Dale G. Friend

Relative erythrocythemia (polycythemia) and polycystic kidney disease, with uremia. Report of a case, with comments on frequency of occurrence.

RECENTLY polycythemia or erythrocythemia apparently associated with renal disease of several diverse types, including hydronephrosis,1 , 2 hypernephroma3 4 5 6 7 8 9 and renal adenoma10 and fibromy...

BIOCHEMICAL AND PRESSOR EFFECTS OF ORAL d, l‐DIHYDROXYPHENYLALANINE IN PATIENTS PRETREATED WITH ANTIDEPRESSANT DRUGS *

In the course of our investigations of catechol amine metabolism in depressed patients,l we have observed that dihydroxyphenylalanine (DOPA), an amino acid-precursor of the catechol amines, may produce a transitory striking elevation of blood pressure in patients pretreated with the monoamine oxidase inhibitor, phenelzine. Other investigators ( Oster and Sorkin2; Degkwitz et a1.,3; Pollin et a1.4; McGeer et aL5) have previously reported the pressor effects of DOPA, when administered under various pharmacological conditions to human subjects. In our studies, patients received the monoamine oxidase inhibitor, phenelzine, in a dose range of 45-60 mgm. daily for a minimum of three weeks prior to DOPA administration. In these pretreated patients, a transitory hypertension with accompanying sinus bradycardia has been observed following the oral administration of 25-200 mgm. of D,L-DOPA. This hypertension was primarily systolic, but elevation of diastolic blood pressure also occurred. The magnitude of the systolic blood pressure elevation appeared to be related to the dose of DOPA administered. Subjective symptoms sometimes occurred during the hypertensive episode. These included: pressure in the head, pounding headache, throbbing in the neck, flushing, cardiac palpitations, and a sense of dread which patients distinguished from simple anxiety.

Action of triethanolamine trinitrate in angina pectoris

Abstract 1. 1. Triethanolamine trinitrate in a dose of 2.0 mg., four times a day by mouth, is no better than a placebo in the treatment of angina pectoris. 2. 2. Nitroglycerin, 2.0 mg., four times a day by mouth, was no better than placebo therapy. 3. 3. Both triethanolamine trinitrate and nitroglycerin were well tolerated. 4. 4. No toxic reactions were observed following both triethanolamine trinitrate and nitroglycerin given in a dose of 2.0 mg., four times a day by mouth, for periods of from two to four weeks.

Pharmacology of muscle relaxants

The chief Wipects of the modern concept of neuromuscular pharmacology are briefly reviewed as a basis for understanding the action of muscle‐relaxing agents. These are considered under one of two headings: (1) centrally acting, having either inhibitory action leading to diminished motor activity or facilitating action leading to increased or even uncontrolled motor activity; (2) locally acting, affecting peripheral structures. Most of the widely used muscle relaxants are of the former type, with the major effect being on polysynaptic pathways, e.g., meprobamate, carisoprodol, chlordiazepoxide, and diazepam. The advantages, limitations, and disadvantages of each are discussed. Drowsiness is a common drawback. Of these drugs, diazepam is cited as relieving muscle spasm associated with cerebral palsy and athetosis. The locally acting agents, e.g., procaine, Xylocaine, as well as toxins (diphtheria, botulism, and puffer toxin), act by interfering with nerve conduction, the release, destruction, and attachment to receptors of acetylcholine, by electrolyte alteration, and by direct action on the myofibrils, having little merit clinically. Despite the development of many centrally acting agents, a really effective and satisfactory muscle relaxant must still be sought.

