Dorothy Adams Campbell

Salt and Water Balance in Migraine

much better result than that obtained by other recognized forms of medication. In contrast with the effect of such drugs asergotamine tartrate, which are commonly employed for the immediate relief of an attack by Nirtue of their action on smooth muscle, it was found that a perseverance of treatment with urea over a long enough period lessened both the frequency and the severity of the attacks in 45 subjects, and procured complete relief in six of this group of patients. Since the main action of urea is that of a diuretic, these clinical findings seem to indicate that diuresis, whether of natural occurrence or induced by urea, is a physiological means of restoring the body fluids to their normal balance.

Effect of diamox on plasma bicarbonate and on the electrolyte balance in relation to intra-ocular pressure in man.

THE primary action of Diamox is to inhibit the enzyme carbonic anhydrase, thereby arresting the formation of bicarbonate ions. This occurs in various tissues which contain the enzyme, notably the kidney, red blood cells, gastric mucosa, and uveal tissue. Its inhibitory action is immediate and highly specific (Mann and Keilin, 1940), and it has been questioned whether its effect on intra-ocular pressure is due to its local or its systemic action. Experimental work on animals has shown that Diamox causes total inhibition of the enzyme in the uveal tissue (Green, Bocher, Calnan, and Leopold, 1955), that it reduces the bicarbonate content of the aqueous (Lee, 1955), that it diminishes the rate of formation of aqueous humour (Langham, 1955), and that it promotes a notable fall in intra-ocular pressure. It was at first believed that these phenomena affected the secretory processes of the eye as described by Friedenwald (1949), but in an able summary of the evidence Duke-Elder (1957) has shown that this cannot be true. Thus, in rabbits, although the activity of carbonic anhydrase is undoubtedly inhibited in the eye by Diamox, the bicarbonate content of the aqueous is merely diminished and its concentration relative to that of the plasma remains unchanged, both being reduced (Green and others, 1955; DukeElder, Perkins and Langham, 1956). In rabbits it has been recorded that, although the carbonic anhydrase may be wholly inhibited in the eye after the intravenous or subconjunctival administration of Diamox, there may be no fall in intra-ocular pressure at all (Green and others, 1955). Aqueous flow is reduced by some 25 per cent. when Diamox is given systemically (Langham and Lee, 1957), but a similar reduction can be achieved by the administration of ammonium chloride, a substance which like Diamox causes an acidosis, but has no effect on carbonic anhydrase (Langham and Lee, 1955). The permeability of the blood-aqueous barrier is also unaffected by Diamox as measured by the fluorescein technique (Langham and Lee, 1957), by the transference of radioactive or non-radioactive sodium, and by the rate of transference of ascorbic acid (Langham and Lee, 1955). The available evidence of what takes place in the human subject, which is sparse owing to the obvious difficulty of obtaining in vivo samples of aqueous,

Vitamin A, total carotenoids, and thymol turbidity levels in plasma; test in normal subjects residing in the Midlands during 1947.

Taylor, H. C., and Scadron, E. N. (1939). Amer. J. Obstel. Gynec., 37, 963. Venning, E. H. (1937). J. biol. Chem., 119, 473. (1948). Obstet. Gynec. Surv., 3, 664. Watts, R. M., and Adair, F. L. (1943). Amer. J. Obstet. Gynec., 46, 183. White, P. (1937). Ibid., 33, 380. (1943). Va med. Mon., 70, 436. (1946). In Joslins Treatmtent of Diabetes Mellitus, 8th ed., p. 769. Kimpton, London. (1947). Penn. med. J., 50, 705. and Hunt, H. (1943). J. clin. Endocrinol., 3, 500. Titus, R. S., Joslin, E. P., and Hunt, H. (1939). Amner. J. mled. Sci., 198, 482.

Effect of neptazane on intra-ocular pressure in relation to its systemic action and its clinical application.

