months revealed a decrease in the dissolution rate when compared to freshly prepared sample. Overall, it was concluded that the dissolution rate of ET significantly improved when dispersed in all the selected carrier systems. However, the solid dispersion of ET/DMPC was observed to be superior to the other combinations used.

Stereospecific pharmacokinetics and pharmacodynamics of beta-adrenergic blockers in humans.

The beta-blockers comprise a group of drugs that are mostly used to treat cardiovascular disorders such as hypertension, cardiac arrhythmia, or ischemic heart disease. Each of these drugs possesses at least one chiral center, and an inherent high degree of enantioselectivity in binding to the beta-adrenergic receptor. For beta-blockers with a single chiral center, the (-) enantiomer possesses much greater affinity for binding to the beta-adrenergic receptors than antipode. The enantiomers of some of these drugs possess other effects, such as antagonism at alpha-adrenergic receptors or Class III antiarrhythmic activity. However, these effects generally display a lower level of stereoselectivity than the beta-blocking activity. Except for timolol, all of these drugs used systemically are administered clinically as the racemate. As a class, the beta blockers are quite diverse from a pharmacokinetic perspective, as they display a high range of values in plasma protein binding, percent of drug eliminated by metabolism or unchanged in the urine, and in hepatic extraction ratio. With respect to plasma concentrations attained after oral or intravenous dosing, in most cases the enantiomers of the beta-blockers show only a modest degree of stereoselectivity. However, the relative magnitude of the concentrations of the enantiomers in plasma is not constant in all situations and varies from drug to drug. Further, various factors related to the drug (e.g., dosing rate or enantiomer-enantiomer interaction) or the patient (e.g., racial background, cardiovascular function, or the patient metabolic phenotype) may affect the stereospecific pharmacokinetics and pharmacodynamics of beta-blockers. An understanding of the stereospecific pharmacokinetics and pharmacodynamics of beta-blockers may help clinicians to interpret and predict differences among patients in pharmacologic responses to these drugs.

A high-performance liquid chromatographic assay for the determination of desbutylhalofantrine enantiomers in rat plasma.

PURPOSE: To develop a stereoselective high performance liquid chromatographic assay for determination of desbutylhalofantrine (DHF) enantiomers in rat plasma. METHODS: After protein precipitation of 100 microL of rat plasma, racemic DHF and internal standard (quinidine sulfate) were extracted into hexane in the presence of pH 8 phosphate buffer. After transfer and evaporation of the hexane, the residue was derivatized using 0.25 M (+)-di-O-acetyl-L-tartaric acid anhydride at 4 degrees C. After 5 min the reaction was stopped by addition of methanol in water, and the tube contents were dried, reconstituted in the mobile phase, and injected into a C(18) analytical column under reverse phase conditions. RESULTS: The derivatized enantiomers were baseline resolved and free of interference from endogenous components in plasma. Standard curves were linear (r(2)>0.99) over the range of enantiomer concentrations from 25-1000 ng/mL. The assay was validated to concentrations as low as 25 ng/mL, based on 100 microL of rat plasma. The nature of diastereomers formed was found to be dependent on the temperature used during the derivatization step. In a preliminary experiment in the rat, stereoselectivity in the plasma concentrations of DHF were observed, indicating stereoselectivity in the pharmacokinetics of the metabolite. CONCLUSIONS: The assay was sensitive and appropriate for use in pharmacokinetic studies of DHF in the rat.

The stereoselective distribution of halofantrine enantiomers within human, dog, and rat plasma lipoproteins.

PURPOSE: To study the in vitro distribution of the enantiomers of the antimalarial drug halofantrine in human, dog and rat plasma lipoprotein-fractions. METHODS: Plasma was spiked with racemic halofantrine (1,000 ng/ml) and incubated for 1 h at 37 degree C. The fractions (high and low density lipoproteins, triglyceride-rich lipoproteins and lipoprotein deficient plasma) were separated using density gradient ultracentrifugation. Fractions were assayed for halofantrine enantiomer using stereospecific high performance liquid chromatography. RESULTS: The (-) enantiomer of halofantrine displayed higher affinity for the lipoprotein-deficient fraction than the (+) enantiomer in all three species. The (+) enantiomer was predominately located in the lipoprotein rich fractions of dog and human plasma (the (+):(-) ratio ranging from 1.2-9.6). In contrast, the (+):(-) ratio was consistently < 1 in lipoprotein-deficient fractions. Dog displayed a large magnitude of stereoselectivity in halofantrine distribution to the plasma fractions tested. There were substantial interspecies differences in the pattern of distribution of halofantrine enantiomers within the different fractions. A significant positive relationship was observed between halofantrine uptake into lipoprotein-rich fractions and the percent of apolar core lipid in those fractions. There was also a strong negative correlation between total protein concentration and the enantiomeric ratio in the lipoprotein-deficient plasma fraction. CONCLUSION: Distribution of halofantrine enantiomer to plasma lipoprotein-fractions is stereoselective and species specific. This differential binding of halofantrine enantiomers to lipoproteins may need to be considered in viewing pharmacokinetic and pharmacodynamic data involving the drug.

