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INDOMETHACIN IN HYPERCALCÆMIA
365 INDOMETHACIN IN HYPERCALCÆMIA
uniformly effective in our few patients. of its administration, its relative lack of the toxicity, plus possibility of an effect in patients refractory to or intolerant of mithramycin, should prompt further studies of indomethacin in the management of hypercalcmmia associated with malignancy.
methacin
SIR,-Dr Blum1 has reported three patients with treated with hypercalcaemia, twoof whom were successfully 2
Brereton et al. have described the correction of hypercalcaemia in a single patient receiving this drug. However, Benvenisti and Goldberg3 have
indomethacin.
was ineffective in a patient with lung carcinoma and hypercalcaemia. We wish to report five additional patients with hypercalcaemia secondary to malignancy who were treated with indomethacin. Four of our patients had multiple myeloma and the fifth had renal-cell carcinoma with bone metastases. Three
reported
was not
However, the
ease
that indomethacin
Roswell Park Memorial Institute, 666 Elm Street, Buffalo, N.Y. 14203, U.S.A. *
AYDIN DINDOGRU* SALMAN GAILANI EDWARD S. HENDERSON H. JAMES WALLACE, JR. JOHN FITZPATRICK.
Present address: Genesee Hospital, Division of Oncology, 224 Alexander Street, Rochester, N.Y. 14607, U.S.A.
CO-TRIMOXAZOLE IN CHRONIC RENAL FAILURE cannot let the article of Dr Tasker and his SiR,—I without comment. colleagues1 pass by We have clearly demonstrated the accumulation of conjugated sulphamethoxazole in patients with a creatinine clearance under 20 mllmin.2 Our results were as follows: Creatinine clearance
rou Group
(mi/min) (mean values)
Daily
patients
serum
calcium levels in five patients during indomethacin trial.
had
developed hypercalcamua while receiving of them was well hydrated before the hypercalcaemic episode. In another patient, hypercalcaEmia was not controlled well with hydration plus two injections of mithramycin (further mithramycin was interdicted by the development of severe thrombocytopenia). Serumprostaglandin determinations were carried out in two patients prior to this trial and the levels were not elevated. During the study period the average daily fluid intake was 2175 c.cm. per sq.m. per day per patient. Indomethacin was administered orally at a daily dose of 2 mg. per kg. in steroids and
one
4-6 divided doses. SerumAll patients tolerated indomethacin well. calcium fell promptly in one patient. The decrease in calcium was gradual in two patients, one of whom had hypercalcaemia that was not controlled with hydration and mithramycin prior to indomethacin. In onepatient the response was slight, while the other patient did not respond to indomethacin. Bone pain was much relieved by this drug in one patient. The exact mechanism of hypercalcsemia in malignancy remains uncertain. Prostaglandins may be responsible in some tumour types.2,4 Although the parathyroid-hormone (P.T.H.) level was not determined, one of Dr Blum’s patients had parathyroid adenoma. The efficacy of indomethacin in this particular case could be explained by the studies of Powles et al.,’> who demonstrated that aspirin, another prostaglandin synthetase inhibitor, significantly reduced the P.T.H.-induced radioactive-calcium release from bone in vitro. The decrease in serum-calcium observed in our cases may be fully or partly attributable to hydration. Indo-
-
Indeed, in 5 uraEmic patients with creatinine clearance of 12-08±4-52 ml/min, we found blood persistence of conjugated sulphamethoxazole of 13-70 ±2-10% of the peak level, 20 days after a single oral dose of 1 g of the drug. This conjugated sulpha has no therapeutic effect but retains all the toxic traits of the drug. A plasma factor which inhibits red-cell hexose monophosphate3 shunt metabolism, and thereby shortens redcell survival, has been found to be accumulated in many uraemic patients.3 In these cases, Heinz-body acute hsemolytic anxmia may occur if oxidant drugs such as sulphonamides are administrated. Renal Unit, Central Emek Hospital, Israel.
3. 4.
5.
