Mephentermine Research Articles

The formation of metabolites of mephentermine by microsomal and cytosolic preparations of male Wistar rat livers.

1. Metabolites of mephentermine (MP), phentermine (Ph), p-hydroxy-MP, p-hydroxy-Ph, N-hydroxy-MP and N-hydroxy-Ph on incubation with rat liver microsomal and cytosolic preparations were identified by g.l.c. and g.l.c.-mass spectrometry. 2. Identification of the metabolites indicated the following new metabolic routes of MP: NADPH-dependent microsomal formation of p-hydroxy-MP from MP, of p-hydroxy-Ph from p-hydroxy-MP, and the NADH-dependent microsomal formation of Ph from N-hydroxy-Ph.

Metabolism of mephentermine in male guinea pigs and male mice

1. Urinary metabolites of mephentermine (MP), after i.p. administration of MP to male Hartley guinea pigs and mice, were identified by g.l.c.-electron impact (EI) mass spectrometry. Excretion of urinary radioactivity, and metabolites of 3H-MP, after i.p. administration, were determined by preparative t.l.c.-liquid scintillation counting. 2. About 27% of the radioactivity administered was excreted in the 24 h urine of guinea pigs, and 36% dose was excreted in 5 days. In mice, about 47% of the radioactivity was excreted in the 24 h urine, and 52% in 5 days. 3. Excretion rates of metabolites detected in the 24 h urine of guinea pigs were phentermine (Ph, 7.8%), a conjugate of N-hydroxyphentermine (N-hydroxy-Ph, 3.6%), p-hydroxyphentermine (p-hydroxy-Ph, 1.0%) and its conjugate (2.9%), and other metabolites (conjugates of MP and Ph, N-hydroxymephentermine (N-hydroxy-MP) and its conjugate, p-hydroxymephentermine (p-hydroxy-MP) and its conjugate, and N-hydroxy-Ph; less than 1.0%). The rates of excretion for mice were Ph (11.7%), conjugates of p-hydroxy-MP (3.1%), Ph (2.7%) and p-hydroxy-Ph (1.6%), and N-hydroxy-Ph (1.2%) and other metabolites (conjugates of MP and N-hydroxy-Ph, N-hydroxy-MP and its conjugate, p-hydroxy-Ph, and p-hydroxy-MP; less than 1.0%). 4. These results indicate that MP administered to mice is metabolized mainly to Ph and p-hydroxy-MP by N-demethylation and p-hydroxylation of the parent compound, and in guinea pigs the primary metabolic reaction of MP is N-demethylation producing Ph.(ABSTRACT TRUNCATED AT 250 WORDS)

Isolation of urinaryp-hydroxylated metabolites of mephentermine and phentermine in male Wistar rats

1. p-Hydroxymephentermine (p-hydroxy-MP) and p-hydroxyphentermine (p-hydroxy-Ph) were isolated as hydrochlorides from urine of male Wistar rats repeatedly dosed with mephentermine (MP). In addition, p-hydroxy-Ph was isolated as the hydrochloride from urine of the rats dosed with phentermine (Ph). 2. These results substantiate previous indications that p-hydroxylation of MP and Ph was a primary metabolic reaction in the rat.

Urinary and biliary metabolites of mephentermine in male Wistar rats.

1. Excretion of urinary and biliary radioactivity, and metabolites of [3H]mephentermine (MP), after i.p. or subcutaneous administration of [3H]MP to male Wistar rats, were determined by preparative t.l.c.-liquid scintillation counting. 2. About 45% of the radioactivity administered i.p. was excreted in the 24 h urine. The major urinary metabolite was conjugated p-hydroxymephentermine (p-hydroxy-MP), which accounted for about 18% of the administered radioactivity in the 24 h urine. 3. About 4.2% of the radioactivity administered subcutaneously was excreted in bile during 24 h. The major biliary metabolite was conjugated p-hydroxy-MP, which accounted for about 39% of the radioactivity excreted in the bile in 24 h. 4. Urinary and biliary minor metabolites detected were phentermine (Ph), p-hydroxyphentermine (p-hydroxy-Ph), N-hydroxyphentermine (N-hydroxy-Ph), N-hydroxymephentermine (N-hydroxy-MP) and their conjugates, and conjugated MP. 5. The conjugates were considered to be glucuronides from the inhibitory effect of saccharic acid 1,4-lactone on their hydrolysis with beta-glucuronidase. 6. Biliary excretion rates of conjugated p-hydroxy-Ph and p-hydroxy-MP reached maxima at 3 to 4 h, and non-conjugated metabolites were maximal at 1 to 2 h, after administration. 50% of the biliary metabolites was excreted within 5 h.