OPHTHALMOLOGISTS are already familiar with the clinical use of Diamox for the reduction of intra-ocular pressure in both acute and chronic cases of glaucoma. It is therefore of considerable interest to find a second compound, Neptazane, of close chemical relationship to Diamox which is a possible alternative or substitute particularly for cases which fail to respond to Diamox or which develop unpleasant side-effects. Neptazane is already being used therapeutically in America and its clinical effects have been reported by Becker (1957). Its immediate effect on intra-ocular pressure is said to be slower and less dramatic than that of Diamox and in short-term therapy it was found to be effective in a smaller percentage of patients (68 as compared with 83 per cent.). It appears to be particularly suitable and equally as effective as Diamox for long-term therapy. It provokes very few unpleasant side-effects, paraesthesia, drowsiness, and gastro-intestinal disturbances being much less common than after Diamox. No instances of ureteral colic have been recorded in spite of the fact that it is excreted slowly. It is effective in smaller doses, 125 mg. Neptazane being regarded as equivalent to 250 mg. Diamox, although thisalone offers no particular reason for its preferential use. The optimum dose has been cited as 100 mg., two or three times daily, very little benefit being obtained with larger or smaller doses. The pharmacological action of Neptazane has been well demonstrated by Sisson and Maren (1956) and Maren (1956) (see also unpublished Lederle reports, 1958). Like Diamox it is a carbonic anhydrase inhibitor with an in vitro action 1-6 times that of Diamox. It penetrates well into the aqueous humour and promotes an immediate diuresis and excretion of electrolytes. In the dog, during the first 6 hrs, there is an increased loss of sodium, potassium, and bicarbonate and a rise in the urinary pH which ceases in 18 hrs after a single dose of 5 mg./kg.

Retinitis pigmentosa vitamin a serum levels in relation to clinical findings

The majority of subjects affected with retinitis pigmentosa show a subnormal level of vitamin A and of carotenoids in the blood. This feature persists for many years both in hereditary and non-hereditary cases, and in a number of their unaffected relatives. The absorption of vitamin A has been found to be normal, and the serum level of vitamin A can be raised by continuous therapy with vitamin A, vitamin E, vitamin A and E together, or by the administration of β -carotene. It falls again within a few weeks of the cessation of treatment. The promotion of the blood vitamin A to a normal level over a considerable period has a beneficial effect on the retina in an appreciable number of cases. It is made evident by an increase of over 10% in the total area of both visual fields (binocular field area) and by an improvement in dark adaptation as shown by the measurements of the cone and rod threshold. The degree of vitamin A deficiency which is found in retinitis pigmentosa is discussed in relation to the carotenoid/vitamin A ratio in the blood and to the mode of action of the vitamins selected for therapeutic trial.

COMBINED ACTION OF DIAMOX AND POTASSIUM BICARBONATE IN THE TREATMENT OF CHRONIC GLAUCOMA

IT has been well established that Diamox causes excretion of cations, especially sodium and potassium, and that in conditions of sodium depletion potassium may be excreted in place of sodium (Milne, 1956). In fact the administration of potassium bicarbonate will increase the systemic effects of Diamox. We have already drawn attention to the correlation between cation excretion and fall in intra-ocular pressure after Diamox (Campbell, Jones, and Tonks, 1956), and were therefore interested to discover whether potassium bicarbonate would have a potentiating effect on the action of Diamox in cases of chronic glaucorha. In common with other observers (Becker and Middleton, 1955; Kupfer, Lawrence, and Linner, 1955), we have noticed that patients under treatment with Diamox often complain of paraesthesia and that this symptom is sometimes associated with a relatively low level of blood potassium. It is interesting to note in this respect that Becker and Middleton have reported the relief of paraesthesia and other side-effects by the addition of potassium chloride given by mouth. On a pharmacological basis, the continued use of Diamox could not be expected to be beneficial in the treatment of chronic glaucoma, since a single dose engenders a state of acidosis from which the body may take 2 to 3 days to recover (Maren and Wadsworth, 1955; Hanley and Platts, 1956). In fact, Arruga (1955) pointed out that, whenever Diamox has been used over long periods with success, it has always been employed in combination with miotics. It is highly probable that the latter masked the diminishing effect of Diamox. Our experiments were designed to elucidate this point as well as to investigate the effects of the addition of a potassium salt.

