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Granulocyte colony-stimulating factor for clozapine-induced agranulocytosis
1097
the effect reported by Smith. This is not unexpected since no link between ceftriaxone and motoneuron degeneration is known, and the neuronal and axonal pathology of MND is not expected to recover over 3 weeks. Many patients with MND follow closely the reported course of this disease. It is clear that they are willing to try whatever new treatment becomes available, and especially so when a new therapy seems to have dramatic effects. To refuse these patients a therapy without side-effects or toxicity is hard, since no alternative can be offered. The medical community should therefore be reluctant to publish single and incomplete observations of treatment results, whether there is a rationale for the treatment or not. Such findings might induce disappointment and despair in patients, may interfere with continuing trials and cause unnecessary drop-outs from trials, can result in expensive and useless therapies, and might take away the interest of other groups to evaluate scientifically the therapy in question. The treatment of MND is threatened by confusion because of the sudden availability of neuroactive substances and lack of knowledge of the primary pathogenesis of the disease. We should be careful not to increase confusion among patients.
reproduce
Department of Neurology, University Hospital Gasthuisberg, B-3000 Leuven, Belgium
WIM ROBBERECHT
1. Smith LG. Improvement of patient with amyotrophic lateral sclerosis given ceftriaxone. Lancet 1992; 339: 1417. 2. Norris FH, Calanchini PR, Fallat RJ, Panchari S, Jewett B. The administration of guanidine in amyotrophic lateral sclerosis. Neurology 1974; 24: 721-28. 3. Plaitakis A, Mandeli J, Smith J, Yahr MD. Pilot trial of branched-chain aminoacids in amyotrophic lateral sclerosis. Lancet 1988; i: 1015-21.
Granulocyte colony-stimulating factor for clozapine-induced agranulocytosis SiR,—The successful use of filgrastim, a granulocyte colonystimulating factor (G-CSF), in the management of neutropenic fever after chemotherapy led us to use it in drug-induced agranulocytosis.1 We have studied four patients with clozapine-induced agranulocytosis2,3 to determine whether early administration of filgrastim would shorten the duration of neutropenia. Each patient had a normal white blood count (WBC) and absolute neutrophil count (ANC) when clozapine was started. Clozapine was discontinued when WBC was under 3 x 109/1 or ANC was below 1-5 x 109/1. Three patients had bone marrow aspiration and biopsy, which documented absence of myeloid precursors. All had severe agranulocytosis with ANC below 0-1 x 109/1 for at least 3 days. Filgrastim 300-600 ug per day subcutaneously was started within 48 h of neutropenia. All received standard prophylactic antibiotics, reverse isolation, and broad-spectrum antibiotics for neutropenic fever, and all myelotoxic drugs were discontinued. The table shows a comparison of the time to neutrophil recovery in our four patients with seven consecutive patients who developed clozapine-induced agranulocytosis in trials between 1977 and 1989. This historical control group all had an ANC nadir under 011x 109/1 and bone marrow examination to document absence of myeloid precursors. They were treated before G-CSF was commercially available, and are representative of the natural history of this disorder (refs 4 and 5, and S. L. G.). The two groups were similar in age, and duration and dose of clozapine treatment. In all patients, toxicity was restricted to the myeloid lineage without evidence of anaemia or thrombocytopenia. Patients receiving G-CSF had a significantly shorter period of agranulocytosis (ANC < 0-5 x 109/1) than the historical group, a mean decrease of 7days. Three of the filgrastim-treated patients continued to receive the growth factor for FILGRASTIM FOR CLOZAPINE-INDUCED AGRANULOCYTOSIS
Mean (SD). *p<0 005 between groups. Unpaged Ranges t10-21 and t6-11 days
t test
48-72 h after recovery of neutrophil count to over 0-5 x 109/1. The peak ANC in these three patients was 48-6 x 109/1 compared with 9-3x109/1 in the patient in whom filgrastim was discontinued within 24 h of recovery. No patient had an adverse reaction to the mean
transient leucocytosis. Our findings suggest that G-CSF reduces the duration of agranulocytosis in patients with the most severe form of clozapineinduced bone marrow suppression, that is in those who have pure myeloid precursor aplasia and ANC nadir under 01 x 109/1. G-CSF may not be indicated for mild neutropenia (ANC > 0-5 x 109/1). However, it is reasonable to use G-CSF in clozapine-treated patients with agranulocytosis for several reasons. First, clozapine may cause a longer period of severe neutropenia than other agents that induce idiosyncratic agranulocytosis and than many chemotherapeutic agents. Second, patients with schizophrenia, especially those with a psychotic withdrawal from clozapine, may communicate poorly, comply badly with neutropenic precautions, and be unable promptly to report high temperature, pain, or overt infections, and thus be more prone to a complication from neutropenic fever. Third, G-CSF may actually decrease costs by accelerating recovery from neutropenia and shorten patients’ stay in an acute facility by 7-8 days. Whatever the mechanism of clozapine-induced granulocytosis,s we suggest that G-CSF is indicated for patients with severe agranulocytosis due to clozapine. Conservative management would seem to be adequate for milder neutropenia. G-CSF should be started within 48 h of the onset of agranulocytosis and discontinued when ANC is over 0-5 x 10"/ul.