Compatibiiity of mephentermine sulfate with hydrocortisone sodium succinate or aminophyiiine in 5% dextrose injection

The compatibility and stability of mephentermine sulfate with hydrocortisone sodium succinate or aminophylline in 5% dextrose injection were studied. Mephentermine sulfate injection (equivalent to mephentermine 300 mg) was added to both hydrocortisone sodium succinate injection (equivalent to hydrocortisone 100 mg--admixture I) and aminophylline injection 250 mg (admixture II), each in 5% dextrose injection 400 ml. The solutions were stored in sealed USP type I containers and stored at 0-4 degrees C, 30 +/- 2 degrees C, and 45 +/- 1 degree C. Aliquots were drawn initially and at 4 and 24 hours for pH, drug content, and degradation product determinations. Mephentermine sulfate content was analyzed by a spectrophotometric method involving ion-pair extraction with tropaeolin 00. Hydrocortisone sodium succinate and aminophylline were analyzed by color reaction with isoniazid and UV spectrophotometry, respectively. The content of mephentermine and total hydrocortisone showed no change in admixture I under all test conditions. Hydrocortisone sodium succinate ester hydrolyzed slowly, but not more than 5% after 24 hours at 45 degrees C. There was no appreciable loss of mephentermine sulfate or aminophylline potency in admixture II. The pH of the solutions did not change over the period of study. The results indicate that both admixtures were compatible and stable under the tested storage conditions for at least 24 hours.

Ion Exchange Method for Determining Mephentermine Sulfate in Drug Formulations: Collaborative Study

Ion exchange chromatography is used to separate mephentermine sulfate from drug formulations. The drug is subsequently measured by ultraviolet spectrophotometry. Assays on 4 commercial samples of tablets and injectables gave recoveries from 97.6 to 104% of declared. A collaborative study involving 2 tablet and 2 liquid formulations gave mean recoveries ranging from 94.7 to 99.3% and coefficients of variation from 1.39 to 2.00%.

Differential effects of the optical isomers of amphetamine on neuronal activity in the reticular formation and caudate nucleus of the rat

The activity of neurons in the caudate nucleus and reticular formation was recorded following intraperitoneal injection of the optical isomers of amphetamine. In general, d-amphetamine sulfate (2.0 mg/kg) produced an initial increase in firing rate of neurons in the caudate nucleus approximately 8—10 min following intraperitoneal injection, and a subsequent depression of firing rate which lasted for a period of time of from 70 to 120 min. Similar injections of l-amphetamine sulfate produced only a depression of activity in the caudate nucleus which was less marked and of lesser duration. Mephentermine sulfate (6.0 mg/kg), a peripheral sympathomimetic, did not produce these effects. Both d-amphetamine and l-amphetamine sulfate at the same dose produced an increase in firing rate of neurons in the reticular formation, although that produced by the l-isomer was less marked and of lesser duration. Mephentermine sulfate also produced an increase in reticular formation neuronal activity comparable to that produced by l-amphetamine sulfate. In some cases, neuronal activity was held for prolonged periods of time following injection. In the caudate nucleus, a rebound increase in firing rate was observed following the marked depression produced by both isomers of amphetamine. A rebound depression of activity was observed in the reticular formation following the initial increase in neuronal activity produced by these drugs. The results are discussed in terms of the known biochemical and behavioral effects of the stereoisomers of amphetamine.