Blum, I. Lancet, 1975, i, 866. Brereton, H. D., Halushka, P. V., Alexander, R. W., Mason, D. M., Keiser, H. R., DeVita, Jr., V. T. New Engl. J. Med. 1974, 291, 83. Benvenisti, D., Goldberg, H. ibid. 1975, 292, 1189. Tashjian, A. H., Voelkel, E. F., Goldhaber, P., Levine, L. Fedn Proc. 1974, 33, 81. Powles, T. J., Easty, D. M., Easty, G. C., Bondy, P. K., MunroNeville, A. Nature New Biol. 1973, 245, 83.
LAZARO GOTLOIB.
HYPERPIGMENTATION AFTER CANCER CHEMOTHERAPY
SiR,—Inoted the comments of Dr Priestman and Dr James (June 14, p. 1337) and those in reply (July 19, p. 128),
describing hyperpigmentation of the nails in patients receiving cancer chemotherapy. The skin tumour, mycosis fungoides, is being treated by topical nitrogen mustard (HN 2).4 This treatment is associated with hyperpigmentation beginning in the flexures and gradually spreading centrally and unevenly.6 It also occurs in Blacks. The mechanism is thought to be due to alteration in melanosome packaging within keratinocytes.6 Caucasoids usually have melanosomes arranged in membrane-bound groups of
cytoplasm.’ 1. 2.
1. 2.
Serum persistence of sulphamethoxazole 24 h after peak level (percentage of peak level) after a single dose of 1 g of the drop
3. 4. 5. 6. 7.
They
are
two or more in the cell smaller than those of negroids
Tasker, P. R. W., MacGregor, G. A., de Wardener, H. E., Thomas, R. D., Jones, N. F. Lancet, 1975, i, 1216. Proceedings of the Eleventh Congress of the European Dialysis and Transplant Association, 1974. Yawata, Y., Howe, R., Jacobs, H. S. Ann. intern. Med. 1973, 79, 362. Van Scott, E. J., Kalmanson, J. D. Cancer, 1973, 32, 18. Van Scott, E. J., Winters, P. L. Archs Derm. 1970, 102, 507. Flaxman, B. A., Sosis, A. C., Van Scott, E. J. J. invest. Derm. 1973, 60, 321. Hori, Y., Toda, K., Pathak, M. A., Clark, W. H., Jr., Fitzpatrick, T. B. J. ultrastruct. Res. 1968, 25, 109.
uniformly effective in our few patients. of its administration, its relative lack of the toxicity, plus possibility of an effect in patients refractory to or intolerant of mithramycin, should prompt further studies of indomethacin in the management of hypercalcmmia associated with malignancy.
methacin
SIR,-Dr Blum1 has reported three patients with treated with hypercalcaemia, twoof whom were successfully 2
Brereton et al. have described the correction of hypercalcaemia in a single patient receiving this drug. However, Benvenisti and Goldberg3 have
indomethacin.
was ineffective in a patient with lung carcinoma and hypercalcaemia. We wish to report five additional patients with hypercalcaemia secondary to malignancy who were treated with indomethacin. Four of our patients had multiple myeloma and the fifth had renal-cell carcinoma with bone metastases. Three
reported
was not
However, the
ease
that indomethacin
Roswell Park Memorial Institute, 666 Elm Street, Buffalo, N.Y. 14203, U.S.A. *
AYDIN DINDOGRU* SALMAN GAILANI EDWARD S. HENDERSON H. JAMES WALLACE, JR. JOHN FITZPATRICK.
Present address: Genesee Hospital, Division of Oncology, 224 Alexander Street, Rochester, N.Y. 14607, U.S.A.
CO-TRIMOXAZOLE IN CHRONIC RENAL FAILURE cannot let the article of Dr Tasker and his SiR,—I without comment. colleagues1 pass by We have clearly demonstrated the accumulation of conjugated sulphamethoxazole in patients with a creatinine clearance under 20 mllmin.2 Our results were as follows: Creatinine clearance
rou Group
(mi/min) (mean values)
Daily
patients
serum
calcium levels in five patients during indomethacin trial.
