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Conduction times were measured from a point of stimulation just below the pulmonary conus to a site 10–12 mm below on the right ventricle and to a second point near the apex on the right ventricle. Atrioventricular conduction time was also observed. Maximal rates of stimuli which the ventricle could follow and ventricular voltage thresholds were measured. Atrial flutter was established by intervenous crush and subsequent atrial electrical stimulation. All these parameters were observed in control periods and after mephentermine, 3 mg/kg by vein. Mephentermine produced the following changes: conduction time via muscle and Purkinje tissue and refractory period of the ventricle were shortened. Atrioventricular conduction time was decreased. The ratio of atrial to ventricular beats in flutter was decreased. The nervous system does not play a role in these changes. It is concluded that the antifibrillatory action of mephentermine depends on decreased ventricular conduction time. This prevents the ventricle from responding to more than one order of excitation. Termination of atrial flutter due to a circus movement also depends on an increased conduction velocity.

Fit volunteers were given three doses of 1.5 μg./kg. of the bases of scopolamine or atropine intravenously over a period of 20 minutes. Heart rates fell at first, then rose greater after scopolamine than atropine. Within 30 minutes after the third dose of scopolamine, a striking secondary bradycardia developed, which lasted for three hours. Secondary bradycardia was not seen after atropine. In one experiment with scopolamine, cardiac output was measured and peripheral vascular resistance was calculated. Output varied directly, and resistance inversely in proportion to heart rate.

During hypotension resulting from conduction anesthesia in gravid ewes, uterine blood flow (UBF) decreased roughly in proportion to the decrease in maternal blood pressure. Ephedrine or mephentermine significantly increased UBF over that accomplished by metaraminol. Presumably, the preferential effe

The oxytocic effect of norepinephrine was established by previous investigations, and the present paper shows the effects of other vasopressor drugs (methoxamine, mephentermine, and Novadral) upon the dynamics of the human pregnant uterus. The study covered a total of 48 doses administered to 26 pregnant women near term with dead or anencephalic fetuses. The effect was investigated by means of continuous monitoring of the amniotic pressure. The stimulating effect was constant. The dangers of using vasopressor drugs in pregnancies near term are noted.

SUMMARY The circulatory effects of single intravenous injections of 0.75 mg/kg mephentermine were investigated in five healthy volunteer subjects. Ninety min after the first injection, atropine 1–2 mg was administered i.v. and the injection of mephentermine repeated. Cardiac output was measured beat-by-beat with an analogue computer-ballistocardio-graph system, validated by dye-dilution cardiac outputs. The first injection of mephentermine increased mean arterial pressure, systemic vascular resistance, and left ventricular minute work, with no change in the other variables. The injection of atropine produced a sudden marked increase in heart rate, cardiac output, arterial pressure, and left ventricular work, and a fall in stroke volume. The repeat injection of mephentermine caused considerably smaller changes in the circulation than either previous injection. Atropine thus unmasked the beta-adrenergic stimulating effects of mephentermine, as well as a surprisingly prolonged action of the agent. It is suggested that the combination of atropine plus mephentermine be investigated as an approach to improved pressor therapy. Mephentermine is relatively slow in onset, with prolonged peak effects. For a given increase in arterial pressure, it produces much less drastic changes in other cardiovascular variables than does methoxamine.

This case history was presented because of two separate etiological factors producing shock, namely, gram-negative ( Aerobacter aerogenes ) bacteremia and myocardial infarction. In this case, shock was preceded by convulsive seizure and coarse tremors of the right arm and leg, instead of the usual occurrence late in the course of events. This was interpreted as an early toxic manifestation of impending gram-negative bacteremia with shock. Of special interest is the marked leukemoid reaction (73,750 white blood cells per cubic millimeter), with metaraminol bitartrate suspect. Leukemoid reaction does not occur in gram-negative bacteremia, which is more likely to produce hemolytic reactions. Leukemoid reaction of this degree is not characteristic of myocardial infarction. Other causes of sepsis were ruled out. The hypotensive state was profound and prolonged for a total of 30 days and responded to conventional therapy. Adrenal insufficiency was suggested as a cause of prolonged hypotension but is not well documented by steroid levels reported or by the Thorn test.