The action of d-amphetamine on spontaneous activity in the caudate nucleus and reticular formation of the rat

Dextro-amphetamine sulfate injected intraperitoneally in paralyzed, locally anesthetized rats, resulted in a biphasic alteration in spontaneous activity in the caudate nucleus. An initial dose-dependent potentiation of activity occurs 510 min after injection followed by a prolonged dose-dependent depression of activity which may last as long as several hours. Similar injections result in a different time-course of alterations in the mesencephalic reticular formation consisting of a prolonged increase followed by a depression of spontaneous activity. Spontaneous activity in the caudate nucleus was relatively unaffected by mephentermine sulfate, a peripheral sympathomimetic. The depression of activity produced by amphetamine could be reversed by haloperidol, a dopaminergic blocking agent. Haloperidol injected alone produced a transient potentiation of activity followed by a return to control firing rate. These results provide electrophysiological support for the inhibitory synaptic function of dopamine in the caudate-putamen and for the alleged action of amphetamine and haloperidol at these sites. Both the differential biochemical and neurophysiological effects of amphetamine on the caudate nucleus and reticular formation may have functionally significant behavioral consequences.

Assay of Official Injections of Amine Salts

A modification of a method previously suggested for mephentermine sulfate injection was applied to some official injections containing at least 20 mg./ml. of amine salt, the amine base of which is soluble and stable in chloroform. The method involves: (a) distributing the aqueous sample over a mixture of chro-matographic magnesium oxide and high flow rate, purified, siliceous earth held in a coarse-porosity, sintered-glass filtering funnel; (b) eluting the liberated base with several small portions of warm chloroform into glacial acetic acid; and (c) titrating the eluates with standard 0.1 N perchloric acid using p-naphtholbenzein indicator.

Intralingual injection site for emergency stimulant drugs

Microcirculation studies at this Institute have indicated a profuse supply of capillary blood to the lateral ventral aspect of the tongue muscles. The present study tested the value of this intralingual area as an injection site for stimulant drugs in an emergency. Effects of four drugs—epinephrine, aminophylline, metaraminol bitartrate, and mephentermine sulfate—were investigated after intralingual and intravenous injections. Physiologic effects monitored were the electrocardiograph reading, respiratory rate and depth, pulse rate, and blood pressure in ten adult monkeys, with the pattern of drug injection varied in different animals. For all drugs tested by both injection routes, no physiologic effect required more than 35 seconds to reach its maximum. In each case the physiologic response occurred in sufficient magnitude, time, and duration to result in resuscitation.

Assay of Mephentermine and Its Preparations

Mephentermine sulfate is assayed by direct titration in glacial acetic acid with perchloric acid titrant and p-naphtholbenzein indicator. Mephentermine sulfate tablets are assayed by mixing the finely powdered sample with purified siliceous earth and magnesium oxide held in a fritted-glass filtering funnel, moistening the mixture with water to release the base, eluting the base with warm chloroform, receiving the eluate in glacial acetic acid, and titrating it with perchloric acid using p-naphtholbenzein indicator. Individual tablets are assayed by receiving the eluate into 10.0ml. of 0.1 N sulfuric acid, shaking to extract the base from the chloroform, and determining the mephentermine spectrophotometrically using the base-line correction method proposed by Rotondaro and the assayed tablet mixture as the standard. Mephentermine sulfate injection is assayed by adsorbing the sample into a controlled amount of siliceous earth-magnesium oxide mixture and proceeding with elution and titration as for the tablets. Loss in drying specifications for mephentermine sulfate are supported by thermo- gravimetric data.

Cardiovascular Effects of Mephentermine Sulfate in Man and Their Modification by Anesthetic Agents

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Cardiovascular effects of mephentermine sulfate* in man and their modification by anesthetic agents

cardiovascular effects of mephentermine sulfate* in man and their modification by anesthetic agents

The effect of mephentermine on isolated dog hearts, normal and pretreated with reserpine.

The inotropic activity of the non-catechol sympathomimetic amine, mephentermine sulphate, on the failing dog heart-lung preparation, was 1/10 to 1/20 that of adrenaline. Mephentermine showed no inotropic effect on preparations from animals pretreated with reserpine. The chronotropic and "calorigenic" actions of mephentermine were tested on modified heart-lung preparations to permit a more accurate measurement of coronary flow, and were found to be greater than its inotropic effect relative to adrenaline. Furthermore, the action of mephentermine was longerlasting than that of adrenaline. If adrenaline was infused 15 min after the termination of mephentermine administration and when the action of the latter was still at a maximum, a further increase in heart rate and especially oxygen consumption was observed. In preparations from dogs treated with enough reserpine to deplete the heart of noradrenaline, mephentermine had only slight chronotropic and calorigenic actions. However, further addition of adrenaline after a 15 min pause caused a rise in heart rate, oxygen consumption, and coronary flow which almost duplicated the additive effects of both amines on the preparations not treated with reserpine. It would appear that adrenaline acted on its own and in addition "restored" the action of mephentermine on the reserpinized preparations. The action of adrenaline alone on reserpinized preparations was not increased compared with that on normal preparations. These observations are relevant to a consideration of the mechanism of action of non-catechol sympathomimetic amines on the heart, and are in harmony with the concept that mephentermine, a non-catechol amine, requires the presence of added or stored catechol amines for its action. Reserpine treatment did not alter the mechanical efficiency of the heart despite its depletion of noradrenaline.

