Development of analytical methods for the detection of metaraminol in the horse.
Aramine (metaraminol bitartrate) has been found in the possession of horse trainers and veterinarians who have been investigated for possible inappropriate drug administration to racing horses. Metaraminol (3-hydroxyphenylisopropanolamine) is a sympathomimetic amine that directly and indirectly affects adrenergic receptors, with alpha effects being predominant. Because it has the potential to affect the performance of a racing horse, its use is prohibited. In the present study, methods for the detection of metaraminol were developed. Metaraminol was found to be extracted with poor recovery (< 50%) from aqueous solutions by routine basic extraction or cation exchange/reversed-phase solid-phase extraction techniques. However, an extractive acetylation method gave good (> 90%) recovery of metaraminol from aqueous samples. Sequential urine samples collected from horses administered metaraminol intramuscularly at 0.02, 0.10, and 0.23 mg/kg were extracted by the developed extractive acetylation procedure and analyzed by gas chromatography-mass spectrometry (GC-MS) in full-scan and selected ion monitoring modes. Norphenylephrine was used as an internal standard for quantitative analysis. The maximum concentration of metaraminol occurred between 1 and 2 h postadministration. Metaraminol was detected in the 0.23 mg/kg administration urine for 24 h postadministration. Metaraminol was detected for the 0.10 and 0.02 mg/kg doses for approximately 8 h postadministration. No apparent biotransformation products were observed in a reaction mixture of metaraminol and horse liver microsomal reaction mixture. Comparison of gas chromatograms of the extracts of the postadministration urine samples with those of the pre-administration samples failed to reveal any exogenous compound other than metaraminol. (+info)
Methanol solvent may cause increased apparent metabolic instability in in vitro assays.
Methanol was widely used as a substrate-delivering solvent in in vitro metabolic stability screenings. Its interaction with enzyme activities, particularly those of cytochrome P450s, has been investigated extensively in the past. Little was known about the interaction of methanol, whether direct or indirect, with substrates. The present study provided data for the first time to show that use of methanol may result in the formation of artifacts, which could mislead the metabolic stability information. The disappearance of LAQ094, metaraminol, and (-)-isoproterenol following 1-h incubation with human liver microsomes was 73, 85, and 66%, respectively, in the presence of 1% methanol, but was only 3, 15, and 24%, respectively, in the absence of organic solvent. The dramatically increased instability in the presence of methanol of these three compounds, each with 1,2-diamino or 1,2-amino hydroxy functional groups, was due to the formation of [M + 12] products resulting from condensation reaction of the substrates with formaldehyde. Formaldehyde was formed from methanol by human liver microsomal enzymes with an apparent K(m) of 35 mM and a V(max) of 7.9 nmol/min/mg of protein. The concentration of formaldehyde reached as high as 600 microM following a 60-min incubation. The [M + 12] products were characterized as five-membered heterocycles by liquid chromatography and tandem mass spectrometry analysis. Inclusion of 10 mM glutathione prevented the formation of such artifacts and is therefore suggested for future in vitro screenings. Our study also documented the novel finding of enzyme-dependent conversion of NADPH to nicotinamide in microsomal incubations. (+info)
Comparison of metaraminol and ephedrine infusions for maintaining arterial pressure during spinal anesthesia for elective cesarean section.
BACKGROUND: Although ephedrine is usually recommended as the first-line vasopressor in obstetrics, its superiority over other vasopressors has not been proven in humans. METHODS: In a double-blind study, the authors randomized women having elective cesarean section with spinal anesthesia to receive an intravenous infusion of ephedrine, starting at 5 mg/min (n = 25), or metaraminol, starting at 0.25 mg/min (n = 25), titrated to maintain systolic arterial pressure in the target range 90-100% of baseline. Umbilical cord gases, maternal hemodynamics, uterine artery puLsatility index, and Apgar scores were compared. RESULTS: Systolic arterial pressure was maintained more closely in the target range in the metaraminol group compared with the ephedrine group. In the metaraminol group, umbilical arterial pH was greater (median and interquartile range, 7.31 and 7.31-7.33 vs. 7.24 and 7.14-7.29; P < 0.0001), and umbilical venous pH was greater (7.36 and 7.35-7.38 vs. 7.33 and 7.26-7.34; P < 0.0001) compared with the ephedrine group. No patient in the metaraminol group had umbilical arterial pH less than 7.2, compared with nine patients (39%) in the ephedrine group (P = 0.0005). Apgar scores were similar between groups. Changes in uterine artery pulsatility index were similar between groups. CONCLUSIONS: When used by infusion to maintain arterial pressure during spinal anesthesia for cesarean section, metaraminol was associated with less neonatal acidosis and more closely controlled titration of arterial pressure compared with ephedrine. (+info)
Relative uptake, metabolism, and beta-receptor binding of (1R,2S)-4-(18)F-fluorometaraminol and (123)I-MIBG in normotensive and spontaneously hypertensive rats.
