- Email: [email protected]
An unusual case of salicylate toxicity
300
Correspondence
patients who show presence of underlying chronic disease, especially diabetes mellitus, generalized atherosclerosis, and infection of the axial region--head, neck, trunk; and perineum, rather than infection of only an extremity. Again, I thank Dr. Wyrick for his comments and hope these communications have emphasized the need for early recognition and treatment in necrotizing fasciitis.
Ronald E. Grimwood, M.D. Ohio State University, Columbus OH 43210-1228
An unusual case of salicylate toxicity To the Editor: The use of topical salicylic acid preparations in dermatology practice is quite common, although application to large areas of the body is less common. The use of oral nonsteroidal anti-inflammatory drugs (NSAIDs) is also extremely common. However, to our knowledge there is no published report of salicylate toxicity resulting from the combination of NSAID and topical salicylic acid.
Case report. We report a case of a 45-year-old white man with a 17-year history of psoriasis. He had a 3-year history of psoriatic arthritis involving the hands and feet. X-ray findings were consistent with early erosive joint changes of both the hands and feet. There was good therapeutic control of his diffuse arthralgias with naproxen (Naprosyn; Syntex Laboratories), 350-500 mg orally twice dailyl While on naproxen, in two prior hospitalizations in May 1983, and in September 1983 he had received the Goeckerman treatment with topical s.alicylic acid combined with crude coal tar in petrolatum to all of his skin, sparing only the head and groin. He denied tinnitus or nausea during either of these hospitalizaiions. On Oct. 22, 1984, the patient was admitted to our inpatient dermatology service for his tenth course of Goeckerman therapy. On admission he was found to have erythematous, scaling plaques involving 50% to 60% of his total body surface area. He continued to receive 375 mg of naproxen twice daily (body weight, 94.7 kg). Laboratory studies found to be within normal limits were complete blood count, sedimentationrate, urinalysis, total thyroxine, and chemistry group (including total protein, albumin, serum creatinine, and aspartate transaminase [AST; SGOT]). He was begun on Goeekerman treatment, consisting of 2% crude coal tar in petrolatum, to all of his skin below the neck three times a day, along with daily ultraviolet B irradiation. On his second hospital day, 3% salicylic acid was added to the crude coal tar preparation and applied to all of his skin below the neck three times a day. On the morning of the sixth hospital day the patient noted tinnitus but had no evidence of other signs of salicyIism. The serum salicylate concentration (measuring both free and protein bound serum salicylate) about 10:00 A.M. was 25.2 mg/ dl (normal, 2-20 mg/dl). A serum naproxen level was not obtained. The naproxen was stopped although the topical
Journal of the American Academyof Dermatology
salicylic acid was continueclwith the use of the same regimen. The tinnitus resolved by the tenth day of hospitalization. A repeat serum salicylate concentration on day 11 was 15.6 mgl dl. On day 17 the naproxen was restarted at 250 mg twice a day without further evidence of salicylism. Comment. The pharmacokinetics concerning the interaction of salicylic acid with the other NSAIDs is very interesting, quite complex, and not fully understood. Salicylic acid is readily absorbed from the intact skin ~ and presumably even more so through inflamed skin. Absorption is increased when applied in ointments and systemic toxicity has been reported with application to large areas of the skin. t Both naproxen (98%-99%) and salicylic acid (80%-90%) are bound to plasma proteins, predominantly to albumin. 1The simultaneous administration of both salicylic acid and naproxen will result in decreased protein binding of each,2 presumably the result of competition for limited protein-binding sites. The resultant increase in free or unbound drug has several proved and several postulated effectsl Both salicylic acid and naproxen are predominantly excreted by the kidney I and the unbound drug is more available for excretion, resulting in increased renal clearance. 2 There are insignificantly lowered peak plasma concentrations of naproxen and salicylic acid when administered simultaneously as compared to the intake of each separately because of the increased renal clearance. 2 Despite these data, however, the toxicity as seen in our patient could be explained via several hypotheses. The increase in unbound salicylic acid and naproxen could result in an increased pharmacologic effect, leading to clinical symptoms ata lower serum concentration of each drug. The increase in unbound salicylate seeondary to concomitant administration of a NSAID could be overlooked because only total serum levels of both free and protein-bound salicylic acid (and naproxen) are routinely measured. Both salicylic acid and naproxen are metabolized in the liver; salicylic acid to salicyluric acid and the glueuronides and naproxen predominantly to glucuronide. The plasma half-life of salicylic acid is 2 to 3 hours at low doses and 15 to 30 hours at high doses because of the limited ability of the liver to form metabolites, l Presumably, because the metabolic pathways in the liver are similar for both drugs, the simultaneous administration of therapeutic doses of naproxen with salicylic acid could prolong the half-life of the salicylic acid, resulting in increased serum levels as seen in our patient. The purpose of this brief report is to alert the clinician to the possibility of clinical toxicity as a result of con-
Volume 15 Number 2, Part 1 August, 1986
comitant oral administration of NSAID and topical salicylic acid.