Supported in part by grant MH47440 from the US Public Health Service and by Sandoz Research Institute. Ireland Cancer Center and Department of Medicine, University Hospitals of Cleveland and Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA
STANTON L. GERSON
California Department of Mental Health, Napa State Hospital, Napa, California
GUY GULLION HONG-SHEN YEH
New
City,
New York
CHARLES MASOR
1. Weide
R, Koppler H, Heymanns J, Pfluger H-K, Haveman K. Successful treatment of clozapine-induced agranulocytosis with granulocyte colony stimulating activity. Br J Haematol 1992; 4: 557-59. 2. Krupp P, Barnes P. Leponex-associated granulocytopenia: a review of the situation. Psychopharmacology 1989; 99: S118-22. 3. Baldessarini RJ, Frankenberg FR. Clozapine: a novel antipsychotic agent. N Engl J Med 1991; 324: 746-54. 4. Pisciotta A, Konings SA, Ciesemier LL, Cronkite CE, Lieberman JA. Cytotoxic activity in patients with clozapine-induced agranulocytosis. J Lab Clin Med 1992; 149: 252-66. 5. Gerson SL, Meltzer H. Mechanisms of clozapine-induced agranulocytosis. Drug Safety 1992; 7: 17-25.
Postoperative TPN-induced lactic acidosis SiR,—Total parenteral nutrition (TPN) has been used to improve the efficacy of surgical intervention in gastrointestinal cancers. However, unexplainable TPN-induced lactic acidosis can occur. Several cases of severe lactic acidosis have been reported to be induced by TPN without thiamin supplementation.1 We have managed 3 such cases. The malnourished patients had advanced gastric cancer. TPN administered to all without thiamin because food was continued. 1-2 weeks after the start of TPN, the patients went into shock with severe metabolic acidosis that did not respond to sodium bicarbonate. Blood lactate was very high. There was no infectious focus which might have induced metabolic acidosis in any case. 2 patients died of shock despite intensive care. The other patient promptly improved after thiamin administration, which was started when we became suspicious about TPN-induced lactic acidosis. Blood thiamin was low in 2 patients but was not measured in the third. Analysis of blood thiamin and the clinical symptoms indicated that the severe lactic acidosis observed in the 3 cases was induced by thiamin deficiency. was
the effect reported by Smith. This is not unexpected since no link between ceftriaxone and motoneuron degeneration is known, and the neuronal and axonal pathology of MND is not expected to recover over 3 weeks. Many patients with MND follow closely the reported course of this disease. It is clear that they are willing to try whatever new treatment becomes available, and especially so when a new therapy seems to have dramatic effects. To refuse these patients a therapy without side-effects or toxicity is hard, since no alternative can be offered. The medical community should therefore be reluctant to publish single and incomplete observations of treatment results, whether there is a rationale for the treatment or not. Such findings might induce disappointment and despair in patients, may interfere with continuing trials and cause unnecessary drop-outs from trials, can result in expensive and useless therapies, and might take away the interest of other groups to evaluate scientifically the therapy in question. The treatment of MND is threatened by confusion because of the sudden availability of neuroactive substances and lack of knowledge of the primary pathogenesis of the disease. We should be careful not to increase confusion among patients.
reproduce
Department of Neurology, University Hospital Gasthuisberg, B-3000 Leuven, Belgium
WIM ROBBERECHT
1. Smith LG. Improvement of patient with amyotrophic lateral sclerosis given ceftriaxone. Lancet 1992; 339: 1417. 2. Norris FH, Calanchini PR, Fallat RJ, Panchari S, Jewett B. The administration of guanidine in amyotrophic lateral sclerosis. Neurology 1974; 24: 721-28. 3. Plaitakis A, Mandeli J, Smith J, Yahr MD. Pilot trial of branched-chain aminoacids in amyotrophic lateral sclerosis. Lancet 1988; i: 1015-21.
