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[Effect of beta-phenylethylamine derivatives on the central nervous system. II. Pharmacological effect of the intracerebral administration of metaraminol on the central nervous system].

Six hours after intracerebral administration, the central effects of metaraminol were examined with the following results. 1) Metaraminol in doses of 40 approximately 160 mug decreased spontaneous motor activity in mice as measured by the photo-cell counters method, the wheel cage method or the open-field test. Ptosis and catalepsy induced at these doses. 2) Metaraminol in doses of 40 approximately 80 mug which influenced the spontaneous motor activity in mice, blocked the avoidance behaviour but not escape. 3) Metaraminol in doses of 1.25 approximately 10 mug which did not influence the spontaneous motor activity in mice, markedly blocked the attaching response induced by the electroshock. 4) Ten min after intraventricular administration, metaraminol in a dose of 500 mug induced the arousal pattern of EEG in sensory cortex of cats and this pattern lasted for 30 min. Ninety min after administration, EEG tracings reverted to the drowsy pattern.

Aggression↗

3H-metaraminol releasing action of mescaline from rat hypothalamus in vitro.

The amine releasing action of mescaline was investigated in rat isolated hypothalamus labeled with 3H-metaraminol. Mescaline had no effect on the uptake of 3H-metaraminol but produced its release in a concentration-related manner. 4 x 10(-4) M mescaline, which produced submaximal effects was used for subsequent experiments. 3 x 10(-5) M cocaine had no effect on the 3H-metaraminol releasing action of mescaline. Mescaline was fully effective in Ca2+-free medium while 6 x 10(-2) M KCl was ineffective. 3 x 10(-7) M tetrodotoxin or 6 x 10(-5) M lidocaine partially blocked mescaline-induced release but substantially or completely blocked 3 x 10(-2) M KCl-induced release. Prior exposure of hypothalamus to 3 x 10(-4) M tyramine reduced the releasing action of mescaline. Thus, mescaline appears to release 3H-metaraminol both by Ca2+-independent (tyramine-like) and Ca2+-dependent (lidocaine-sensitive) mechanisms. 3 x 10(-4) M tyramine and 6 x 10(-2) M KCl released 14C from control hypothalamus labelled with 14C-mescaline, but not from reserpinized hypothalamus. The amounts of 14C recovered in 14C-mescaline labeled control and reserpinized hypothalamus at the end of 50 min of efflux were similar suggesting a poor retention of 14C-mescaline by storage particles.

Animals↗

Improved stability and release control of levodopa and metaraminol using ion-exchange fibers and transdermal iontophoresis.

Achievement of controlled drug delivery and stability of drugs during storage is a problem also in transdermal drug delivery. The objective of this study was to determine, whether an easily oxidized drug, levodopa, could be stabilized during storage using pH-adjustment and ion-exchange fibers. Controlled transdermal delivery of the zwitterionic levodopa was attempted by iontophoresis and ion-exchange fiber. Ion-exchange kinetics and transdermal permeation of a cationic (presumably more stable) model drug, metaraminol, were compared to the corresponding data of levodopa. Levodopa was rapidly oxidized in the presence of water, especially at basic pH-values. At acidic pH-values the stability was improved significantly. Ion-exchange group and the pH had a clear effect on the release of both the levodopa and metaraminol from the ion-exchange fiber. The adsorption/release kinetics of metaraminol were more easily controllable than the corresponding rate and extent of levodopa adsorption/release. Iontophoretic enhancement of drug permeation across the skin was clearly more significant with the positively charged metaraminol than with the zwitterionic levodopa. Ion-exchange fibers provide a promising alternative to control drug delivery and to store drugs that are degraded easily.

Delayed-Action Preparations↗

Metaraminol infusion for maintenance of arterial blood pressure during spinal anesthesia for cesarean delivery: the effect of a crystalloid bolus.