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.

Mephentermine in non-stimulating doses (1 mg/kg) produces an acute ergotropic response (AER) when given intravenously with reserpine (1 mg/kg). The EEG and behavioral arousal obtained in rabbits by this drug combination was attributed to the release of brain norepinephrine because the precursor of norepinephrine (DL-DOPA) restored the AER in previously reserpinized animals. Conversely, norepinephrine, dopamine and the precursor of serotonin (5-HTP) all failed to restore the AER in reserpinized animals. The effects of iproniazid pretreatment, alpha methyl meta tyrosine pretreatment, chlorpromazine, pentobarbital, scopolamine, desmethylimipramine and imipramine on the AER are described. The AER was also produced in dogs. Reserpine given in combination with phenylethylamines may be a useful method for revealing important indirect central actions of the latter. In this regard, reserpine affected the central actions of mephentermine and methamphetamine differently. When given together, reserpine clearly enabled non-stimulant doses of mephentermine to cause an excitation that was not mimicked by subthreshold doses of methamphetamine. Conversely, pretreatment of rabbits with reserpine clearly reduced or abolished the CNS stimulation caused by high doses of mephentermine; whereas, threshold doses of methamphetamine characteristically produced CNS stimulation. The results suggest that mephentermine, in contrast to methamphetamine, acts predominantly or completely through indirect mechanisms in causing CNS stimulation.

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.

A procedure is described for the quantitative determination of amphetamine and p-methoxyamphetamine and for the semiquantitative determination of methamphetamine, mephentermine, and normephentermine in human urine. An internal reference compound, phenethylamine, is added to 5 ml of urine. The urine is extracted at low pH to remove acidic contaminants, then at high pH with chloroform, in which the amines were acetylated with acetic anhydride. After evaporation, the residue, dissolved in dioxane, is injected onto a column at 215°C, packed with 8% ethyleneglycol adipate on Chromosorb W, 100-120 mesh, except at both ends, where the packing was 8% silicon rubber SE 30 on Chromosorb W, 100-120 mesh. The excretion rate of amphetamines by patients admitted with a diagnosis of amphetamine psychosis was measured.

SELF-POISONING with combinations of drugs is becoming increasingly common and such cases present considerable therapeutic problems. The difficulty in measuring blood and urine levels of many new sedatives and tranquillizers has meant that no firm guide-lines for treatment have been laid down; in particular, little evidence exists as to the value of measures such as forced diuresis and haemodialysis in increasing the rate of removal of the drugs from the body. In addition, precise details of the multiple drugs ingested are seldom available, and treatment often resolves itself into the application of good respiratory care and the correction of shock. This latter problem is often difficult, and persistent hypotension commonly contributes to the patient's death. The present case is reported because of the success of the therapeutic methods used, and the initial failure of forced diuresis.

The authors present case reports of three patients with similar pathology in their social, vocational, and sexual adjustment who developed paranoid or paranoid hallucinatory syndromes in conjunction with the abuse of mephentermine from Wyamine inhalers. Their symptomatology appeared clinically identical to amphetamine psychosis or acute paranoid schizophrenia. The authors conclude that, if abused, the Wyamine inhaler is potentially dangerous and that its availability on the market constitutes a loophole in the current regulations governing stimulant drugs.

In reserpine-induced ulcers in rats, the centrally acting sympathomimetic amines (amphetamine, mephentermine and ephedrine) produced a significant protection. Only amphetamine had a beneficial effect in restraint ulcers. Tyramine, a preponderant peripherally acting sympathomimetic amine, was inefficient in both experimental models. It is suggested that the protective activity is due to the influence of these amines on the adrenergic structures, mainly at central level.

