THE USE OF CEVITAMIC ACID IN THE SYMPTOMATIC AND COSEASONAL TREATMENT OF POLLINOSIS

ETHAN ALLAN BROWN, M.D., F.A.C.A.

Boston, Massachusetts

and

SIMON L RUSKIN, M.D.

New York, New York

The value of large doses of cevitamic acid in the control of allergic coryza was first observed, in 1938, as used in association with calcium ascorbate. 16 Until then, the currently accepted daily dosage of Vitamin C was 40 to 60 mg. With the introduction of calcium ascorbate, it was possible to inject as much as 450 mg. Since it was administered intramuscularly, a dose could be considered equivalent to double the quantity taken orally. Immediately subsequent to these studies, Jollife 11 stated that the therapeutic levels might be more than 1,000 mg. daily.

It was soon apparent that cevitamic acid might act at two “levels,” functioning as a vitamin when given in small amounts, and as a drug when given in massive doses. 8 One such effect, the diuretic action, has been evaluated. 9

Since vitamin C may act by means of a number of mechanisms, determinations were made to discover whether the apparent beneficial effects seen in both infectious and allergic coryza were due to the Vitamin C, the calcium, or both. 16 For this purpose, the anti-histamine effect of Vitamin C and calcium ascorbate were studied by the microscopic examination of bronchiolar reactions. 16 The results of these investigations, presented at the American Chemical Society in 1940, demonstrated that Vitamin C and calcium ascorbate possessed anti-histamine properties, while calcium gluconate had a histamine-like action and would thus present no anti-allergic activity.

In 1942, Holmes 10 reported a similar use of Vitamin C in daily doses ranging from 250 to 1,000 milligrams. Taken orally by the five patients studied, it was said to have caused an objective clinical improvement. Following this report, various clinical impressions contradictory as to the usefulness of Vitamin C in allergy, were published. These have been reviewed by Brown. 3

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While it was possible to secure animal experimental study on the antihistamine effects of Vitamin C, it was extremely difficult to devise satisfactory objective experiments with patients, especially since Cody 5 had stated that vasomotor rhinitis might be an early symptom of latent or subclinical scurvy. It was, therefore, decided to study a moderately large clinical group of subjects presenting a similar condition, namely, hay fever, under completely independent observations in two cities of equivalent pollen seasons, Boston and New York. Unmarked tablets of Vitamin C with elements of Vitamin B Complex were made available to us. Each tablet contained ascorbic acid, 250 mg. and thiamine, 1 mg.

The doses varied from one tablet four times daily to three tablets three times daily; that is, 1,000 to 2,250 mg. daily.

The following questionnaires were collected from each patient at the end of the pollen season. Although the reports were purely clinical, it is interesting to note that approximately similar results were obtained by both observers. The data are tallied in the accompanying reports.

REPORT ON STUDIES IN BOSTON
43 Patients
1. How many seasons of hay fever? 1 to 36 years.
2. Food allergy also present: None — 19
Some — 3
Doubtful — 21.
3. Concomitant attacks of bronchial asthma: No — 26
Yes — 15.
4. First hay fever symptoms by date: Earliest — May 15
Latest — September 13.
5. How would you consider your present attacks as measured against previous years? Worse — 10
Same — 11
Better — 19
Doubtful — 3 (first season of hay fever).
6. The effects of increasing the dose gave results as: Same — 12
Better — 8
Others — 3
No increase — 20.
7. Do you think the tablets were: Not helpful — 16
Helpful — 25
Doubtful — 3.
8. Did the tablets cause gastric irritation? No — 34
Yes — 4
Doubtful — 5
The doubtful patients did not take a sufficient amount to enable them to judge.
9. Any increase in urination? No — 38
Yes — 0
Doubtful — 5 (sufficient amount not taken).
10: Do you feel generally: Same — 8
Worse — 8
Better — 22
Doubtful — 5 (sufficient amount not taken).
11. Did you also receive injection treatment for hay fever? No — 13
Yes — 30.
12. Have you received injections in previous years? No — 33
Yes — 10.
13. Do you consider the tablets modified your attacks? No — 21
Yes — 21
Doubtful — 5 (sufficient medication not taken).