We randomly allocated women having elective cesarean delivery to receive either no bolus (Control Group, n = 31) or 20 mL/kg lactated Ringer's solution (Bolus Group, n = 35) IV before spinal anesthesia. An infusion of metaraminol started at 0.25 mg/min was titrated to maintain systolic arterial blood pressure in the target range 90%-100% of baseline. The total dose of metaraminol required up to the time of uterine incision was similar between the Control Group and the Bolus Group (3.62 +/- 1.20 vs 3.27 +/- 1.39 mg, P = 0.3). However, the Control Group required more metaraminol in the first 5 min (1.29 +/- 0.60 vs 0.96 +/- 0.58 mg, P = 0.025) and a faster maximum infusion rate (0.45 +/- 0.20 vs 0.32 +/- 0.13 mg/min, P = 0.002) compared with the Bolus Group. There was no difference between groups in regards to changes in systolic arterial blood pressure or heart rate over time, or maternal or neonatal outcome. We conclude that when metaraminol is used to maintain arterial pressure during spinal anesthesia for cesarean delivery, crystalloid bolus is not essential provided that sufficient vasopressor is given in the immediate postspinal period.

Adult↗

[Metaraminol does not prolong the duration of spinal anesthesia using glucose-free bupivacaine in the upper dermatomes].

The effects of metaraminol on the duration of plain bupivacaine spinal anaesthesia were investigated in a double-blind study of 80 elderly patients. Each patient received a basic solution of 0.5% plain bupivacaine to which was added either physiological saline, or 1 mg, 2 mg or 3 mg metaraminol. There were no significant differences between the four groups in the mean time from injection to recovery from analgesia in the two and four uppermost segments. However the addition of metaraminol increased the mean durations of analgesia at the L2 level and of the motor block. It is concluded that, in an attempt to prolong plain bupivacaine spinal anaesthesia in the uppermost segments, addition of metaraminol does not appear to be justified.

Aged↗

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.

Asthma↗

High-performance liquid chromatographic determination of metaraminol bitartrate in the presence of parabens.

A high-performance liquid chromatographic (HPLC) procedure was developed for the determination of metaraminol bitartrate in the presence of methylparaben and propylparaben. Reversed-phase ion-pair chromatography was employed using dioctyl sodium sulfosuccinate as the counterion. The current official USP procedure for the determination of metaraminol requires dilution, extraction, and measurement of UV absorption. The HPLC procedure is rapid and precise and correlates well with the USP XX procedure. It can be used for metaraminol injectables as well as the raw material.

Chromatography, High Pressure Liquid↗

The effect of prophylactic metaraminol on systemic hypotension caused by induction of anaesthesia with propofol in patients over 55 years old.

We conducted a double-blind, randomised, placebo-controlled study evaluating the efficacy of prophylactic metaraminol for preventing propofol-induced hypotension. Thirty patients aged 55-75 years undergoing general anaesthesia were randomly allocated to receive either metaraminol 0.5 mg or saline before administration of fentanyl 1 microg.kg(-1) and propofol 2 mg.kg(-1). Induction of anaesthesia was associated with a decrease in mean and systolic arterial pressure in both groups (p = 0.0001). However, there was no significant difference between the two groups. These results show that prophylactic use of metaraminol 0.5 mg does not prevent the decrease in blood pressure following fentanyl and propofol induction in older patients.

Adrenergic alpha-Agonists↗

Metaraminol-induced reversal of acute myocardial ischaemia associated with hypotension and refractory to intravenous nitroglycerin.

In seven patients, acute myocardial ischaemia associated with ST segment elevation (5.7 +/- 1.6 mm, mean +/- SEM) and arterial hypotension (systolic blood pressure 57 +/- 9 mmHg), was reversed within 9 min (mean time to reversal 274 +/- 45 s) by the intravenous administration of metaraminol (1.9 +/- 0.2 mg). This myocardial ischaemia was refractory to nitroglycerin and, in every patient, the increases in blood pressure induced by metaraminol (to a mean systolic blood pressure of 191 +/- 22 mmHg) preceded reversal of the ECG changes. It is suggested that, in some patients, transmural myocardial ischaemia of recent onset associated with hypotension can be reversed by transiently increasing blood pressure with metaraminol.

Aged↗

The effect of narcotic analgesics on the uptake of 5-hydroxytryptamine and (-)-metaraminol by blood platelets.

