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Short-term treatment with indinavir fails to reduce the glucose requirement in a patient with malignant insulinoma
Letters to the Editor
is associated with a different set of infections, including unusual organisms such as Pneumocystis, Listeria, Mycobacterium tuberculosis, Nocardia, and herpes viruses (7). Our patient was not neutropenic, but the marked reduction in the CD4 count after treatment with fludarabine and steroids may have led to the cryptococcal infection. This complication adds to the expanding spectrum of opportunistic infections associated with fludarabine therapy. Chor Sang Chim, MBChB Raymond Liang, MD Department of Medicine Samson Sai Yin Wong, MBBS Kwok Yung Yuen, MD Department of Microbiology Queen Mary Hospital University of Hong Kong Hong Kong, China 1. Diamond RD. Cryptococcus neoformans. In: Mandell GL, Bennett JE, Dolin R. Principle and Practice of Infectious Diseases. 4th ed. New York: Churchill Livingstone; 1995: 2331–2340. 2. Mitchell TG, Perfect JR. Cryptococcosis in the era of AIDS—100 years after the discovery of Cryptococcus neoformans. Clin Microbiol Rev. 1995;8:515–548. 3. Powderly WG, Saag MS, Cloud GA, et al. A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. NEJM. 1992; 326:793–798. 4. Paya CV. Fungal infections in solid-organ transplantation. Clin Infect Dis. 1993;16: 677– 688. 5. McLaughlin P, Hagemeister FB, Romaguera YE, et al. Fludarabine, mitoxantrone and dexamethasone: an effective new regimen for indolent lymphoma. J Clin Oncol. 1996; 14:1262–1268. 6. O’Brien S, Kantarjian H, Beran M, et al. Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis derived prognostic model for response to treatment. Blood. 1993;82:1695–1700. 7. Morrison VA. The infectious complications of chronic lymphocytic leukemia. Semin Oncol. 1998;25:98 –106.
524
April 15, 2000
SHORT-TERM TREATMENT WITH INDINAVIR FAILS TO REDUCE THE GLUCOSE REQUIREMENT IN A PATIENT WITH MALIGNANT INSULINOMA To the Editor: A 78-year-old woman with unresectable metastatic insulinoma presented with recurrent severe hypoglycemia requiring intravenous glucose administration. She had been treated successfully with systemic chemotherapy for the previous 2 years. Because she continued to require intravenous glucose after treatment with diazoxide and octreotide, we attempted to reduce insulin sensitivity with indinavir, a human immunodeficiency virus (HIV) protease inhibitor. Treatment of HIV-infected patients with protease inhibitors appears to be associated with the development of insulin resistance (1). After obtaining informed consent, indinavir (800 mg) was administered three times per day (at 6 AM, 2 PM, and 10 PM) for 4 days. The patient was allowed to eat during the day (6 AM to 4 PM), and the effects of indinavir on glucose requirement were evaluated during starvation at night (8 PM to 6 AM). Serum C-peptide and leptin levels were measured every 3 hours. The patient was observed for a total of 11 days; measurements were taken during treatment (days 2 to 5) and on 3 nontreatment days (days 1, 7, and 11). Treatment with indinavir did not change the required glucose infusion rate (treatment days 9.5 ⫾ 0.2 [mean ⫾ SD] mg/kg/min versus nontreatment days 9.4 ⫾ 05 mg/kg/min). Leptin concentrations fell (day 1, 5.3 ⫾ 0.07 g/L, versus day 11, 3.65 ⫾ 0.09 g/L) and C-peptide levels rose
THE AMERICAN JOURNAL OF MEDICINE威
Volume 108
constantly (day 1, 7.75 ⫾ 0.47 g/L, versus day 11, 14.4 ⫾ 0.85 g/L), as occurs during protease inhibitor treatment of HIV-infected patients (2,3). As no decrease in glucose requirement was observed, the development of insulin resistance was unlikely to explain the rise in C-peptide levels. It is possible that treatment with indinavir resulted in a direct stimulation of beta or tumor cells. Alternatively, indinavir could have had an effect on C-peptide degradation or elimination. Because unresectable metastatic insulinoma is rare, experience in the treatment of these patients is limited. The trial with indinavir may have failed to reduce our patient’s glucose requirement because the 4-day treatment period was too short to induce alterations of insulin sensitivity. We conclude that indinavir does not appear to be an efficient drug for the treatment of metastatic insulinoma. Morten Schu¨tt, MD Sven Philip Aries, MD Mathias Rosenfeldt Achim Peters, MD Harald H. Klein, MD Departments of Internal Medicine I and II Medical University of Lu¨beck Lu¨beck, Germany 1. Walli R, Herford O, Michl GM, et al. Treatment with protease inhibitors associated with peripheral insulin resistance and impaired glucose tolerance in HIV-1 infected patients. AIDS. 1998;12:167–173. 2. Carr A, Samaras K, Thorisdottir A, et al. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet. 1999;353: 2093–2099. 3. Behrens G, Dejam A, Schmidt H, et al. Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patients under treatment with protease inhibitors. AIDS. 1999;13:63–70.