Stereoselective pharmacokinetics of desbutylhalofantrine, a metabolite of halofantrine, in the rat after administration of the racemic metabolite or parent drug.

The main objective of this study was to determine the pharmacokinetics of the enantiomers of desbutylhalofantrine (DHF), a metabolite of halofantrine (HF), in the rat. Rats received either intravenous (2 mg/kg) or oral (7 mg/kg) (+/-)-DHF HCl, or (+/-)-HF HCl intravenously (3 mg/kg). Enantiomer concentrations in plasma were determined by a stereospecific assay. In all rats, the plasma concentrations of (+)-DHF exceeded those of (-)-DHF. After (+/-)-DHF, the mean (+):(-) ratios of AUC(0-infinity) after oral and intravenous dosing were 3.7 and 2.8, respectively. After intravenous doses of DHF, the (-):(+) enantiomeric ratios of Cl and V(dss) were approximately 2.8. There were no significant differences between the enantiomers in t(1/2) (mean 14-23 h) or t(max) (mean 10-12 h) after intravenous or oral administration of DHF. Oral bioavailability estimates of DHF enantiomers (>59%) were higher than those previously estimated for HF in the rat. The stereoselectivity in HF kinetics was not as pronounced as for DHF. It was estimated that over 44% of the dose of HF is metabolized to DHF enantiomers. It was concluded that DHF possesses a pharmacokinetic profile similar to that of HF, each possessing low values of clearance and high volume of distribution. DHF differed from HF in its degree of stereoselectivity in pharmacokinetics, and in its extent of oral bioavailability.

High-performance liquid chromatographic assay of (+/-)-lactic acid and its enantiomers in calf serum.

Two high-performance liquid chromatographic methods are described for the determination of lactic acid and its enantiomers in calf serum. A 300x8.0 mm I.D. column packed with sulfonated styrene-divinylbenzene copolymer and a 50x4.6 mm ODS column with N,N-dioctyl-L-alanine were used. UV detection was at 205 and 236 nm for the non-chiral and chiral assays, respectively. Both assays demonstrated excellent linear relationships between peak area ratios and serum concentrations over a range of 0.5 to 20 mM, based on 100 microl bovine serum. Recovery was complete. Inter- and within-batch bias and relative standard deviation were <15%.

Pharmacokinetics of ethopropazine in the rat after oral and intravenous administration.

The pharmacokinetics of the anticholinergic drug ethopropazine (ET) have been studied in the rat after intravenous (i.v.) and oral administration. After i.v. doses of 5 and 10 mg/kg ET HCl, mean +/- S.D. plasma AUC were 9836 +/- 2129 (n = 4 rats) and 13096 +/- 4186 ng h/mL (n = 5 rats), respectively. The t1/2 after 5 and 10 mg/kg i.v. doses were 17.9 +/- 3.3 and 20.9 +/- 6.0 h, respectively. The Cl and V(dss) after 5 mg/kg i.v. doses were 0.48 +/- 0.10 L/h/kg and 7.1 +/- 2.3 L/kg, respectively. Statistically significant differences were present between the 5 and 10 mg/kg dose levels in Cl and V(dss). Oral administration of 50 mg/kg ET HCl (n = 5 rats) yielded mean AUC of 2685 +/- 336 ng h/mL. Mean plasma C(max), t(max) and t1/2 after oral doses were 236 +/- 99 ng/mL, 2.2 +/- 1.4 h and 26.1 +/- 5.4 h, respectively. Less than 1% of the dose was recovered unchanged in urine and bile. Ethopropazine is extensively distributed in the rat, and has relatively slow Cl in relation to hepatic blood flow in the rat. The drug appears to be extensively metabolized in the rat, and nonlinearity is present between the 5 and the 10 mg/kg i.v. doses. The drug displayed poor bioavailability (< 5%) after oral administration.