David L. Shupp, M.D., and Arnold L. Schroeter, M.D. Mayo Clinic, Rochester, MN 55905
Correspondence
301
REFERENCES 1. Jones RE, Austin C, Ackerman AB: Extrarnammary Paget's disease--a critical reexamination. Am J Dermatopathol 1:101-132, 1979. 2. Sitakalin C, AckerrnanAB: Mammary and extramammary Paget's disease. Am J Dermatopathol 7:335-340, 1985.
REFERENCES 1. Gilman AG, Goodman LS, Gilman A: The pharmacological basis of therapeutics, ed. 6. New York, 1980, MacMillan Publishing Co., Inc. 2. Segre EJ, Chaplin M, Forchielli E, et al: Naproxen-aspirin interactions in man. Clin Pharmaeol Ther 15:374-379, 1974.
Extramammary Paget's disease To the Editor: In a recent review of Extramammary Paget's disease, (J AM ACAD DERMATOL 13:10091014, 1985), Joseph J. Chanda, M.D., reviews the cases in the English literature, from 1962 to 1982, and presents one case of his own. He failed to include the largest single series of cases of extramammary Paget's disease, reported in the American Journal of Dermatopathology in 1979.' Therefore, no mention was made that in these cases there were no examples of an underlying adnexal neoplasm associated with extramammary Paget's disease. The confusion in the interpretation of the histogenesis of extramammary Paget's disease evolves because it is more than one disease. Usually only the epidermis is involved, and rarely the epidermis is involved from a contiguous adenocarcinoma such as adenocarcinoma of the rectum. In mammary Paget's disease there is almost always an under-. lying adenocarcinoma. Because this is rare in extramammary Paget's disease, the two diseases are not analogous. Also, the Paget cells of extramammary Paget's disease are usually different, on sections stained with hematoxylin and eosin and with special stains, from the ceils of mammary Paget's disease? It was not the intent of our article to establish the incidence of internal malignancy in extramammary Paget's disease or to add specifically to the number of reported cases, but our intent was to discuss fifty-five eases clinically, histologically, and biologically so that there would be a better understanding of the entity. Dr. Chanda states, "These series were collated into a large group and analyzed as a whole in the hope that more information about the disease would become apparent," but he failed to give a complete review of the subject. Robert E. Jones, Jr., M.D. 1025 South 18th St., Birmingham, AL 35256
Reply To the Editor: Dr. Jones apparently took umbrage at the fact that in my recent review of extramammary Paget's disease I did not include his article discussing fifty-five cases of extramammary Paget's disease reported in 1979. ~ At the time I wrote my review I was aware of Dr. Jones' article and had thoroughly read it. I chose not to include his cases in my review for several reasons. The single most important reason was that Dr. Jones did not identify, anywhere in his article, the source or sources of his case material, and consequently I was unable to determine if any, some, all, or none of his cases had been reported previously. There was a brief acknowledgment at the end of Dr. Jones' article suggesting that some of his case material had been obtained from other institutions and, therefore, may have been reported previously, but again no definite information in this regard was provided. Because I could not determine if any of his cases represented duplication of previously reported material, I was reluctant to include them in my review. In addition, Dr. Jones' article (which focused primarily on the histopathogenesis and histopathology of extramammary Paget's disease) did not provide the reader with any clinical information on approximately 20% of his cases. The clinical information provided on the remaining 80% of his cases was less than complete (i.e., treatment unspecified in numerous cases; presence or absence of internal malignancy unspecified in fifty-two of fifty-five cases; concurrence data about internal malignancy unspecified; completion or lack of completion of internal malignancy search unspecified). Because my review emphasized clinical features, i.e., prognosis and relationship to internal malignancy, I believed that such information as Dr. Jones' article lacked was vital to my review. Dr. Jones is apparently disturbed by the discrepancy in incidence of underlying cutaneous adnexal adenocarcinoma in exlxamammary Paget's disease reported in his article (0 of 55 cases; 0%) and that in my review (46 of 194 cases; 24%). However, I clearly state that this figure represents an average for my entire series, with a range of 0% to 54%. Perhaps this discrepancy represents differing opinions by different histopathol-
Correspondence
patients who show presence of underlying chronic disease, especially diabetes mellitus, generalized atherosclerosis, and infection of the axial region--head, neck, trunk; and perineum, rather than infection of only an extremity. Again, I thank Dr. Wyrick for his comments and hope these communications have emphasized the need for early recognition and treatment in necrotizing fasciitis.