REPORT ON STUDIES IN NEW YORK
27 Patients
1. How many seasons of hay fever? 1 to 36 years.
2. Food allergy also present: No — 15
Yes — 12
3. Concomitant bronchial asthma: No — 12
Yes — 15.
4. Date of first hay fever symptoms: Mid-May —5
June — 1
August — 17
September — 4.
5. How would you consider your present attacks as compared to previous years? Worse — 3
Same — 6
Less — 14
Doubtful — 3 (First season of hay fever).
6. Did increase in dosage give: Same — 0
Better — 18
Others — 9 (Either no effect or doubtful).
7. Do you think the tablets were: Not helpful — 5
Helpful — 20
Doubtful — 2.
8. Did the tablets cause gastric irritation? No — 17
Yes — 6
No answer — 4.
9. Any increase in urination? No — 17
Yes — 10.
10: Do you feel generally: Same — 4
Worse — 4
Better — 17
Doubtful — 2 (First year of symptoms).
11. Did you also receive injections for hay fever? No — 15
Yes — 30.
12. Have you received injections in previous years? No — 33
Yes — 9
No answer — 3.
13. Do you consider the tablets modified your attacks? No — 3
Yes — 24.

Although it has been shown by a number of observers that a Vitamin C deficiency will affect the susceptibility of animals to allergization, there are reports which indicate a lack of such effects. Among negative reports are those of Cohen 6 and of McDonald and Johnson, 13 who stated that Vitamin C had no effect upon an animal’s capacity for becoming sensitized eczematogenously to arsphenamine or to poison ivy or on the animal’s tendency to go into anaphylactic shock. Dragstedt and his colleagues 7 reported that the administration of Vitamin C, prior to the induction of peptone shock, failed to prevent anaphylactic reactions in dogs, stating that Vitamin C did not inhibit the liberation of histamine.

Walther, 19 using both guinea pigs and rabbits, pretreated for seven days with large amounts of Vitamin C, and then, shocked by the intratracheal introduction of the specific pneumococcus antigen, made histological studies of the tissues. He stated that the Vitamin C did not decrease the local anaphylactic pulmonary response and, in some cases, seemed to intensify it. Ardy 1 reported that guinea pigs showed no variation in the amount of their blood complement when kept on either high or low Vitamin C diets. In 1938, Walzer 20 stated that it had not been proved that Vitamin C had played a definite role in human hypersensitivity. Bundesen, 4 in 1941, maintained that there was no clear evidence that Vitamin C intake could affect allergic conditions. Sulzberger and Oser 18 reported, in 1935, that guinea pigs could be sensitized to arsphenamine much more readily when deficient in Vitamin C than when taking normal or decreased amounts. Steinbach and Klein 17 affirmed that in animals there was an increased tolerance to tuberculin when sufficient cevitamic acid was given. Kile and Pepple 12 observed that those animals showing marked Vitamin C deficiency, could be sensitized. Yoshikawa 21 helped solve the problem with his report that guinea pigs were more easily sensitized when given small quantities of Vitamin C, but were incapable of being sensitized when given large amounts. When there was a moderate intake, there was no effect.

As previously mentioned, the subject has been reviewed recently by Brown. 3 Other reviews, which may be consulted by the interested reader, include those by Banerjee 2 and by Pijoan, 14 each giving a picture of the complexity of the subject. The inter-relationship between Vitamin C, protein metabolism, calcium, and other minerals, 15 such as manganese, have not yet been explored fully. The work of Yoshikawa 21 is therefore of special interest. His statement that the administration of daily doses of 2.5 mg. of Vitamin C increased the allergic sensitivity in guinea pigs, moderate doses had no effect and larger doses (100 mg.) possessed an inhibiting influence, evidently is of great importance. Especially to be noted as an essential part of the present investigation is the magnitude of the dose employed.

An extremely skeptical analysis of the forty-three questionnaires by one of us (EAB), gave the following impressions:

Three patients, F. D., M. C., and N. N., complained of ill effects, due supposedly to the medication. The first patient stated that the tablets were laxative and the second and third reported flushing of the head and shoulders and severe headaches. If these symptoms were due to the Vitamin C and the B Complex, it would suggest that approximately 5 per cent of the patients might suffer mild, although easily controlled, side reactions.

