Biological and Molecular Properties of a Turnip mosaic virus (TuMV) Strain that Breaks TuMV Resistances in Brassica napus.

A new resistance-breaking strain of Turnip mosaic virus (TuMV) overcomes TuMV resistance genes that currently suppress spread of this virus in Brassica napus crops in the Liverpool Plains region of eastern Australia. Isolates 12.1 and 12.

Longitudinal assessment of a P-glycoprotein-mediated drug interaction of valspodar on digoxin.

Objectives: Valspodar is a P-glycoprotein modulator currently under development as a multidrug resistance reversal agent in clinical oncology. A multiple-dose drug interaction study was performed to assess the influence of valspodar on digoxin, a substrate for P-glycoprotein.

Methods: Twelve healthy volunteers received an oral digoxin loading dose of 1 mg on day 1, followed by 0.

Routine determination of morphine, morphine 3-beta-D-glucuronide and morphine 6-beta-D-glucuronide in human serum by liquid chromatography coupled to electrospray mass spectrometry.

A robust liquid chromatographic mass spectrometric method capable of quantifying morphine, morphine 3-beta-D-glucuronide and morphine 6-beta-D-glucuronide down to 1.0 ng/ml, 5.0 ng/ml and 2.

Effect of meal timing not critical for the pharmacokinetics of tegaserod (HTF 919).

This study assessed the pharmacokinetic profiles of administering tegaserod (HTF 919) at different time intervals with respect to a meal. It was a randomized, open-label, two-phase, five-period crossover study. In the first phase, 18 healthy subjects received a single 12 mg oral dose of tegaserod administered either 30 or 15 minutes prior to the start of the 600-calorie, fat-rich breakfast.

Effects of terbinafine on the pharmacokinetics of digoxin in healthy volunteers.

Study Objective: To assess the potential effects of terbinafine, a new synthetic allylamine antifungal agent, on the pharmacokinetics of a single 0.75-mg oral dose of digoxin.

Design: Randomized, double-blind, placebo-controlled, crossover study consisting of two treatment periods.

Evaluation of effects of terbinafine on single oral dose pharmacokinetics and anticoagulant actions of warfarin in healthy volunteers.

Study Objective: To evaluate the potential effects of oral terbinafine, a new synthetic antifungal agent of the allylamine class, on the pharmacokinetics and pharmacodynamics of racemic warfarin.

Design: Randomized, double-blind, placebo-controlled, crossover study.

Subjects: Sixteen healthy men.

Cyclosporine and nonsteroidal antiinflammatory drugs: exploring potential drug interactions and their implications for the treatment of rheumatoid arthritis.

A series of clinical pharmacology studies was performed to screen for possible pharmacokinetic/dynamic contributions to drug interactions reported in rheumatoid arthritis patients receiving cyclosporine and nonsteroidal antiinflammatory drugs (NSAIDs). No clinically relevant pharmacokinetic changes in any of the drugs were noted when single-dose cyclosporine was coadministered during a steady-state regimen of aspirin, indomethacin, or piroxicam in healthy volunteers. Only with diclofenac was an interaction observed whereby the diclofenac area under the concentration-time curve was doubled in the presence of cyclosporine.

Diclofenac combined with cyclosporine in treatment refractory rheumatoid arthritis: longitudinal safety assessment and evidence of a pharmacokinetic/dynamic interaction.

Objective: (1) To characterize potential changes in diclofenac pharmacokinetics and renal function in patients with rheumatoid arthritis (RA) treated with diclofenac and cyclosporine; (2) to prospectively collect longitudinal safety data during use of this drug combination.

Methods: Twenty patients with severe, treatment refractory RA were sequentially treated with stable doses of diclofenac (100-200 mg/day) for one month followed by diclofenac combined with cyclosporine (3 mg/kg/day) for one month. Pharmacokinetic profiles of diclofenac were obtained at the end of each treatment period.

A mathematical model for dynamics of cardiovascular drug action: application to intravenous dihydropyridines in healthy volunteers.

A physiologically based mathematical model was built to describe the pharmacodynamic effects in response to the administration of intravenous (iv) dihydropyridine drugs in healthy volunteers. This model incorporates a limited number of hemodynamic variables, namely, mean arterial blood pressure (MAP), cardiac output (CO) or heart rate (HR), stroke volume (SV), and total peripheral resistance (TPR), into a closed-loop system supposed to represent essential features of the cardiovascular regulation. We also defined an additional auxiliary control variable (U) which is thought to represent primarily the role of the baroreceptor reflex.

The preparation and acute antihypertensive effects of a nanocapsular form of darodipine, a dihydropyridine calcium entry blocker.

We have addressed two problems associated with the use of dihydropyridine calcium entry blockers in antihypertensive therapy, namely, potent vasodilation and short half-lives, by incorporating the representative blocker, darodipine, into a nanocapsular vehicle. In awake, renovascular hypertensive rats, darodipine nanocapsules lowered blood pressure when given orally or intramuscularly, and the initial fall in blood pressure was less marked than that observed with the same dose of darodipine dissolved in polyethylene glycol 400 (PEG). Intramuscular administration of the nanocapsular form of darodipine had an antihypertensive effect which lasted for at least 24 hr.