EVALUATION OF CATECHOL AMINE LEVELS IN RENAL INSUFFICIENCY

The estimation of epinephrine (E) and norepinephrine (NE) in plasma and urine has become important as a procedure in physiological research and as an aid in the diagnosis of pheochromocytoma. With the development of fluorometric procedures the chemical estimation of E and NE in biological fluids and tissues was made possible. The fluorometric procedures used most commonly are modifications of the trihydroxyindole method of Lund (1) and the ethylenediamine (EDA) condensation method of Weil-Malherbe and Bone (2, 3). The trihydroxyindole method is not sensitive enough to permit measurements of E and NE in small amounts of normal peripheral plasma (1), and its practical usefulness is limited to the assay of urine. The sensitivity of the EDA condensation method is such that extremely small amounts of E and NE can be measured; however, it is not as specific as the trihydroxyindole method and will detect phenolic compounds other than E and NE (4). While employing the EDA condensation method as an aid in the diagnosis of pheochromocytoma, we have observed, in some individuals with renal insufficiency who later were found not to have a pheochromocytoma, levels of E and NE much higher than those which occur in normal patients. The purpose of the present study was to determine whether the high levels of E and NE frequently observed in patients with renal insufficiency are true values or are due to the presence of substances which interfere with the EDA method and produce false high values of E and NE. The presence of large amounts of these substances may be due to an abnormal or increased production of E, NE or interfering compounds, or an inability on the part of the kidneys to excrete the normal amounts of these substances present in the blood. Among possible interfering substances which occur in abnormal amounts in the blood of patients with renal insufficiency are urea, creatinine, uric acid and phenolic compounds. Of these, the phenolic compounds are most likely to be involved. The phenols are excreted in both free and conjugated forms, with a normal daily output in the urine of 200 to 500 mg. (5). They are derived mainly from bacterial putrefaction of aromatic amino acids in the intestine. A minor portion comes from the presence of sex hormones, epinephrine, norepinephrine and tyrosine in the blood. The normal blood levels calculated as phenol range from 1 to 2 mg. per 100 ml., whereas in uremic patients they may reach 6 to 10 mg. per 100 ml. (6). The importance of these compounds in the pathogenesis of uremic symptoms has been reviewed by Harrison and Mason (7). In order to determine whether the presence of large amounts of phenolic compounds in the plasma of patients with renal insufficiency can account for the high levels of E and NE as measured by the EDA condensation method, the effect of various phenolic compounds on this method and the trihydroxyindole method was investigated, and the specificity of these two fluorometric procedures for estimating catechol amines was compared. Plasma E and NE levels were assayed by both methods in normal individuals and patients with renal disease. The high E and NE levels found in the patients with renal insufficiency were then evaluated in the light of information developed from the differences in specificity established for the two methods.

Antidepressant drug therapy

Medicine had very little to offer in the treatment of the mentally depressed patient until the advent of shock therapy and the first monamine oxidase inhibitor, iproniazid. Unquestionably, the rather striking effects of iproniazid on mentally depressed individuals did much to stimulate interest in chemotherapy for this widespread and severely incapacitating mental condition. A large proportion of those with depression have a spontaneous remission 3 to 6 weeks after onset, but the situation may be serious during that period. In some, the condition does not undergo remission, grows steadily worse, and in others, leads to suicide. Continuous severe depression bringing about severe withdrawal of the individual from the main stream of life, ultimately leads to untreatable deteriorated states. It is, therefore, important that diagnosis be made as early as possible and treatment initiated promptly. Fortunately, drug therapy is now available which has much to offer these patients and even in the hands of the non psychiatrically oriented physician, oftentimes affords such relief as to return a patient to a much more useful and satisfactory existence.