The arterial pressure fell abruptly in 23.38% of 124 psychic patients during the first days of treatment with neuroleptics. About two weeks later it gradually rose to its initial values. The patients who do not feel well with the low arterial pressure need peripheral stimulants such as Effortil, Mephentermin, etc. Other complications of the neuroleptic therapy are the rhythm and conduction cardiac disorders (19.96% of the patients over 60 years of age showed rhythm and conduction disorders--polytopic and multiple extrasystoles, ventricular paroxysmal tachycardia, atrioventricular block III degree). These patients need active surveillance and emergency treatment with antiarrhythmic drugs. The modern treatment of psychic diseases with larger doses of neuroleptics requires regular clinical and ECC control, especially in older patients.

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%.

To evaluate the safety of prophylactic vasopressor administration prior to obstetric conduction anesthesia, equipotent doses of ephedrine, metaraminol, mephentermine, and methoxamine were administered to 16 nonanesthetized pregnant ewes near term. When the maternal blood pressure was increased by 50

A method is presented for the simultaneous identification and quantification of several CNS stimulants, including amphetamine in plasma and urine by GC/FID using mephentermine as an internal standard. No derivation is necessary and after a single alkaline extraction, GC analysis for the 11 compounds tested is achieved in 23 min. The lower limit of detectability was found to be 4 ng/ml for amphetamine in plasma. This method is sensitive, reproducible, selective and applicable in forensic and clinical toxicological analyses. Toxicological findings, after a fatality involving phendimetrazine are presented as an application of the procedure.

Accelerated hypertension after ingestion of mephentermine sulphate.Dupont AG.

Dependence on mephentermine, a widely used sympathomimetic pressor agent, is so far unreported, although misuse of inhalers is recognised. A case of mephentermine dependence associated with chronic psychosis is reported here. Psychosis initially surfaced with chronic dexamphetamine abuse, but was sustained for 3 years by mephentermine. After a period of remission lasting for 4 years, the patient again developed psychosis on restarting abuse of mephentermine, which lasted for 5 years.

The effects of verapamil on myocardial isometric force on contraction, cardiac adenosine 3,'5'-monophosphate (cyclic AMP) and heart phosphorylase alpha activity were studied in the isolated perfused rat heart. When hearts were perfused with verapamil (5.98 times 10- minus 8 M), force of contraction was reduced approximately 50% within 4 to 5 minutes; at this point, the concentration of cyclic AMP was significantly lower than control but phosphorylase alpha activity was unchanged. In hearts perfused continuously for 60 minutes with verapamil, force of contraction and cyclic AMP levels returned to normal within 20 minutes after administration of verapamil was begun. Isoproterenol (0.355 nmol/min) reversed the depressant effect of verapamil on cardiac contractility and restored heart cyclic AMP levels to normal. Methoxamine (35.5 nmol/min) given to verapamil-depressed hearts, caused contractile force to return to normal, but cardiac cyclic AMP levels remained low. Mephentermine (23.0 nmol/min) had no effect on cardiac contraction, cyclic AMP or phosphorylase alpha activity in hearts depressed by verapamil. It was concluded that with the concentration of verapamil used in these experiments, the drug caused a transient decrease in force of contraction and myocardial cyclic AMP. Both the depression in myocardial contractility and in cardiac cyclic AMP caused by verapamil were reversed promptly by isoproterenol, whereas methoxamine overcame acutely only the negative inotropic effect of verapamil. Mephentermine had no effect on hearts depressed by verapamil.

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.

10 late pregnant women with hypotension were examined before and after the intravenous injection of 30 mg mephentermin with the method of quantitative sphygmometry, the bloodless graphic registration of the arterial blood pressure and direct electronic timing of pulse wave velocity. Systolic and diastolic blood pressure increase significantly. The cause of this rise in arterial blood pressure is the increase of stroke volume exclusively. Heart rate and total peripheral resistance remain constant. This hemodynamic mode of action is a favourable one in regard to protection of uteroplacental blood flow. Therefore mephentermin is suitable for treatment of hypotension in pregnancy.