Kinetics and hemodynamic effects of intravenous nicardipine modified by previous propranolol oral treatment.

Intravenous nicardipine, 5 mg, was administered in two comparable groups of eight patients with chronic coronary artery disease but no clinical signs of heart failure. One group had received no previous treatment and served as a control group, and the other had received long-term treatment with large oral doses of propranolol. Blood concentrations of nicardipine were higher, and the area under the plasma concentration curve was greater in the group previously treated by propranolol.

Simultaneous study of the pharmacokinetics of intravenous and oral nicardipine using a stable isotope.

The systemic elimination of nicardipine has been studied by an initial oral administration of nicardipine followed 1.25 h later by intravenous injection of the deuterium-labelled molecule (D3 nicardipine). To check that intravenous kinetics was not modified by the oral administration, an i.

Influence of digestive secretions and food on intestinal absorption of nicardipine.

The role of digestive absorption in the pharmacokinetics of nicardipine has been studied by the perfusion technique. Nicardipine (40 mg) was perfused in six healthy subjects at 5 ml/min for 2 h either in isotonic saline with (Experiment A) or without (B) an occlusive balloon isolating the test segment from digestive secretions, or in a nutrient solution (Experiment C). In Experiments A and B, 100% of nicardipine was absorbed from the jejunal lumen in a 25 cm test segment and in Experiment C it was slightly lower (94%).

Role of isoflurane on hemodynamic properties and disposition of nicardipine.

Nicardipine properties (30 micrograms/kg i.v.) were studied in a group of eight dogs awake and anesthetized with isoflurane 1.

Effect of nicardipine in elderly hypertensive patients.

The purpose of this study was to test tolerance and the antihypertensive effect of nicardipine, a new calcium antagonist, in 31 elderly patients aged 57-95 years. The study was conducted as a double-blind trial. The patients were allocated randomly to either active or placebo treatment.

Quantification of ketotifen and its metabolites in human plasma by gas chromatography mass spectrometry.

Gas chromatography mass spectrometry with selected ion monitoring has been used to develop a method for the quantification of ketotifen and its demethylated, 10-hydroxy and 10-hydroxy demethylated metabolites in human plasma. The minimum detectable concentrations for ketotifen and its demethylated metabolites were 50 pg ml-1 and 300 pg ml-1 for the 10-hydroxy metabolite. The methodology has been applied in studies of the kinetics of the drug in man, and plasma levels of the unchanged drugs and its metabolites in free and conjugated form are reported.

Estimation of the absolute oral bioavailability of pindolol by two analytical methods.

The absolute oral bioavailability of pindolol has been estimated by two analytical methods, fluorimetry and GLC-ECD. The study was carried out in six healthy subjects who received either i.v.

Pharmacokinetic aspects of guanfacine withdrawal syndrome in a hypertensive patient with chronic renal failure.

The unusual observation of a withdrawal syndrome due to guanfacine in a hypertensive patient with chronic renal failure led to a study of the kinetics of the drug in this patient. The principal pharmacokinetic parameters of guanfacine were greatly altered, with extended biotransformation and a decrease in the half-life compared to the values observed in other cases of severe renal insufficiency. Associated treatment with phenobarbital had had a considerable effect, as shown by the results of a further kinetic study 2 months after withdrawal of the phenobarbital.

Determination of 3-hydroxy-guanfacine in biological fluids by electron-capture gas-liquid chromatography.

An electron-capture gas-liquid chromatographic method was developed for measuring 3-hydroxy-guanfacine, the main metabolite of guanfacine in human plasma and urine. After extraction, the metabolite was derivatized by condensing the amidino group with hexafluoroacetylacetone and by methylating the NH and OH groups with methyl iodide. The obtained derivative possessed good bioanalytical gas chromatographic properties, using a capillary column.

Determination of pindolol in biological fluids by electron-capture GLC.

An electron-capture GLC method was developed for measuring pindolol in human plasma and urine. The unchanged drug was extracted with benzene from alkalinized plasma or urine using propranolol as the internal standard. Both compounds subsequently were back-extracted into 0.

Determination of guanfacine in biological fluids by electron-capture GLC.

A quantitative electron-capture GLC method with good sensitivity is described for the determination of guanfacine in human plasma and urine. By condensing its amidino group with hexafluoroacetylacetone, guanfacine is converted to a pyrimidino derivative with better GLC properties than the parent drug. This method allows the determination of guanfacine in plasma and urine at concentrations as low as 0.

The effect of food and clopamide on the absorption of pindolol in man.

Plasma levels and urinary excretion of pindolol were measured in each of two groups of eleven subjects in order to compare the absorption of the drug when administered alone in the fasting state, and either with food or Binaldix. The data were analyzed according to a one-compartment model with first order absorption. No significant differences in absorption of pindolol were obtained in each study.