CORRELATION OF THE SYSTEMIC AND INTRA-OCULAR EFFECTS OF DIAMOX

MANY opinions have been expressed in favour of the theory that Diamox causes a fall in intra-ocular pressure by virtue of its local inhibition of carbonic anhydrase within the eye. There has been very little attempt to correlate the ocular effects of Diamox with its extensive systemic action, i.e. in causing diuresis and an increased excretion of electrolytes especially of sodium and potassium, (Counihan, Evans, and Milne, 1954; Hanley and Platts, 1956). Since water imbibition causes a rise in tension it might well be expected that diuresis would have the reverse effect, and that the loss of sodium, an ion which is intimately associated with the retention of water within the body, might also be expected to favour the loss of extracellular fluid not only from the blood but from the eye. A single dose of Diamox (250 mg. or more) will produce its systemic effects almost immediately; these last for 24 hours, but on subsequent days or with repeated doses occur to only a slight extent. The patient is left in a state of acidosis which persists after diuresis has ceased (Hofbauer, Kaindl, and Reinhardt, 1955). In the treatment of cardiac oedema (Maren, Wadsworth, Yale, and Alonso, 1954) or of glaucoma, the patient may become resistant to the action of Diamox. Some cases of glaucoma are resistant from the outset. These phenomena are still unexplained. The cessation of acidosis in the normal subject may take 2 to 4 days after a single dose, and from 5 to 7 days after repeated doses (Hanley and Platts, 1956). One should therefore consider whether it is desirable to use repeated doses in the treatment of glaucoma or whether Diamox would be more wisely employed in single doses at intervals of several days with miotics in the interim. Hofbauer and others (1955) have found that this is the most efficacious form of therapy in cases of caidiac oedema, and recommend its use for a period of three successive days at the most. Langham (1955) reports that, although the concentration of bicarbonate in the aqueous is diniinished after the administration of Diamox, its concentration relative to that in the plasma is unchanged; Gloster and Perkins (1955), from their records of the fall in intra-ocular pressure after intravenous Diamox, consider that the rapidity of its action should not be accepted as proof of a local effect upon the eye.

THE RÔLE OF CALCIUM IN NAPHTHALENE CATARACT

naphthalene daily for eight days. Retinal exudates and peripheral striae were present on the second day. The exudates rapidly enlarged and became confluent; by the ninth day the entire periphery of the retina had atrophied. The lens striae developed during 20 days; on the 24th true lens opacities were present; complete cataract of both eyes subsequently developed about one month after the last (iose of naphthalene. (e) Rabbit number 50:-Black, weight 2,010 grams. Received two grams of naphthalene daily for two days. The ocular lesions developed rapidly. Retinal exudates and peripheral lens striae were present on the second day; by the fifth day the exudates had become confluent and the lens striae were rapidly extending towards the centre; by the ninth day the lens striae had still further increased and the affected areas of the retina had become atrophic. The animal died on the 10th day after having manifested all the signs of severe toxaemia including loss of appetite, weakness, torpor, and severe diarrhoea. The sound of the breathing indicated the presence of fluid in the lungs. There was a very rapid decrease in weight, amounting to a total of 700 grams. (f) Rabbit number 51 :-Gey, weight 1,900 grams. Received five two-gram doses of naphthalene. The ocular lesions were extensive and developed rapidly. The retina was covered with large patclhes of watery exudate on the second day; these rapidly became confluent, and by the fifth day, the whole retina was atrophic. Peripheral lens striae were present on the second day; these increased and by the ninth day, had extended throughout the lens; on the 14th day true lens opacities were present. The animal died on the 19th day, having developed anorexia and having lost 350 grams in weight.

A COMPARISON OF DARK ADAPTATION IN MINERS WITH THEIR NUTRITIONAL STATE

A CAREFUL inquiry was made into the nutritional state of about 100 miners-i.e., their access to food, choice of diet, number in family, etc. In addition, estimations of plasma vitamin A and of carotene were undertaken to run parallel with the dark adapta. tion tests, to ascertain whether they were commensurate with the threshold value. The possibility of a deficiency in vitamin D was also considered, since miners working underground sweat heavily and are likely to lose surface fat, i.e., potential vitamin D. Moreover, they are rarely exposed to sunlight which favours the manufacture of vitamin D, and the present day diet is unlikely to produce the required daily intake of 300-600 I.U. of vitamin D. The estimation of plasma alkaline phosphate was taken as the indication of any possible deficiency of vitamin D, while a liver function test was used as a check against the possibility that an abnormal vitamin A content, or a raised blood phosphatase might be due to liver dysfunction. The normal range for the blood constituents is as follows:-

Binocular Vision in Miners.

markedly, whereas depressives even where some anxiety background had been revealed,, seemed capable of making a reasonable effort. Although the tests for dark adaptation do not involve thesame mental judgment as night vision tests-it was considered interesting in the case of miners to compare the threshold values obtained by Dr. Sharpley with the psychological tests made by Dr. Stern. The resul-ts are recorded in Table 1. It will be seen that for the total 65 miners tested, the average threshold values in the cases of hysterics, anxiety neurosis and malingerers are tne same as for normal mentality, whereas it is higher in manic depressives and in the dull and backward. In the group of control miners, the psychologically abnormal had a lower threshold than the normal, while in t-he certified cases the rise in threshold in hysteria and anxiety neurosis was more marked in those wifhout nystagmus than in those with active oscillations.