Ronald E. Grimwood, M.D. Ohio State University, Columbus OH 43210-1228
An unusual case of salicylate toxicity To the Editor: The use of topical salicylic acid preparations in dermatology practice is quite common, although application to large areas of the body is less common. The use of oral nonsteroidal anti-inflammatory drugs (NSAIDs) is also extremely common. However, to our knowledge there is no published report of salicylate toxicity resulting from the combination of NSAID and topical salicylic acid.
Case report. We report a case of a 45-year-old white man with a 17-year history of psoriasis. He had a 3-year history of psoriatic arthritis involving the hands and feet. X-ray findings were consistent with early erosive joint changes of both the hands and feet. There was good therapeutic control of his diffuse arthralgias with naproxen (Naprosyn; Syntex Laboratories), 350-500 mg orally twice dailyl While on naproxen, in two prior hospitalizations in May 1983, and in September 1983 he had received the Goeckerman treatment with topical s.alicylic acid combined with crude coal tar in petrolatum to all of his skin, sparing only the head and groin. He denied tinnitus or nausea during either of these hospitalizaiions. On Oct. 22, 1984, the patient was admitted to our inpatient dermatology service for his tenth course of Goeckerman therapy. On admission he was found to have erythematous, scaling plaques involving 50% to 60% of his total body surface area. He continued to receive 375 mg of naproxen twice daily (body weight, 94.7 kg). Laboratory studies found to be within normal limits were complete blood count, sedimentationrate, urinalysis, total thyroxine, and chemistry group (including total protein, albumin, serum creatinine, and aspartate transaminase [AST; SGOT]). He was begun on Goeekerman treatment, consisting of 2% crude coal tar in petrolatum, to all of his skin below the neck three times a day, along with daily ultraviolet B irradiation. On his second hospital day, 3% salicylic acid was added to the crude coal tar preparation and applied to all of his skin below the neck three times a day. On the morning of the sixth hospital day the patient noted tinnitus but had no evidence of other signs of salicyIism. The serum salicylate concentration (measuring both free and protein bound serum salicylate) about 10:00 A.M. was 25.2 mg/ dl (normal, 2-20 mg/dl). A serum naproxen level was not obtained. The naproxen was stopped although the topical
Journal of the American Academyof Dermatology
salicylic acid was continueclwith the use of the same regimen. The tinnitus resolved by the tenth day of hospitalization. A repeat serum salicylate concentration on day 11 was 15.6 mgl dl. On day 17 the naproxen was restarted at 250 mg twice a day without further evidence of salicylism. Comment. The pharmacokinetics concerning the interaction of salicylic acid with the other NSAIDs is very interesting, quite complex, and not fully understood. Salicylic acid is readily absorbed from the intact skin ~ and presumably even more so through inflamed skin. Absorption is increased when applied in ointments and systemic toxicity has been reported with application to large areas of the skin. t Both naproxen (98%-99%) and salicylic acid (80%-90%) are bound to plasma proteins, predominantly to albumin. 1The simultaneous administration of both salicylic acid and naproxen will result in decreased protein binding of each,2 presumably the result of competition for limited protein-binding sites. The resultant increase in free or unbound drug has several proved and several postulated effectsl Both salicylic acid and naproxen are predominantly excreted by the kidney I and the unbound drug is more available for excretion, resulting in increased renal clearance. 2 There are insignificantly lowered peak plasma concentrations of naproxen and salicylic acid when administered simultaneously as compared to the intake of each separately because of the increased renal clearance. 2 Despite these data, however, the toxicity as seen in our patient could be explained via several hypotheses. The increase in unbound salicylic acid and naproxen could result in an increased pharmacologic effect, leading to clinical symptoms ata lower serum concentration of each drug. The increase in unbound salicylate seeondary to concomitant administration of a NSAID could be overlooked because only total serum levels of both free and protein-bound salicylic acid (and naproxen) are routinely measured. Both salicylic acid and naproxen are metabolized in the liver; salicylic acid to salicyluric acid and the glueuronides and naproxen predominantly to glucuronide. The plasma half-life of salicylic acid is 2 to 3 hours at low doses and 15 to 30 hours at high doses because of the limited ability of the liver to form metabolites, l Presumably, because the metabolic pathways in the liver are similar for both drugs, the simultaneous administration of therapeutic doses of naproxen with salicylic acid could prolong the half-life of the salicylic acid, resulting in increased serum levels as seen in our patient. The purpose of this brief report is to alert the clinician to the possibility of clinical toxicity as a result of con-
Volume 15 Number 2, Part 1 August, 1986
comitant oral administration of NSAID and topical salicylic acid.