The objective of the study was to compare relative uptake, metabolism, and beta-receptor affinity of the new positron-emitting uptake-1 tracer (1R,2S)-4-(18)F-fluorometaraminol (4-FM) with those of the SPECT pharmaceutical meta-(123)I-iodobenzylguanidine (MIBG) in Wistar Kyoto (WKY) rats and spontaneously hypertensive (SHR) rats. METHODS: No-carrier-added 4-(18)F-FM was applied to SHR and WKY rats in vivo and to retrogradely perfused hearts in vitro. Cardiac and extracardiac distribution was assessed, and metabolite formation was determined by thin-layer chromatography. The in vivo experiments were repeated with no-carrier-added (123)I-MIBG. By means of autoradiography, the beta-receptor affinity of 4-FM was compared with that of MIBG and propranolol (10 micromol/L) through displacement of (125)I-iodocyanopindolol (1.5 pmol/L) in slices of heart and spleen. RESULTS: Cardiomyopathic hearts showed heterogeneous 4-(18)F-FM uptake with gradients up to 3.6 in vivo and in vitro between different regions of the heart. Control hearts showed such gradients in 4-(18)F-FM uptake only in vitro. (123)I-MIBG exhibited a less heterogeneous in vivo distribution in SHR hearts. Extracardiac differences between WKY and SHR were found for uptake of 4-(18)F-FM in the spleen (63.3% plus minus 4% vs. 38.8% plus minus 5.7% of cardiac activity) and for renal uptake of (123)I-MIBG (373% plus minus 27% vs. 81.4% plus minus 17% of cardiac activity). Metabolites of 4-(18)F-FM were found only in the liver and those of (123)I-MIBG were found in the liver and kidney with a nearly equal relative fraction in both types of animals of about 20%, 60%, and 30%, respectively. 4-FM suppressed cardiac-specific beta-receptor binding of (125)I-iodocyanopindolol in heart and spleen of both types of animals significantly, whereas MIBG had almost no effect. CONCLUSION: The more heterogeneous cardiac distribution of 4-(18)F-FM suggests that it reflects alterations in uptake-1 better than (123)I-MIBG in addition to the possibility of quantification and higher spatial resolution by PET compared with SPECT. Altered biotransformation in cardiomyopathic diseases may also impair the evaluation of (123)I-MIBG-SPECT data. The beta-receptor binding of 4-(18)F-FM must be further elucidated. (+info)
No-reflow phenomenon in the cerebral circulation of the gerbil.
The no-reflow phenomenon has been produced in the cerebral hemispheres of the gerbil by 30 minutes of bilateral carotid artery occlusion. The no-reflow phenomenon was found to develop in relation to the fall in blood pressure which occurred on release of bilateral carotid clips. Metaraminol tartrate intravenously prevented the fall of blood pressure and significantly reduced the occurrence of the no-reflow phenomenon. Metaraminol tartrate, however, did not alter the morbidity or mortality of carotid artery occlusion for 30 minutes. There is thus no support from these experiments for the view that the no-relow phenomenon plays an important functional role in the reversibility of the effects of severe cerebral ischaemia. (+info)
BACTEREMIC SHOCK--A MEDICAL EMERGENCY.
Bacteremic shock is second in frequency only to myocardial infarction as a cause of hypotension and death in hospitalized medical patients. The clinical course is marked by fever, usually with chills, and hypotension with a full pulse and warm extremities, followed by shock, often resistant to treatment. Anticipation of this complication in patients with certain predisposing diseases or factors facilitates early recognition of the symptoms and signs of bacteremic shock and prompt treatment. Early and effective treatment of the offending infection often prevents progression of hypotension to the stage of frank vascular collapse. (+info)
SHOCK CAUSED BY CONTINUOUS INFUSION OF METARAMINOL BITARTRATE (ARAMINE).
Increasing doses of metaraminol bitartrate (Aramine) in a continuous intravenous infusion were used to support the blood pressure in four patients. Under such treatment a state of shock developed, characterized by intense peripheral vasoconstriction, hypotension and anuria. In spite of an adequate fluid intake all patients showed severe hemoconcentration, and a critically low plasma volume could be demonstrated in two. While metaraminol (Aramine) was ineffective, noradrenaline still caused a moderate blood pressure response. Treatment with plasma expanders (Intradex) and small doses of noradrenaline (Levophed) resulted in transient improvement in one patient and complete recovery from shock in three. The peripheral vasoconstriction persisted up to 12 hours and renal function improved on the second day after the withdrawal of metaraminol. The etiology of this shock syndrome is believed to be similar to that of experimental shock produced with adrenaline and noradrenaline. (+info)
HOSPITAL EXPERIENCE WITH CARDIAC RESUSCITATION.
In three cases of cardiac arrest in which resuscitation was successful, there were striking similarities. The patients were men with anterior myocardial infarction and the mode of cardiac arrest was ventricular fibrillation. Corrective action was begun promptly after arrest occurred. In each case vasopressor agents were required for three to five days after resuscitation before the cardiovascular system was able to maintain a normal blood pressure without this aid. Convalescence was satisfactory and each patient returned to his usual occupation. The procedure that was used for cardiac resuscitation was based on artifical respiration (by any of several methods) and artificial circulation by external cardiac compression to provide a flow of oxygenated blood to the brain. Once this is established, time is afforded to determine what other steps are needed. (+info)