The purpose of the present study was to assess the effects of intravenously administered vasopressors upon uterine artery blood flow velocity (UBFV) in the gravid guinea pig subjected to ritodrine infusion. Fourteen experiments were performed in 14 chronically instrumented pregnant guinea pigs near term. Immediately following a 1-h intravenous infusion of ritodrine (0.05-0.20 mg.kg.min-1), each animal received an intravenous bolus of vasopressor solution: 1) epinephrine, 0.001 mg/kg; 2) phenylephrine, 0.01 mg/kg; 3) mephentermine, 1.0 mg/kg; 4) ephedrine, 1.0 mg/kg; or 5) placebo. The experimental sequence was performed five times, so that each animal received all five solutions. The vasopressor sequence was randomly altered between animals. Infusion of ritodrine increased maternal heart rate 18 +/- 1% (P less than .0001), decreased maternal mean arterial pressure (MMAP) 4 +/- 1% (P less than .01), and decreased UBFV 5 +/- 1% (P less than .001). The four active vasopressor solutions resulted in similar, though not equivalent, increases in MMAP. Further, the MMAP response to each active vasopressor differed from the response to placebo (P less than .0001). Epinephrine and phenylephrine each significantly decreased UBFV (P less than .002). Ephedrine clearly preserved UBFV, whereas mephentermine appeared to result in an intermediate response.

A survey was done on over 10,000 urine samples from the Los Angeles County Probation Department and methadone maintenance programs to determine the frequency of use of eight sympathomimetic amine drugs including amphetamine, methamphetamine, ephedrine, mephentermine, phendimetrazine, beta-phenethylamine, phenmetrazine, and phentermine. As expected, the frequency of use of amphetamine was relatively high followed by phentermine, ephedrine, and methamphetamine. The extensive use of ephedrine and phentermine may warrant testing for these drugs on a more routine basis in drug monitoring programs.

In haemodynamic investigations of altogether 40 male probands with normal and restricted functional capacity of the lungs the result of an intravenous injection of mephentermine (30 mg) or methamphetamine (15 mg) was a transient increase of the mean pressure in the pulmonary artery and of the resistance of the pulmonary vessels. Temporarily parallel the arterial mean pressure and the resistance of the vessels in the greater circulatory system in most cases increased by about the same, in healthy persons after application of methamphetamine by a smaller relative amount. In the dosage used the vasoconstrictive effect of methamphetamine was altogether only somewhat more expressed. At the time of the maximum increase of the mean pressure of the pulmonary artery in healthy persons methamphetamine had a negative chronotropic and inotropic effect. It is referred to practical therapeutic consequences.

The effect of verapamil on myocardial contractility, heart adenosine 3', 5'-monophosphate (cyclic AMP) and cardiac phosphorylase a activity was studied in isolated perfused rat hearts. In a concentration of 0.025 mug/ml, verapamil decreased force of contraction 50% and caused a significant fall in heart cyclic AMP within 4 to 5 min after perfusion with the drug was begun. When perfusion of the heart with medium containing verapamil was continued for 60 min, contractile force gradually returned to control. at the end of 60 min of perfusion with verapamil, the myocardial concentration of cyclic AMP was not different from that measured in hearts perfused with contro medium for a similar time period. Isoproterenol, given at the point of maximal contractile depression induced by verapamil, restored normal force of contraction and raised cardiac cyclic AMP to the same level as that observed when the catecholamine was given to untreated hearts; When methoxamine was administered to hearts depressed by verapamil, contractility returned to normal, but cyclic AMP content remained below control values.

For many years the treatment of septic shock essentially concentrated on the restoration of systemic blood pressure. Metaraminol, mephentermine, noradrenaline, angiotensin and other vasoconstrictors were widely used with rather limited success. More recently, dopamine has become the agent of choice as a vasopressor in the management of circulatory shock. There are several reasons for this. In the first place it combines alpha- and beta-mimetic properties of various strengths according to the dose administered, so that the drug can easily be titrated according to the clinical status of the patient. Secondly, it induces tachyarrhythmias less frequently than other available catecholamines. Finally, it can selectively dilate renal and mesenteric vascular beds when low doses are used.

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.