Granulocyte colony-stimulating factor for clozapine-induced agranulocytosis SiR,—The successful use of filgrastim, a granulocyte colonystimulating factor (G-CSF), in the management of neutropenic fever after chemotherapy led us to use it in drug-induced agranulocytosis.1 We have studied four patients with clozapine-induced agranulocytosis2,3 to determine whether early administration of filgrastim would shorten the duration of neutropenia. Each patient had a normal white blood count (WBC) and absolute neutrophil count (ANC) when clozapine was started. Clozapine was discontinued when WBC was under 3 x 109/1 or ANC was below 1-5 x 109/1. Three patients had bone marrow aspiration and biopsy, which documented absence of myeloid precursors. All had severe agranulocytosis with ANC below 0-1 x 109/1 for at least 3 days. Filgrastim 300-600 ug per day subcutaneously was started within 48 h of neutropenia. All received standard prophylactic antibiotics, reverse isolation, and broad-spectrum antibiotics for neutropenic fever, and all myelotoxic drugs were discontinued. The table shows a comparison of the time to neutrophil recovery in our four patients with seven consecutive patients who developed clozapine-induced agranulocytosis in trials between 1977 and 1989. This historical control group all had an ANC nadir under 011x 109/1 and bone marrow examination to document absence of myeloid precursors. They were treated before G-CSF was commercially available, and are representative of the natural history of this disorder (refs 4 and 5, and S. L. G.). The two groups were similar in age, and duration and dose of clozapine treatment. In all patients, toxicity was restricted to the myeloid lineage without evidence of anaemia or thrombocytopenia. Patients receiving G-CSF had a significantly shorter period of agranulocytosis (ANC < 0-5 x 109/1) than the historical group, a mean decrease of 7days. Three of the filgrastim-treated patients continued to receive the growth factor for FILGRASTIM FOR CLOZAPINE-INDUCED AGRANULOCYTOSIS
Mean (SD). *p<0 005 between groups. Unpaged Ranges t10-21 and t6-11 days
t test
48-72 h after recovery of neutrophil count to over 0-5 x 109/1. The peak ANC in these three patients was 48-6 x 109/1 compared with 9-3x109/1 in the patient in whom filgrastim was discontinued within 24 h of recovery. No patient had an adverse reaction to the mean
transient leucocytosis. Our findings suggest that G-CSF reduces the duration of agranulocytosis in patients with the most severe form of clozapineinduced bone marrow suppression, that is in those who have pure myeloid precursor aplasia and ANC nadir under 01 x 109/1. G-CSF may not be indicated for mild neutropenia (ANC > 0-5 x 109/1). However, it is reasonable to use G-CSF in clozapine-treated patients with agranulocytosis for several reasons. First, clozapine may cause a longer period of severe neutropenia than other agents that induce idiosyncratic agranulocytosis and than many chemotherapeutic agents. Second, patients with schizophrenia, especially those with a psychotic withdrawal from clozapine, may communicate poorly, comply badly with neutropenic precautions, and be unable promptly to report high temperature, pain, or overt infections, and thus be more prone to a complication from neutropenic fever. Third, G-CSF may actually decrease costs by accelerating recovery from neutropenia and shorten patients’ stay in an acute facility by 7-8 days. Whatever the mechanism of clozapine-induced granulocytosis,s we suggest that G-CSF is indicated for patients with severe agranulocytosis due to clozapine. Conservative management would seem to be adequate for milder neutropenia. G-CSF should be started within 48 h of the onset of agranulocytosis and discontinued when ANC is over 0-5 x 10"/ul.
Supported in part by grant MH47440 from the US Public Health Service and by Sandoz Research Institute. Ireland Cancer Center and Department of Medicine, University Hospitals of Cleveland and Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA
STANTON L. GERSON
California Department of Mental Health, Napa State Hospital, Napa, California
GUY GULLION HONG-SHEN YEH
New
City,
New York
CHARLES MASOR
1. Weide
R, Koppler H, Heymanns J, Pfluger H-K, Haveman K. Successful treatment of clozapine-induced agranulocytosis with granulocyte colony stimulating activity. Br J Haematol 1992; 4: 557-59. 2. Krupp P, Barnes P. Leponex-associated granulocytopenia: a review of the situation. Psychopharmacology 1989; 99: S118-22. 3. Baldessarini RJ, Frankenberg FR. Clozapine: a novel antipsychotic agent. N Engl J Med 1991; 324: 746-54. 4. Pisciotta A, Konings SA, Ciesemier LL, Cronkite CE, Lieberman JA. Cytotoxic activity in patients with clozapine-induced agranulocytosis. J Lab Clin Med 1992; 149: 252-66. 5. Gerson SL, Meltzer H. Mechanisms of clozapine-induced agranulocytosis. Drug Safety 1992; 7: 17-25.
Postoperative TPN-induced lactic acidosis SiR,—Total parenteral nutrition (TPN) has been used to improve the efficacy of surgical intervention in gastrointestinal cancers. However, unexplainable TPN-induced lactic acidosis can occur. Several cases of severe lactic acidosis have been reported to be induced by TPN without thiamin supplementation.1 We have managed 3 such cases. The malnourished patients had advanced gastric cancer. TPN administered to all without thiamin because food was continued. 1-2 weeks after the start of TPN, the patients went into shock with severe metabolic acidosis that did not respond to sodium bicarbonate. Blood lactate was very high. There was no infectious focus which might have induced metabolic acidosis in any case. 2 patients died of shock despite intensive care. The other patient promptly improved after thiamin administration, which was started when we became suspicious about TPN-induced lactic acidosis. Blood thiamin was low in 2 patients but was not measured in the third. Analysis of blood thiamin and the clinical symptoms indicated that the severe lactic acidosis observed in the 3 cases was induced by thiamin deficiency. was