J. Richard Crout

Determination of 3-methoxy-4-hydroxymandelic acid in urine

Abstract A specific method is described for the quantitative determination of 3-methoxy-4-hydroxymandelic (MOMA) acid in normal urine as well as in patients with pheochromocytoma. The procedure includes extraction of the acid from urine, followed by treatment of the extract with periodate to form vanillin, which is then determined spectrophotometrically.

Urinary excretion of catecholamines and their metabolites in pheochromocytoma.

Abstract Twenty-four-hourspecimens of urine from 23 patients with pheochromocytoma and a large group of hypertensive subjects were assayed for free catecholamines (norepinephrine plus epinephrine), total metanephrines (metanephrine plus normetanephrine), and 3-methoxy-4-hydroxymandelic acid. Twenty of the 23 patients with tumors had a diagnostic increase in the urinary excretion of all catecholamine metabolites. In the other 3 patients the assay of free catecholamines was the single most reliable test. Because of its over-all reliability and ease of performance, the assay of total metanephrines is favored for screening hypertensive patients for the presence of pheochromocytoma. In the occasional patient whose value is equivocal by this assay, the determination of free catecholamines is considered to be the most helpful test in confirming or excluding the diagnosis.

Clinical and Chemical Studies with α-Methyl-Dopa in Patients with Hypertension

A series of observations in 52 hypertensive patients is presented indicating that &agr;-methyl-dopa is an effective antihypertensive agent. The antihypertensive properties of the agent were discovered in the course of biochemical studies with the racemic compound the form used in initial therapeutic trials. Studies on metabolism of DL-&agr;-methyl-dopa indicate incomplete intestinal absorption and rapid excretion in the urine as unchanged drug and as &agr;-methyl-dopamine. The former finding does not seem to be a significant deterrent to its use orally. Comparisons of the D and L isomers of &agr;-methyl-dopa in hypertensive patients showed that all the chemical and pharmacologic effects reside in the L-isomer (Aldomet). Thus, recent studies have been performed with Aldomet exclusively. From observations to date the impression has been gained that Aldomet has several advantages over other antihypertensive agents; these include effectiveness against all degrees of hypertension, frequent lowering of recumbent as well as standing blood pressure, smoothness of effect, and tranquilizing effects. Questions of toxicity and tolerance are not yet completely answered. Sympathetic blockade at a central or peripheral site is the probable basis of the drugs action. This effect may be unrelated to the biochemical property of inhibiting the decarboxylation of aromatic L-amino acids and is possibly due to depletion of tissue stores of norepinephrine by a mechanism not yet fully defined.

A comparative study of the effects of five general anesthetics on myocardial contractility. I. Isometric conditions.

Isolated cat papillary muscles driven at a rate of 12 beats/min at 37.5 C were exposed tojeoncen-trations of cyclopropane, diethyl ether, Ethrane, halothanc, and methoxyflurane similar to those required to produce general anesthesia m vivo. Each anesthetic depressed peak developed ten-sion, maximal dp/dt, and the force-time integral of the twitch, and each shortened the time to peak tension. These variables were altered in qualitatively similar ways by all anesthetics tested, implying a common mode of action on the con-tractile process. When administered in cquieffec-tivc concentrations from the standpoint of producing general anesthesia (i.e at equal MACs), the order of activity of the anesthetics in depressing contractility (from most to least depressant) was: Ethrane > halothanc > methoxyflurane > cyclopropane > diethyl ether.

Chronic Extrinsic Cardiac Denervation by Regional Neural Ablation: Description of the Operation, Verification of the Denervation, and Its Effects on Myocardial Catecholamines

A technique for complete extrinsic denervation of the heart by the ablation of neural structures in the mediastinum is described. The completeness of denervation was verified by direct electrical stimulation of the main vagal and sympathetic trunks. Total deple tion of myocardial catecholamines followed the procedure in chronic survivors. Animals prepared in this manner are useful in the study of the neurologically isolated heart and simulate this aspect of the problem of cardiac transplantation.

Catecholamines in the Localization of Pheochromocytoma

Data on urinary catecholamines in a collected series of 75 cases of pheochromocytoma, including 18 of our own cases, indicate that the differential assay of urinary norepinephrine and epinephrine may be of value in predicting the location of the tumor preoperatively. If there is a significant elevation of urinary epinephrine (42 per cent of all cases), the tumor may be expected to lie in or adjacent to one of the adrenal glands in about 95 per cent of cases. Other tumors of this type have been found only in the organs of Zuckerkandl. If the urine contains norepinephrine alone (58 per cent of all cases), the tumor will be found in one of the adrenal areas in about two thirds of the cases and in an extra-adrenal location in the remainder. In a few patients (6 per cent) of this type, the tumor may be extra-abdominal. In some unusual cases more precise information on the location of the tumor must be obtained preoperatively. The demonstration of a marked step-up in plasma catecholamine concentration at the level of the tumor, the sampling being done by venous catheterization, is a useful and safe means of localizing the tumor. Five cases are presented illustrating the use of this procedure.

Effect of Inhibiting both Catechol-O-Methyl Transferase and Monoamine Oxidase on Cardiovascular Responses to Norepinephrine

Summary The simultaneous inhibition of catechol-O-methyl transferase and monoamine oxidase (by pyrogallol and JB-835) produced only moderate prolongation of the cardiovascular effects of injected l-norepinephrine in anesthetized dogs. This prolongation of pharmacological action in presence of enzyme inhibitors was correlated with a delayed disappearance of injected norepinephrine from the circulation. While these results indicate that metabolism by these enzymes contributes to removal of circulating norepinephrine from the plasma in the dog, they further suggest that the physiological inactivation of circulating norepinephrine at the receptor sites does not require metabolic destruction of the amine by these enzymes.

Adverse Effects of Newly Marketed Drugs

In this issue of the Journal, Van Thiel et al. describe effects of cimetidine that have not been reported previously in man. Their paper also provides an opportunity to consider the general problem...

The Effects of Inhalation Anesthetics on the Uptake and Metabolism of l-3H-Norepinephrine in Guinea-pig Atria

The uptake and deaminative metabolism of l-3H-norepinephrine have been studied in vitro in contracting guinea-pig left atria exposed to halothane, cyclopropane, Ēthrane, and dietliyl ether. In the presence of severe (50 per cent) decreases in myocardial isometric contractile force, no alterations were seen in either the rate of uptake of l-norcpinephrinc or the activity of intrancuronal monoaminc oxidase.

Guidelines of the Food and Drug Administration for Study of New Drugs in Human Subjects

The Food and Drug Administration recently has published general guidelines for the clinical evaluation of drugs used in adults and in infants and children. Specific guidelines for a number of drug classes, including anti-infective drugs, are also available. Marketing approval of a new drug requires that its benefits be judged to exceed its risks, that it be accurately and truthfully labeled, and that it be manufactured properly. Foreign studies are commonly accepted in support of new drugs, but approval requires at least one domestic trial unless the disease does not occur in the United States (for examply, tropical diseases).