Two patients, C. S., and H. M., were difficult to evaluate. The first patient followed a pattern similar to that of the previous year and felt that her symptoms were decreasing at the time of the Vitamin C ingestion. She stated that she was certain she would have improved without medication. The second patient, who had tree and grass pollen sensitivity, was given doses of 600 mg. daily after his tree symptoms had been present for two weeks and the pollen count had decreased. He left Boston at the beginning of the grass season and did not communicate with the physician for a further supply of medicine. His hay fever was especially severe during June and July. Neither of these patients can be used for statistical purposes.

Ten patients reported that their attacks were the same as in previous years, and that they could see no difference in their symptoms after taking four tablets daily for one week. Analysis of their histories showed that their symptoms were of the same severity before they started taking the tablets, during the time they took them, and for the remainder of the season after they ceased taking them. Forty tablets, four daily for ten days. had no demonstrable effect upon their condition.

Of these patients, three. C. P., H. P., and J. W., suffered from pollen asthma. One of this group, J. W., and another, N. P., were clinically sensitive to foods. These foods supposedly were eliminated from their diets during the period of treatment.

Eight patients complained that they were much worse while taking the tablets. Two of the patients in this group began to improve as soon as they were given coseasonal intradermal doses of ragweed pollen extract. Three of the patients, S. B., J.G.. and E. C., felt that a one-week period was not a sufficient trial, but it was concluded that since they actually felt worse for the week of medication, there was no point in giving them higher doses, or additional treatment.

The patients, who reported that they could see no measurable effects or were worse, totalled eighteen. Those who said they were improved totalled nineteen, an almost equal number. The majority of the patients were requested to report that they were not improved unless it was very clearly and objectively noticeable, and unless the improvement could be termed at least a 50 per cent or a much greater change as compared to the previous season.

One patient, in this group, P. B., presented a vasomotor coryza, perennial in type. While still taking the Vitamin C tablets she suffered a recurrence of her condition and therefore is only classified for the time period between August 15 and 'October 1. Fourteen of the patients in this group had received injections of pollen extracts for their hay fever, in some instances, this was considered a sufficient amount of material to insure a fairly satisfactory result. In no instance, however, were the tablets given until the patient showed some symptoms, and in all of them the improvement seemed to occur within a day or two, and seemed to be directly related to the medication.

One patient, C. D., received intradermal doses of ragweed pollen extract (5 units) at weekly intervals. The remaining three of the nineteen who improved, had no coseasonal treatment whatsoever, except occasionally a symptomatic type for nasal or ocular relief.

With as moderate and objective a conclusion as any clinical study warrants, it can be said that about half of the patients studied in Boston presented an improvement, which they judged to be greater than 50 percent. These results would suggest that cevitamic acid therapy is suitable for the adjuvant treatment of pollinosis. A careful examination of the patients’ histories showed no apparent reason for relief in some patients and none in others. The number who improved was not great. However, the reason for the present report, lies in the fact that in the patients whose conditions did improve, the change was quite striking, and occurred at any point in the season, within forty-eight hours after the initiation of Vitamin C therapy. It could be related neither objectively to any change in meteorologic conditions nor subjectively to purely psychologic factors.

An analysis of the patients studied in New York revealed the following:

Three took the Vitamin C tablets for a short period of time and found it of doubtful value. One of these patients, M. D., ceased treatment because of the appearance of periorbital urticaria. The other two subjects did not deem the treatment worthy of continuation.

Four patients felt that there was no benefit following the ingestion of the tablets, but nineteen patients reported benefit. Thirteen felt a marked improvement following the advancement of the dosage from 3 to 6 or 9 tablets daily.

The difference between the results in patients in Boston and those in New York may be attributed to the higher doses taken by the latter patients.

Only occasionally was there evidence of gastric irritation and there was an increase in diuresis. The feeling of well-being, experienced by the patients taking the tablets, was striking and was commented upon by both groups independently of the effect upon the pollinosis. Psychological factors, difficult to evaluate, may have played some part in these reports, especially since some patients wished to continue with the tablets after the pollen season had ended.

SUMMARY

A clinical survey of sixty patients, given Vitamin C during the ragweed hay-fever season, showed an improvement of 50 per cent or more in about half of the patients who took 250 mg. three or four times daily.