THE EVALUATION OF NEUROSPASMOLYTIC AGENTS IN MAN BY OBJECTIVE MEANS

The evaluation of muscle-relaxant agents in man, whether for musculoskeletal or neurological disorders, has heretofore been done essentially on a qualitative basis, quantitative appraisal having been carried out on experimental animals, utilizing various highly refined techniques. This paper offers an approach to the quantitative evaluation of muscle-relaxant therapy in man, with particular emphasis on neurospasmolytic agents. The studies to be described have been carried out by the Neurological Research Team of the Veterans Administration Outpatient Clinic. Test subjects have been selected from the large group of multiple sclerosis patients known to this clinic, in whom spasticity is a prominent sign and symptom. The patients used in our studies are at a fairly static level of disability, thereby reducing changes due to natural fluctuations of the disease to a minimum. The method used depends on a cooperative team approach that includes the patient, while a t the same time permitting independent functioning of the professional staff within the various categories of the study. Medication is prescribed and dispensed by double-blind administration, with central control remaining in the hands of our chief pharmacist. The three physicians on the team are assigned their respective duties as follows. The first regulates the maintenance dose of medication, initiates and terminates the double-blind period, interviews the patients, and keeps clinical notes. The second physician performs clinical examinations and assessments of spasticity on a clinical basis, grading this from 0 to 4 as follows: 0 = no resistance to passive flexion and extension a t knee; 1 = slight resistance to passive flexion at knee, without increase in spasticity to extension-flexion thrust; 2 = moderate resistance to passive flexion at knee with moderate degree of increase in spasticity with extension-flexion thrust; 3 = marked resistance to passive flexion at knee, with boardlike spasticity as result of extension-flexion thrust that yields little to downward pressure below the knee; and 4 = marked resistance to passive flexion a t knee with boardlike spasticity as result of extension-flexion thrust that does not yield to downward pressure below the knee. The third physician is concerned with the administration of various stimuli to induce spasm and the interpretation of polygraph data. The chief technician is charged with operation of the polygraph equipment, with placement of electrodes, and with assisting the third physician in administering stimuli to induce spasm. Test subjects are oriented regarding the over-all project, including doubleblind methodology, and are given 3 weekly polygraph tests before taking the muscle relaxant being studied. Two weeks are then spent in building up to

Effect of 5‐imino‐2,2,4,4‐tetrakis (trifluoromethyn imidazolidine (EXP 338) on spasticity: A quantitative evaluation

In preclinical studies, 5‐imino‐2,2,4,4‐tetrakis (trifluoromethyl) imidazolidine (EXP 338) revealed potential muscle relaxant action at nontoxic levels in experimental animals. Our evaluation was carried out on 15 spastic multiple sclerosis patients. Eotablished methods of inducing spasticity and recording skeletal muscle hypertonia and quantitatively extracting integrated electromyogram data were used. Five patients were tested directly in the polygraph laboratory and 10 were tested at home via telephone telemetry (telemedography). Blood and urine were unaffected by the test drug. Adverse effects included muscle weakness, insomnia, paranoid reaction, sexual excitement, irritability, dry mouth, and limb pains. The alerting effect of EXP 338 suggests its trial as an antidepressant. The polygraph data revealed that a daily dose of 10 to 20 mg. of EXP 338 resulted in an average reduction of 62 per cent in skeletal muscle hypertonia in half the spastic subjects tested.

Drugs for peripheral vascular disease

The problem presented by inadequate peripheral circulation is exceedingly common and at times serious. Consequently there has been a search for more and better agents for the treatment of various peripheral obstructive states. As a result, there are now several agents promoted for the treatment of peripheral vascular disease.

The action of L‐dihydroxyphenylalanine in patients receiving nialamide

Nialamide produces effective monamine oxidase inhibition resulting in a three‐ to fivefold increase in tryptamine excretion when administered in a dose of 100 mg. for 10 days. L‐Dihydroxyphenylalanine, given in a dose of 75 to 100 mg. to normal volunteers receiving nialamide in a dose of 100 mg. daily for 10 days, produces a prompt and prolonged elevation in the blood pressure. Flushing of the face, heat, and pounding of the heart were poduced in most subjects. The blood pressure elevation was considered to be secondary to the intake of large amounts of the potent precursor in the presence of effective monamine oxidase inhibition. The active amine was not identified but could have been dopamine, norepinephrine, or a mixture of the two.