Electromembrane extraction of polar basic drugs from plasma with pure bis(2-ethylhexyl) phosphite as supported liquid membrane.

Electromembrane extraction (EME) of polar basic drugs from human plasma was investigated for the first time using pure bis(2-ethylhexyl) phosphite (DEHPi) as the supported liquid membrane (SLM). The polar basic drugs metaraminol, benzamidine, sotalol, phenylpropanolamine, ephedrine, and trimethoprim were selected as model analytes, and were extracted from 300 µL of human plasma, through 10 µL of DEHPi as SLM, and into 100 µL of 10 mM formic acid as acceptor solution. The extraction potential across the SLM was 100 V, and extractions were performed for 20 min. After EME, the acceptor solutions were analyzed by high-performance liquid chromatography-ultraviolet detection (HPLC-UV). In contrast to other SLMs reported for polar basic drugs in the literature, the SLM of DEHPi was highly stable in contact with plasma, and the system-current across the SLM was easily kept below 50 µA. Thus, electrolysis in the sample and acceptor solution was kept at an acceptable level with no detrimental consequences. For the polar model analytes, representing a log P range from -0.40 to 1.32, recoveries in the range 25-91% were obtained from human plasma. Strong hydrogen bonding and dipole interactions were probably responsible for efficient transfer of the model analytes into the SLM, and this is the first report on efficient EME of highly polar analytes without using any ionic carrier in the SLM.

Pharmacokinetic study of three cardiovascular drugs by high-performance liquid chromatography using pre-column derivatization with 9,10-anthraquinone-2-sulfonyl chloride.

A new method was developed to analyze three cardiovascular drugs in rat plasma, Mexiletine hydrochloride (MXL), Methoxamine hydrochloride (MTX), and Metaraminol bitartrate (MTR), by high-performance liquid chromatography (HPLC) using 9,10-anthraquinone-2-sulfonyl chloride (ASC) as the derivatization reagent. The derivatization modes and conditions for this method were optimized. The quantitative analysis was achieved using a C18 column at room temperature (25 degrees C), with various volume ratios of methanol-water as the mobile phase and a detection wavelength at 256 nm. Analytical linearity was obtained for the method over the concentration range of 0.04-8.0 microg mL(-1) for all the three drugs. The lower limit of quantification (LLOQ) was 0.04 microg mL(-1). This method was successfully applied to the analysis of the three drugs in rat plasma and their pharmacokinetic studies. The t1/2 values of the three drugs in rats were found to be 5.38+/-0.61, 4.49+/-0.53, and 3.70+/-0.19 h for MXL, MTX, and MTR, respectively.

Planar chromatographic analysis and quantification of short-lived radioactive metabolites from microdialysis fractions.

A sensitive radiochromatographic method for the quantitative determination of compounds labelled with short-lived beta-emitting radionuclides in microdialysates is described. The method is well suited for microdialysis (MD) samples, which have small volumes and low concentrations of compounds. An 18F-labelled (beta+; T(1/2)=109.8 min) radiopharmaceutical, (1R,2S)-4-[18F]fluorometaraminol (FMR), was injected intravenously into rats, and microdialysis fractions were then collected from the blood at 15 min intervals. Fractions were analyzed for FMR and its radioactive metabolites by planar chromatography combined with digital photostimulated luminescence autoradiography. The lowest detectable 18F-radioactivity was 0.24 Bq/application and the limit of quantification was 0.31 Bq/application with 4-16 h exposure. The method was found to be highly sensitive and linear in the range of 0.1 Bq-2 kBq. This method thus allows the quantification of beta-emitting radiopharmaceuticals in sequential microdialysis fractions with good time-resolution.

Metaraminol uptake by human thrombocytes: a poor model for neuronal noradrenaline uptake.

The IC50 of a number of antidepressants and related drugs on the uptake of 1-metaraminol and serotonin into human thrombocytes, and of noradrenaline and serotonin into rat midbrain synaptosomes were compared. In accordance with previous reports, it was found that platelets provide a good model for the study of neuronal uptake of serotonin. Platelet uptake of 1-metaraminol, although correlated to some extent with noradrenaline uptake into synaptosomes, seems to be an unsatisfactory model for the neuronal uptake of the latter amine.

Distribution of metaraminol and its relation to norepinephrine.

A modified fluorometric procedure of high specificity and sensitivity id described for the analysis of metaraminol (MET) in biological material. With this method the distribution of MET was studied in the rat. Except for brain, peripherally administered MET was well distributed. Organs with a large population of norepinephrine (NE) storage vesicles such as the heart, spleen and adrenal, took up relatively large amounts of MET and retained it longer than those tissues with few vesicles such as the liver, lung and kidney. MET had a longer blood half-life than described for NE in other species. In part, this can be attributed to the lack of metabolism of MET as well as our finding that MET, unlike NE, was concentrated in the cellular fraction of blood. Under the conditions of these experiments there was no close correlation on a concentration or time basis with respect to the appearance and disappearance of MET and NE in various organs. This was particularly evident in the adrenal gland where MET resembled reserpine in that one unit of drug displaced many units of catecholamines. In this case, however, we did not rule out a possible contributing effect via the CNS.

Vasopressors for treating shock.

PIP: Shock must be treated by correcting the cause, for any treatment of hypotension or shock, as such, is only an adjunctive measure; but the hemodynamic manifestations also need treatment. Vasopressors are helpful and effective under the right circumstances. Unless the blood volume is normal, the use of drugs that block the sympathetic nervous system (e.g., phenoxybenxamine) can be extremely hazardous and hasten death. However, the effect of adrenergic blocking drugs in endotoxic shock and other types of toxic shock is still to be determined; use of such drugs should be considered experimental until the results have been studied more extensively. Clinically, the most common forms of vascular shock are associated with blood loss, myocardial infarction, and endotoxemia. Characteristic hemodynamics of each situation are presented tabularly, and the physicians need to understand the differences is emphasized. The pharmacology of vasopressors, relating primarily to hemodynamic considerations and the response to vasopressors when severe reduction in blood pressure is associated with the shock syndrome is discussed. Drugs that stimulate the adrenergic receptors in the heart and blood vessels, with the exception of isoproteronol, are commonly referred to as vasopressors. The adrenergic stimulators may be classified into 3 groups: alpha (phenylephrine hydrochloride), beta (epinephrine), and alpha-beta (l-norepinephrine). Because alpha stimulators do not usually increase cardiac output, alpha-beta and beta-adrenergic stimulators are generally the most useful for treating shock. Routine use of adrenergic stimulators with the exclusion of other therapies, however, is generally unwarranted.^ieng