Pharmacokinetics of halofantrine in the rat: stereoselectivity and interspecies comparisons.

The antimalarial drug, halofantrine, is chiral and is administered clinically as the racemate. In order to define the pharmacokinetic properties of halofantrine enantiomers in the rat, male Sprague-Dawley rats (264-311 g) were given halofantrine HCl orally (n = 5; 14 mg/kg) or intravenously (i.v.) (n = 5; 2 mg/kg). Plasma samples were collected over a 72 h period, and these were assayed for halofantrine enantiomer concentrations using a stereospecific reverse phase HPLC assay. After dosing by both routes of administration the (+) enantiomer was found to have significantly higher AUC, and higher Cmax after oral dosing. Pharmacokinetic analysis indicated that in the rat, the (+) enantiomer is cleared slower, and is less extensively distributed than its antipode. The bioavailability of the enantiomers after oral administration was less than 27%. Urinary excretion was a negligible route of elimination of unchanged drug. Using allometry, the pharmacokinetics of (+/-)-halofantrine in rats scaled nicely with literature data from dogs and humans. The pharmacokinetic properties of halofantrine enantiomers in the rat resembled those seen in humans, indicating that the rat is a good model for the study of halofantrine pharmacokinetics.

Disposition of ethopropazine enantiomers in the rat: tissue distribution and plasma protein binding.

PURPOSE: To determine the in vitro plasma protein binding, and the in vivo brain, heart and plasma concentrations of ethopropazine (ET) enantiomers in the rat after iv doses. METHODS: For in vivo assessment of ET enantiomer concentrations, rats with implanted jugular vein cannulae were injected with 10 mg/kg of (+/-)-ET HCl. At selected times after dosing, rats were sacrificed and heart, brain, and plasma were collected. Equilibrium dialysis was used to determine the unbound fraction of ET in rat plasma over a concentration range of 150 to 4000 ng/mL of each enantiomer. A stereospecific assay was used to measure concentrations of ET enantiomer. RESULTS: No stereoselectivity was observed in plasma or tissues after iv dosing. Area under the concentration vs. time curves indicated that highest uptake of ET occurred in brain tissue, followed by heart tissues, then plasma. There was no noticeable difference between concentrations of ET enantiomers in different parts of brain (substantia nigra, cortex, or striatum). There was no observed stereoselectivity in plasma protein binding of ET enantiomers in rat plasma. Saturation of binding to plasma proteins was observed between 500 and 2000 ng/mL of each ET enantiomer, but unbound fraction was constant at concentrations below and above that range. CONCLUSION: Ethopropazine displays nonstereoselectivity in its pharmacokinetics. The drug shares distribution features similar to those of other phenothiazine derivatives. Based on the in vitro plasma protein binding results, there appears to be saturation of some, but not all, plasma binding proteins of ET within the range of concentrations studied.

Anticholinergic drugs used in Parkinson's disease: An overlooked class of drugs from a pharmacokinetic perspective.

Anticholinergic drugs were the first pharmacological agents used in the treatment of Parkinson"s disease. Although levodopa and other centrally acting dopaminergic agonists have largely supplanted their use, they still have a place in treatment of the disease. As a therapeutic class, there is little pharmacokinetic information available for these drugs, which is inclusive of benztropine, biperiden, diphenhydramine, ethopropazine, orphenadrine, procyclidine and trihexyphenidyl. Pharmacokinetic information is largely restricted to studies involving young health volunteers given single doses. In general, this class of drugs is rapidly absorbed after oral administration to humans. Oral bioavailability is variable between the different drugs, ranging from 30% to over 70%. Each of the drugs appears to possess a large Vd in humans and animals, and distribution to tissues is rapid. The drugs are all characterized by relatively low clearance relative to hepatic blood flow, and appear to be extensively metabolized, primarily to N-dealkylated and hydroxylated metabolites. The available information suggests that excretion of parent drug and metabolite is via the urine and bile. Although the existence of a plasma concentration vs. therapeutic effect relationship has not been explored, there is some evidence suggesting a relationship between concentration and peripheral side effects. Elderly tolerate the drugs less well than do younger patients. There is a notable lack of pharmacokinetic information for these drugs in the elderly. The lack of pharmacokinetic information for multiple dose administration and in the elderly may be a possible hindrance in the safe and effective use of these drugs in patients with Parkinson"s disease.