had
developed hypercalcamua while receiving of them was well hydrated before the hypercalcaemic episode. In another patient, hypercalcaEmia was not controlled well with hydration plus two injections of mithramycin (further mithramycin was interdicted by the development of severe thrombocytopenia). Serumprostaglandin determinations were carried out in two patients prior to this trial and the levels were not elevated. During the study period the average daily fluid intake was 2175 c.cm. per sq.m. per day per patient. Indomethacin was administered orally at a daily dose of 2 mg. per kg. in steroids and
one
4-6 divided doses. SerumAll patients tolerated indomethacin well. calcium fell promptly in one patient. The decrease in calcium was gradual in two patients, one of whom had hypercalcaemia that was not controlled with hydration and mithramycin prior to indomethacin. In onepatient the response was slight, while the other patient did not respond to indomethacin. Bone pain was much relieved by this drug in one patient. The exact mechanism of hypercalcsemia in malignancy remains uncertain. Prostaglandins may be responsible in some tumour types.2,4 Although the parathyroid-hormone (P.T.H.) level was not determined, one of Dr Blum’s patients had parathyroid adenoma. The efficacy of indomethacin in this particular case could be explained by the studies of Powles et al.,’> who demonstrated that aspirin, another prostaglandin synthetase inhibitor, significantly reduced the P.T.H.-induced radioactive-calcium release from bone in vitro. The decrease in serum-calcium observed in our cases may be fully or partly attributable to hydration. Indo-
-
Indeed, in 5 uraEmic patients with creatinine clearance of 12-08±4-52 ml/min, we found blood persistence of conjugated sulphamethoxazole of 13-70 ±2-10% of the peak level, 20 days after a single oral dose of 1 g of the drug. This conjugated sulpha has no therapeutic effect but retains all the toxic traits of the drug. A plasma factor which inhibits red-cell hexose monophosphate3 shunt metabolism, and thereby shortens redcell survival, has been found to be accumulated in many uraemic patients.3 In these cases, Heinz-body acute hsemolytic anxmia may occur if oxidant drugs such as sulphonamides are administrated. Renal Unit, Central Emek Hospital, Israel.
3. 4.
5.
Blum, I. Lancet, 1975, i, 866. Brereton, H. D., Halushka, P. V., Alexander, R. W., Mason, D. M., Keiser, H. R., DeVita, Jr., V. T. New Engl. J. Med. 1974, 291, 83. Benvenisti, D., Goldberg, H. ibid. 1975, 292, 1189. Tashjian, A. H., Voelkel, E. F., Goldhaber, P., Levine, L. Fedn Proc. 1974, 33, 81. Powles, T. J., Easty, D. M., Easty, G. C., Bondy, P. K., MunroNeville, A. Nature New Biol. 1973, 245, 83.
LAZARO GOTLOIB.
HYPERPIGMENTATION AFTER CANCER CHEMOTHERAPY
SiR,—Inoted the comments of Dr Priestman and Dr James (June 14, p. 1337) and those in reply (July 19, p. 128),
describing hyperpigmentation of the nails in patients receiving cancer chemotherapy. The skin tumour, mycosis fungoides, is being treated by topical nitrogen mustard (HN 2).4 This treatment is associated with hyperpigmentation beginning in the flexures and gradually spreading centrally and unevenly.6 It also occurs in Blacks. The mechanism is thought to be due to alteration in melanosome packaging within keratinocytes.6 Caucasoids usually have melanosomes arranged in membrane-bound groups of
cytoplasm.’ 1. 2.
1. 2.
Serum persistence of sulphamethoxazole 24 h after peak level (percentage of peak level) after a single dose of 1 g of the drop
3. 4. 5. 6. 7.
They
are
two or more in the cell smaller than those of negroids
Tasker, P. R. W., MacGregor, G. A., de Wardener, H. E., Thomas, R. D., Jones, N. F. Lancet, 1975, i, 1216. Proceedings of the Eleventh Congress of the European Dialysis and Transplant Association, 1974. Yawata, Y., Howe, R., Jacobs, H. S. Ann. intern. Med. 1973, 79, 362. Van Scott, E. J., Kalmanson, J. D. Cancer, 1973, 32, 18. Van Scott, E. J., Winters, P. L. Archs Derm. 1970, 102, 507. Flaxman, B. A., Sosis, A. C., Van Scott, E. J. J. invest. Derm. 1973, 60, 321. Hori, Y., Toda, K., Pathak, M. A., Clark, W. H., Jr., Fitzpatrick, T. B. J. ultrastruct. Res. 1968, 25, 109.