is associated with a different set of infections, including unusual organisms such as Pneumocystis, Listeria, Mycobacterium tuberculosis, Nocardia, and herpes viruses (7). Our patient was not neutropenic, but the marked reduction in the CD4 count after treatment with fludarabine and steroids may have led to the cryptococcal infection. This complication adds to the expanding spectrum of opportunistic infections associated with fludarabine therapy. Chor Sang Chim, MBChB Raymond Liang, MD Department of Medicine Samson Sai Yin Wong, MBBS Kwok Yung Yuen, MD Department of Microbiology Queen Mary Hospital University of Hong Kong Hong Kong, China 1. Diamond RD. Cryptococcus neoformans. In: Mandell GL, Bennett JE, Dolin R. Principle and Practice of Infectious Diseases. 4th ed. New York: Churchill Livingstone; 1995: 2331–2340. 2. Mitchell TG, Perfect JR. Cryptococcosis in the era of AIDS—100 years after the discovery of Cryptococcus neoformans. Clin Microbiol Rev. 1995;8:515–548. 3. Powderly WG, Saag MS, Cloud GA, et al. A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. NEJM. 1992; 326:793–798. 4. Paya CV. Fungal infections in solid-organ transplantation. Clin Infect Dis. 1993;16: 677– 688. 5. McLaughlin P, Hagemeister FB, Romaguera YE, et al. Fludarabine, mitoxantrone and dexamethasone: an effective new regimen for indolent lymphoma. J Clin Oncol. 1996; 14:1262–1268. 6. O’Brien S, Kantarjian H, Beran M, et al. Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis derived prognostic model for response to treatment. Blood. 1993;82:1695–1700. 7. Morrison VA. The infectious complications of chronic lymphocytic leukemia. Semin Oncol. 1998;25:98 –106.
524
April 15, 2000
SHORT-TERM TREATMENT WITH INDINAVIR FAILS TO REDUCE THE GLUCOSE REQUIREMENT IN A PATIENT WITH MALIGNANT INSULINOMA To the Editor: A 78-year-old woman with unresectable metastatic insulinoma presented with recurrent severe hypoglycemia requiring intravenous glucose administration. She had been treated successfully with systemic chemotherapy for the previous 2 years. Because she continued to require intravenous glucose after treatment with diazoxide and octreotide, we attempted to reduce insulin sensitivity with indinavir, a human immunodeficiency virus (HIV) protease inhibitor. Treatment of HIV-infected patients with protease inhibitors appears to be associated with the development of insulin resistance (1). After obtaining informed consent, indinavir (800 mg) was administered three times per day (at 6 AM, 2 PM, and 10 PM) for 4 days. The patient was allowed to eat during the day (6 AM to 4 PM), and the effects of indinavir on glucose requirement were evaluated during starvation at night (8 PM to 6 AM). Serum C-peptide and leptin levels were measured every 3 hours. The patient was observed for a total of 11 days; measurements were taken during treatment (days 2 to 5) and on 3 nontreatment days (days 1, 7, and 11). Treatment with indinavir did not change the required glucose infusion rate (treatment days 9.5 ⫾ 0.2 [mean ⫾ SD] mg/kg/min versus nontreatment days 9.4 ⫾ 05 mg/kg/min). Leptin concentrations fell (day 1, 5.3 ⫾ 0.07 g/L, versus day 11, 3.65 ⫾ 0.09 g/L) and C-peptide levels rose
THE AMERICAN JOURNAL OF MEDICINE威
Volume 108
constantly (day 1, 7.75 ⫾ 0.47 g/L, versus day 11, 14.4 ⫾ 0.85 g/L), as occurs during protease inhibitor treatment of HIV-infected patients (2,3). As no decrease in glucose requirement was observed, the development of insulin resistance was unlikely to explain the rise in C-peptide levels. It is possible that treatment with indinavir resulted in a direct stimulation of beta or tumor cells. Alternatively, indinavir could have had an effect on C-peptide degradation or elimination. Because unresectable metastatic insulinoma is rare, experience in the treatment of these patients is limited. The trial with indinavir may have failed to reduce our patient’s glucose requirement because the 4-day treatment period was too short to induce alterations of insulin sensitivity. We conclude that indinavir does not appear to be an efficient drug for the treatment of metastatic insulinoma. Morten Schu¨tt, MD Sven Philip Aries, MD Mathias Rosenfeldt Achim Peters, MD Harald H. Klein, MD Departments of Internal Medicine I and II Medical University of Lu¨beck Lu¨beck, Germany 1. Walli R, Herford O, Michl GM, et al. Treatment with protease inhibitors associated with peripheral insulin resistance and impaired glucose tolerance in HIV-1 infected patients. AIDS. 1998;12:167–173. 2. Carr A, Samaras K, Thorisdottir A, et al. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet. 1999;353: 2093–2099. 3. Behrens G, Dejam A, Schmidt H, et al. Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patients under treatment with protease inhibitors. AIDS. 1999;13:63–70.