The circulatory response to smoking: The effect of small doses of hexamethonium and of mephentermine on the pattern of response

Observations were made on the circulatory response to smoking a single cigarette following small intravenous injections of hexamethonium, of mephentermine, or of placebo (isotonic sodium chloride solution). These substances were given in random order in a series of separate double blind tests. Seven healthy white male subjects had 8 tests apiece on different days, 3 with each of the active pharmacological preparations and 2 with the placebo. Two other subjects had smaller numbers of tests. The aim was to produce minimal measurable effects, and since sensitivity varies from subject to subject, the appropriate dose had to be found by experiment. After injection of the placebo, the average circulatory response to smoking one cigarette was similar to that in a larger series previously reported, in which no injection was given. From the duplicate placebo tests an estimate of the average variability of these tests could be made. Hexamethonium did not influence the mean response to smoking so far as could be judged by a paired comparison with the placebo tests. Individual differences were noted, but it is difficult to assess their importance. When the mephentermine sulfate and placebo tests were compared, both the change in systolic pressure and in cardiac output after smoking were significantly altered by mephentermine. The other variables were not thus affected. The constancy within the individual of the measurements obtained after a cigarette is smoked, previously reported as the “ceiling phenomenon,” is impaired but not entirely abolished by small doses of these drugs. In this respect the “ceiling phenomenon” resembles a cardiovascular homeostatic mechanism.

Hemodynamic Effects of a Pressor Amine (Methoxamine) with Predominant Vasoconstrictor Activity

A pressor amine (methoxamine) which produces peripheral vasoconstriction, while lacking a significant, direct, positive inotropic effect upon ventricular heart muscle, has been shown to produce hemodynamic effects that are in distinct contrast to those resulting from the injection or infusion of l -epinephrine and l -norepinephrine in "physiologic" concentrations or of mephentermine sulfate. The latter 3 amines, possessing a positive inotropic action in addition to varying vasoconstrictor effects, decrease right and left atrial mean pressures while increasing femoral and pulmonary arterial pulse and mean pressures, right and left ventricular stroke works and the cardiac index. Methoxamine injection or infusion, in contrast, resulted in linear increases in the calculated total peripheral resistance and left and right atrial mean pressures. There was a simultaneous rise in right and left ventricular stroke works which were maintained until a maximum rise in the mean arterial pressure was reached. The average stroke volume indices were maintained at near control values in both blocked and unblocked animals. The cardiac index of the normal unblocked dogs decreased in proportion to the decrease in heart rate. Following the peak pressor response to methoxamine, a progressive fall in mean femoral arterial pressure occurred resulting from ventricular failure rather than "tachyphylaxis" to the vasoconstrictor activity of methoxamine. This decrease in systemic arterial pressure was accompanied by: (1) a further rise in calculated total peripheral resistance and in right and left atrial mean pressures, and (2) a fall in right and left ventricular stroke work and stroke volume indices and in the cardiac indices.

Use of cardiotonic agent (mephentermine) in myocardial depression due to potassium.

Recent studies have demonstrated that prolonged induced cardiac arrest is followed by myocardial damage^1,2and depressed ventricular function³in the dog. It has also been shown that this depression may be limited by prophylactic digitalization⁴and by hypothermia.⁵' The present communication reports our experiences with the use of mephentermine sulfate (Wyamine), a cardiotonic and pressor agent,⁶in dogs in which myocardial function has been depressed by a 30-minute period of asystole induced by potassium citrate. <h3>Methods</h3> Mongrel dogs of 8.5 to 12.5 kg. body weight were used. Anesthesia was induced by intravenous thiopental sodium. Complete respiratory paralysis was obtained with intravenously administered succinylcholine. The animals were respired⁷with 100% oxygen at pressures of 15 to 20 cm. water. Esophageal temperature was recorded by a thermistor probe. Femoral arterial pressure was measured by means of a P23A Statham transducer. Arterial blood was sampled by way

Mephentermine.