High-performance liquid chromatographic assay of (+/-)-ethopropazine and its enantiomers in rat plasma.

Two high-performance liquid chromatographic (HPLC) methods are described for determination of (+/-)-ethopropazine (ET) in rat plasma. After deproteination and liquid-liquid extraction, assay of (+/-)-ET was performed using either a C18 column (non-stereospecific assay) or an (alpha-R-naphthyl)ethylurea column (stereospecific assay). The UV detection was at 250 nm. Mean recovery was >85%. Both assays demonstrated excellent linear relationships between peak height ratios and plasma concentrations; quantitation limits were < or =25 ng/ml, based on 100 microl rat plasma. Accuracy and precision were <17% with both methods. Both methods were applied successfully to the measurement of ET plasma concentrations in rats given the drug intravenously.

SK&F107647: a synthetic hematoregulatory peptide in patients with solid tumor malignancies: a phase I trial.

SK&F107647 is a synthetic hematoregulatory peptide (HP) increases both the number and function of progenitor cells, enabling improved survival after lethal myelosuppression, lethal fungal infection, and lethal herpes simplex virus infection in murine models. This Phase I single-blind placebo-controlled dose-rising crossover trial examined the efficacy of SK&F107647 in patients who had incurable solid tumor malignancies. Sixteen patients were treated. Six adverse events in 3 patients were considered to be possibly related to SK& F107647; all were mild to moderate in nature (mild nervousness and agitation at 0.01 ng/kg, moderate fever and mild nausea at 0.1 ng/kg, elevated hepatic enzymes at 0.1 ng/kg, and mild vomiting at 1.0 ng/kg). Plasma half-life was 2.44 hours (+/-1.07 standard deviation). The observed area volume of distribution was 16.7 L (+/-7.7 standard deviation) and clearance was 5.04 L/hour (+/-1.83 standard deviation). When administered as a single 2-hour intravenous infusion at doses ranging from 0.01 to 100 ng/kg, SK&F107647 is safe and well tolerated.

Evening dosing is associated with higher plasma concentrations of pranlukast, a leukotriene receptor antagonist, in healthy male volunteers.

AIMS: To study the magnitude of differences in the pharmacokinetics of pranlukast, after morning and evening administration. METHODS: Pranlukast (300 mg) was administered to 12 healthy male volunteers on two separate occasions, either in the morning or evening. Both doses were given 30 min after a standard high fat content meal. Blood samples were collected up to 18 h postdose. Plasma was assayed by high performance liquid chromatography. Standard pharmacokinetic and statistical analyses were performed. RESULTS: Statistically significant (P < 0.05) increases were noted in AUC(o,t) (56%) and tmax (2.5 h) after evening administration. Cmax was 14% higher after evening dosing (95% C.I. 0.71-1.84). CONCLUSIONS: Pranlukast bioavailability is apparently increased after evening dosing as compared with morning administration. Higher night-time and early morning plasma concentrations may confer additional therapeutic benefit at a time when asthmatics are at greatest risk of developing bronchospasm.

The pharmacokinetics of pranlukast in healthy young and elderly subjects.

Pranlukast is a novel LTD4 antagonist under development for the treatment of asthma. To assess the effect of age, the pharmacokinetics of pranlukast were studied in healthy young (9 females, 10 males, mean 30 years) and elderly subjects (9 per sex, mean 70.4 years). After an overnight fast volunteers were given 300 mg of pranlukast orally, 30 min after a light breakfast. Serial blood samples were collected for 24 hs, and the plasma was assayed by HPLC/UV. Pranlukast was well tolerated by the volunteers. The resultant mean plasma concentration vs. time data were very similar for both age groups. The estimated geometric mean AUCO-t and Cmax ratios (95% CI in parentheses) for elderly : young were 1.00 (0.71, 1.41) and 0.93 (0.66, 1.33), respectively. Median Tmax occurred at 4.5 h in both age groups. There were no significant differences observed in the pharmacokinetics of pranlukast between healthy young and elderly subjects. On stratifying the young and elderly data with respect to gender, no marked differences were observed between male and female subjects in the mean pharmacokinetic parameters of pranlukast, and the respective plasma concentrations profiles were very similar.