David L. Shupp, M.D., and Arnold L. Schroeter, M.D. Mayo Clinic, Rochester, MN 55905
Correspondence
301
REFERENCES 1. Jones RE, Austin C, Ackerman AB: Extrarnammary Paget's disease--a critical reexamination. Am J Dermatopathol 1:101-132, 1979. 2. Sitakalin C, AckerrnanAB: Mammary and extramammary Paget's disease. Am J Dermatopathol 7:335-340, 1985.
REFERENCES 1. Gilman AG, Goodman LS, Gilman A: The pharmacological basis of therapeutics, ed. 6. New York, 1980, MacMillan Publishing Co., Inc. 2. Segre EJ, Chaplin M, Forchielli E, et al: Naproxen-aspirin interactions in man. Clin Pharmaeol Ther 15:374-379, 1974.
Extramammary Paget's disease To the Editor: In a recent review of Extramammary Paget's disease, (J AM ACAD DERMATOL 13:10091014, 1985), Joseph J. Chanda, M.D., reviews the cases in the English literature, from 1962 to 1982, and presents one case of his own. He failed to include the largest single series of cases of extramammary Paget's disease, reported in the American Journal of Dermatopathology in 1979.' Therefore, no mention was made that in these cases there were no examples of an underlying adnexal neoplasm associated with extramammary Paget's disease. The confusion in the interpretation of the histogenesis of extramammary Paget's disease evolves because it is more than one disease. Usually only the epidermis is involved, and rarely the epidermis is involved from a contiguous adenocarcinoma such as adenocarcinoma of the rectum. In mammary Paget's disease there is almost always an under-. lying adenocarcinoma. Because this is rare in extramammary Paget's disease, the two diseases are not analogous. Also, the Paget cells of extramammary Paget's disease are usually different, on sections stained with hematoxylin and eosin and with special stains, from the ceils of mammary Paget's disease? It was not the intent of our article to establish the incidence of internal malignancy in extramammary Paget's disease or to add specifically to the number of reported cases, but our intent was to discuss fifty-five eases clinically, histologically, and biologically so that there would be a better understanding of the entity. Dr. Chanda states, "These series were collated into a large group and analyzed as a whole in the hope that more information about the disease would become apparent," but he failed to give a complete review of the subject. Robert E. Jones, Jr., M.D. 1025 South 18th St., Birmingham, AL 35256
Reply To the Editor: Dr. Jones apparently took umbrage at the fact that in my recent review of extramammary Paget's disease I did not include his article discussing fifty-five cases of extramammary Paget's disease reported in 1979. ~ At the time I wrote my review I was aware of Dr. Jones' article and had thoroughly read it. I chose not to include his cases in my review for several reasons. The single most important reason was that Dr. Jones did not identify, anywhere in his article, the source or sources of his case material, and consequently I was unable to determine if any, some, all, or none of his cases had been reported previously. There was a brief acknowledgment at the end of Dr. Jones' article suggesting that some of his case material had been obtained from other institutions and, therefore, may have been reported previously, but again no definite information in this regard was provided. Because I could not determine if any of his cases represented duplication of previously reported material, I was reluctant to include them in my review. In addition, Dr. Jones' article (which focused primarily on the histopathogenesis and histopathology of extramammary Paget's disease) did not provide the reader with any clinical information on approximately 20% of his cases. The clinical information provided on the remaining 80% of his cases was less than complete (i.e., treatment unspecified in numerous cases; presence or absence of internal malignancy unspecified in fifty-two of fifty-five cases; concurrence data about internal malignancy unspecified; completion or lack of completion of internal malignancy search unspecified). Because my review emphasized clinical features, i.e., prognosis and relationship to internal malignancy, I believed that such information as Dr. Jones' article lacked was vital to my review. Dr. Jones is apparently disturbed by the discrepancy in incidence of underlying cutaneous adnexal adenocarcinoma in exlxamammary Paget's disease reported in his article (0 of 55 cases; 0%) and that in my review (46 of 194 cases; 24%). However, I clearly state that this figure represents an average for my entire series, with a range of 0% to 54%. Perhaps this discrepancy represents differing opinions by different histopathol-