Mephentermine.

Treatment of cardiac shock by metaraminol.

An 80% mortality has been reported in shock following acute cardiac infarction (Hellerstein et ai, 1952 ; Griffith et al., 1954). However, this figure is probably an underestimate, as it is based on hospital experience alone. The early use of pr?ssors has been advocated by Griffith et al. (1954): in a series of cases treated for shock within three hours of its onset only 13% died. Noradrenaline infusions have reduced the overall mortality to between 40% and 50% (Mover et al., 1953 ; Sampson and Zipser, 1954 ; Garai and Smith, 1958). However satisfactory noradrenaline may be in hospital practice, the use of a drip in a patient's home presents many difficulties, and this drug is rarely used in domiciliary treatment of shock. This complication may therefore persist for several hours, with a consequently poorer prognosis, before the patient reaches hospital. Moreover, in some cases the shock is too severe to allow removal to hospital. The immediate requirement for such patients is a drug similar to noradrenaline, yet possible to administer by intravenous, intramuscular, or subcutaneous injections. Such a substance might be used either for continued therapy at home or to counter shock temporarily to allow transfer to a hospital. Noradrenaline has been shown to increase the contractile force of the heart, increase coronary flow, and raise the peripheral vascular resistance without inducing arrhythmias or tachycardia (Burn and Hutcheon, 1949 ; Gazes et al., 1953 ; Denison et ai, 1956). Other pressors such as phenylephrine work by a purely peripheral action on the systemic resistance and have been found less effective in the treatment of cardiac shock. This difference is attributed to the direct myocardiai action of noradrenaline (Gazes et al., 1953). Mephentermine sulphate has been used successfully in the treatment of cardiac shock by Brofman et al. (1952), Hellerstein et al. (1952), and Garai and Smith (1958). This drug may be given by injection or by drip, and causes a rise in systemic pressure and an increased coronary blood flow. Recent experimental studies in dogs have shown that the pressor effects of mephentermine are due to its central action rather than to peripheral vasoconstriction (Welch et al, 1958). Clinically the only drawback to this drug is the occasional development of tachyphylaxis : an increasing refractoriness to repeated injections necessitating larger doses of mephentermine in order to achieve a satisfactory pressor response. Metaraminol bitartrate ( aramine ; laevo-1 (hydroxyphenyl) 2 amino 1 propanol hydrogen d tartrate) seems to possess the properties of direct action on the heart as well as on the peripheral resistance. It may be administered by repeated injections without the development of tachyphylaxis. In experimental cardiac ischaemia Sarnoff et al. (1954) produced a fall of arterial pressure, of cardiac output, and of ventricular stroke work, with a rise of left atrial pressure. Subsequent intravenous metaraminol returned these values to near normal levels and increased coronary flow. This and other experiments indicated that metaraminol produced a sustained increase of myocardial contractility without requiring increased coronary flow per unit of ventricular work. This central action, together with the peripheral effects, achieve the most desirable results?namely, increased arterial pressure and cardiac output at a low atrial pressure. No arrhythmias or tachycardia were observed.

Mephentermine sulfate for treatment of arterial hypotension.

The possibility of using mephentermine sulfate to treat various types of hypotension was studied in three groups of patients. Group 1 consisted of 10 patients who had hypotensive episodes during a rigorous course of treatment for essential hypertension or hypertensive renal disease. Group 2 consisted of 10 patients who had hypotensive episodes related either to diabetes or to cerebral arteriosclerosis. Group 3 consisted of 10 patients with a variety of nonspecific hypotensive syndromes. Measurements of blood pressure, of maximum ventricular excursion by roentgenkymography, of the I-J wave in ballistocardiograms, of blood flow in the finger, and of peripheral vascular resistance showed that mephentermine in the dosages used corrected the hypotension by both central and peripheral action. It was active when given orally, intramuscularly, or intravenously. For the type of hypotension seen in group 2, a daily oral dose of 12.5 mg. after the morning or noonday meal usually sufficed.