There were no untoward reactions, other than one instance of hives, and one patient, who, despite gastric irritation, continued the treatment. It may be concluded, therefore, that the use of cevitamic acid may be a suitable type of symptomatic adjuvant treatment for seasonal hay fever. It can be administered safely in doses ranging from 1,000 to 2,250 mg. daily.

While the analysis of the patients studied by one of us (EAB) showed a marked improvement in about half the number of the subjects, those studied by the other (SLR) demonstrated about three-quarters of the patients reporting improvement. This may be attributed to the fact that the former were kept on 3 or 4 tablets daily, while the latter were advanced to 6 or 9 tablets daily. The larger dose may have played a part in producing the apparently greater improvement in the larger percentage of patients.

REFERENCES

  1. Ardy, C. : Complementary activity of the serum and Vitamin C. Rev. di. Clin. Pediat., 37 :495, 1939.
  2. Banerjee, S. : Vitamin C in health and disease. Science and Culture, 9 :38, 1943. (119 references).
  3. Brown, Ethan Allan : The vitamins and allergy. Ann. Allergy, 2 :136, 1944 (56 references).
  4. Bundesen, H. N. : Detoxifying action of ascorbic acid in arsenical therapy. J.A.M.A. 117 :1692, 1941.
  5. Cody, C. C. : Vitamin therapy in otolaryngology. Arch. Otolaryngol., 41 :208, 1945.
  6. Cohen, M. B. : Vitamin C deficiency. J. Allergy, 10 :15, 1938.
  7. Dragstedt, C. A., Eyer, S. W., and Arelland, M. R. : Vitamin C and peptone shock in dogs. Proc. Soc. Exp. Biol. & Med., 38 :847, 1938.
  8. Editorial : Vitamin C and infection. Lancet, 2 :118, 1944.
  9. Editorial : Ascorbic acid as a diuretic. Lancet, 2 :186, 1944.
  10. Holmes, H. N. : Hay fever and Vitamin C. South Med. & Surg., 105 :36, 1943.
  11. Jollife, N. : Preventive and therapeutic use of vitamins. J.A.M.A., 129 :613, 1945.
  12. Kile, R. L. and Pepple, A. W. : Further investigations of poison ivy hypersensitiveness in guinea pigs. J. Invest. Dermat., 1 :59, 1938.
  13. McDonald, F. M. and Johnson, H. H. : Ascorbic acid and arsphenamine dermatitis. Arch. Dermat. & Syph., 43 :682, 1941.
  14. Pijoan, N. and Lozner, E. L. : The physiological significance of Vitamin C in man. New England M. J., 231 :14, 1944 (87 references).
  15. Rudra, M. N. : Role of manganese in the biological significance of ascorbic acid. Nature, 153 :743, 1944.
  16. Ruskin, S. L. : Studies on parallel action of Vitamin C and calcium. Am. J. Dig. Dis., S :408, 1938; Further contribution to comparative studies of physicochemical properties of gluconate and cevitamate of calcium and vitamin C. Am. J. Dig. Dis., 5 :676. 1938; Influence of Vitamin C on the anti-histamine action of various drugs. Arch. Otolaryngol., 36 :853, 1942.
  17. Steinbach, M. M. and Klein, S. J. : Effect of ascorbic acid on tolerance to tuberculin. Proc. Soc. Exper. Biol. & Med., 35 :151, 1936.
  18. Sulzberger, M. D. and Oser, B. L. : Influence of ascorbic acid of diet on sensitization of guinea pigs to neoarsphenamine. Proc. Soc. Exp. Biol. & Med. 32 :716, 1935.
  19. Walther, C. : Allergic pneumonia and Vitamin C. Ztschr. t. d. ges. exper. Med., 106 :749, 1939.
  20. Walzer, M. : A critical review of the recent literature on the dust atopen and Vitamin C. J. Allergy, 10 :74, 1938.
  21. Yoshikawa, K. : On the antiallergic effect of Vitamin C. Nagasaki Igakkai Zassi, 17 :165, 1939.

From Annals of Allergy, Volume 7, Number 1, January-February 1949, pp. 65-70, 154

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