1. The effects of narcotic analgesic and related drugs were studied on the uptake of 5-hydroxytryptamine (5-HT) and (-)-metaraminol by blood platelets.2. The most potent drug in inhibiting the uptake of 5-HT (10 muM) by human platelets was methadone, followed by pentazocine>piminodine approximately pethidine approximately anileridine approximately cyclazocine approximately thebaine > dextropropoxyphene. Alphaprodine, papaverine, apomorphine, nalorphine, codeine, and morphine were almost without effect. Methadone was slightly less active than desipramine, and had 10% of the activity of imipramine under similar conditions. Naloxone did not antagonize the effect of methadone on 5-HT uptake.3. The most potent inhibitor of metaraminol (3 muM) uptake by human platelets was piminodine, followed by pentazocine>/=anileridine>cyclazocine=methadone > dextropropoxyphene approximately thebaine >/= papaverine approximately alphaprodine >pethidine>morphine. The activity of morphine was 1% of that of piminodine. Piminodine was more potent than desipramine and protriptyline under similar conditions. The order of potency of drugs studied in inhibiting the uptake of metaraminol by rabbit platelets was similar to that obtained with human platelets.4. The effects of the analgesics studied on inhibiting uptake of monoamines did not correlate with their pain-relieving properties.

Alphaprodine↗

Inhibitory effect of two steroids on the accumulation of [3H]metaraminol by rat tissues in vivo.

The present experiments were designed to investigate the effect of methylprednisolone and dexamethasone on tritiated metaraminol uptake in the whole animal. Rats received i.p. injections of methylprednisolone (5, 10 and 20 mg kg-1) or dexamethasone (1, 2 and 4 mg kg-1) on each of 3 consecutive days. Under light ether anaesthesia 5 min before death the rats received radioactive metaraminol (3 microgram kg-1) via the femoral vein. Samples of various organs were removed and prepared for scintillation counting. The highest radioactivity was observed in the lungs and heart, followed by the kidney medulla, aorta, kidney cortex and submaxillary gland. Both steroids significantly inhibited uptake of metaraminol in the tissues examined. Dexamethasone seems to be more potent that methylprednisolone. It is concluded that these steroids may modify the uptake mechanism responsible for inactivation of the sympathomimetic neurotransmitter.

Animals↗

Intracavernosal metaraminol for treatment of intraoperative penile erection.

Four patients developed penile erection when regional anaesthesia was induced with spinal block. In another patient, penile erection developed during fentanyl-induced general anaesthesia. Injection of metaraminol into corpus cavernosum successfully achieved detumescence in all these patients. The dose of metaraminol ranged from 10 to 25 micrograms, much less than that required for the treatment of vasodilator-induced priapism. Intracavernosal injection of metaraminol is a simple, effective and safe method for immediate relief of intraoperative penile erection. It is most useful when urogenital operation would be delayed by penile tumescence.

Adult↗

Effects of noradrenaline and metaraminol on isolated aortic strips and auricles obtained from untreated and reserpine-treated rabbits.

The isolated aortic strips of the untreated rabbits responded to noradrenaline in concentrations ranging from 20 to 160 ng/mL, whereas similar preparations from reserpine-treated animals responded to lower concentrations (from 2.5 to 10 ng/mL) and larger effects were produced by concentrations ranging from 20 to 160 ng/mL. Comparatively stronger concentrations (from 0.4 to 1.6 microgram/mL) of metaraminol were required to produce suitable contractile responses, which were not modified by reserpine pretreatment. On the isolated auricles obtained from untreated rabbits, noradrenaline was used in concentrations of 20 and 80 ng/mL, but these concentrations were reduced to 2.5 and 10 ngmL in the case of tissues obtained from reserpinized rabbits. Comparatively stronger (0.2 and 0.8 microgram/mL) concentrations of metaraminol were required to produce a stimulant effect on this preparation, and the sensitivity was not altered by reserpine pretreatment. These observations lead to the conclusions that though reserpine pretreatment produces a well-marked increase in the sensitivity of isolated rabbit aortic strips and auricles to noradrenaline, it does not modify the sensitivity of these preparations to metaraminol. Reserpine was used in 0.3 mg/kg doses injected subcutaneously for 3 successive days.

Animals↗

Metaraminol (Aramine) in the management of a significant amlodipine overdose.

OBJECTIVE: To report a patient with a significant amlodipine self-poisoning who failed to clinically respond to conventional treatment and was managed with metaraminol (Aramine). PATIENT: A 43-year old male presenting after ingestion of 560 mg amlodipine, who failed to respond clinically to treatment with fluid resuscitation, calcium salts, glucagon and norepinephrine/epinephrine inotropic support. MAIN RESULTS: Following a loading bolus of 2 mg and intravenous infusion (83 microg/min) of metaraminol (Aramine) there was improvement in his blood pressure, cardiac output and urine output. CONCLUSIONS: This is the first case report of the beneficial use of metaraminol (aramine) in the management of significant amlodipine poisoning unresponsive to conventional therapy.

Adrenergic alpha-Agonists↗

Fluorometric determination of metaraminol bitartrate injection.

A fluorescence assay for metaraminol bitartrate injection has been developed which uses o-phthalaldehyde as a fluorogenic reagent, and dose not require prior isolation of metaraminol. It is 50 times more sensitive than the USP assay. Six analyses of 2 vials of the same lot of metaraminol bitartrate injection gave 96 +/- 0.4% of label declaration.

Dosage Forms↗

Effects of metaraminol bitartrate on intraocular pressure in dogs under halothane anesthesia.

The effects of metaraminol bitartrate on intraocular pressure (IOP) were studied in dogs anesthetized with halothane. Forty-five healthy, adult, mixed-breed dogs, of both sexes, were divided into three groups of 15 dogs each (GI, GII and GIII) and maintained under general anesthesia with halothane after tranquilization with levomepromazine and induction with thiopental. Saline (0.9%) was administered intravenously (IV) to GI through continuous infusion, at a velocity of 0.125 mL kg-1 min-1. GII and GIII received metaraminol 0.004% IV, at a dose of 5 &mgr;g kg-1 min-1, at 0.125 mL kg-1 min-1 and at a dose of 2 &mgr;g kg-1 min-1, at 0.06 mL kg-1 min-1, respectively. IOP was measured by applanation tonometry (Tono-Pen) before and during anesthesia. Results showed that IOP decreased in GI, increased in GII, and remained at basal levels in GIII. Continuous infusion of metaraminol at 2 &mgr;g kg min-1 maintained IOP at pretest levels, while infusion at 5 &mgr;g kg-1 min-1 produced an elevation of IOP.

Journal Article↗

RELEASE OF METARAMINOL (ARAMINE) FROM THE HEART BY SYMPATHETIC NERVE STIMULATION.

Cats were injected intravenously with metaraminol, an amine which depletes norepinephrine from the sympathetic nerve endings; their hearts were then perfused in vitro. Stimulation of the sympathetic nerve supply released metaraminol from the hearts, demonstrating that a synthetic compound can replace norepinephrine and serve as a transmitter at adrenergic nerve endings

Cats↗

[125I] radioiodinated metaraminol: a new platelet-specific labeling agent.

In our search for a platelet-specific labeling agent, metaraminol (MA), a low-toxic pharmaceutical for the treatment of hypotension and cardiogenic shock, attracted our attention. Its active incorporation and accumulation by platelets have been recognized. At first, the preparation of 125I radioiodinated metaraminol (125I-MA) was carried out using the chloramine-T method. Then, upon the harvest of platelets as platelet-rich plasma (PRP), their labeling with this new radiopharmaceutical was easily performed by incubation for 10 min at 37 degrees C. The cell-labeling efficiency was dependent on cell density, reaching 63.0% +/- 3.1% at 2.4 X 10(9) cells/ml. The specific incorporation of 125I-MA by an active transport system similar to that of 5-hydroxytryptamine (5-HT) as well as by passive diffusion was demonstrated. In in vitro studies, the unaltered state of 125I-MA-labeled platelets with their cellular functions fully retained was estimated. In vivo studies carried out in rabbits with induced thrombi in the femoral artery showed a rather rapid disappearance of the radioactivity from circulating blood, reaching a high thrombus-to-blood activity ratio of 19.8 +/- 4.3 within 30 min of the administration of 125I-MA-labeled autologous platelets. Thus, with the potential availability of 123I, 123I-MA-labeled platelets appear to be a promising agent for thrombus imaging using single-emission computed tomography (CT) studies.

Animals↗