- Email: [email protected]
Treatment of pulmonary hypertension with bombesin antagonist
THE LANCET
AML-M2. After one cycle of amsacrine and high dose of cytosar, blast cells disappeared from her bone marrow, and there was a questionable decrease in the size of the chest wall mass. No further decrease in the size of the chest wall mass occurred after a second course of chemotherapy with etoposide and mitoxantrone. 4 months after the diagnosis of recurrent breast cancer and AML, she underwent uneventful allogeneic PBSCT from a fully HLA-matched brother. 10 weeks after transplantation she was treated with donor blood lymphocyte infusion at a cell dose equivalent to 105 T cells/kg. 20 weeks after transplantation, a higher dose of donor blood lymphocytes, 0·6106 T cells/kg was given. At 29 weeks, a maculopapular skin rash was noted in the upper trunk. A skin biopsy specimen showed an allergic reaction, possible secondary to co-trimoxazole; however, graft-versushost disease (GVHD) could not be excluded. After low-dose prednisone the skin lesions gradually disappeared. 12 months after transplantation, no chest wall mass was seen and the patient was event free with no evidence of either breast cancer or AML. No evidence of chronic GVHD developed. We suggest that graft-versus-tumour effect, similarly to GVL in leukaemia, might have played a part in achieving and maintaining a complete response of breast cancer recurrence. *R Ben-Yosef, R Or, A Nagler, S Slavin Department of Bone Marrow Transplantation & The Cancer Immunobiology Research Laboratory, Hadassah-Hebrew University School of Medicine, Jerusalem, 91120, Israel
1
2 3
Salvin S, Naparstek E, Nagler A. Allogeneic cell therapy for relapsed leukemia following bone marrow transplantation with donor peripheral blood lymphocytes. Exp Hematol 1995; 23: 1553–62. Horowitz M, Gale R, Sondel P, et al. Graft versus leukemia reactions after bone marrow transplantation. Blood 1990; 75: 555–62. Ebil B, Schwaighhofer H, Nachbaur D, et al. Evidence of graft versus tumor effect in a patient treated with marrow ablative chemotherapy and allogeneic bone marrow transplantation for breast cancer. Blood 1006; 88: 1501–08.
Treatment of pulmonary hypertension with bombesin antagonist SIR—Plexogenic arteriopathy is a histological subtype of primary pulmonary hypertension found in some cases of portal hypertension and cirrhosis. Treatment options are limited. The pulmonary neuroendocrine system secretes bombesin-like peptides (BLPs) including gastrin-releasing peptide (GRP). These are growth factors for bronchial epithelium, trigger cytokine release from alveolar macrophages, and may have vasoactive properties within the pulmonary endothelium.1 Several studies have described increased density of BLP-staining cells and raised concentrations of BLPs in plexogenic arteriopathy.2 We therefore hypothesised that a BLP antagonist may have a beneficial effect. GRP stimulates gastric acid secretion prompting the development of specific antagonists. One antagonist BIM26226 has been infused into normal volunteers at 5–500 g kg1 h1 without adverse effects and maximum acid suppression at 500 g kg1 h1.3,4 We administered an infusion of BIM26226 to a man aged 44 with pulmonary hypertension and liver disease. A previous trial of diltiazem (360 mg daily) had no effect. He had not received any other agents. After insertion of a pulmonary artery flow catheter and arterial line he received a 24 h placebo infusion of normal saline at 50 mL/h. BIM26226, reconstituted in saline, was then infused initially at 5 g kg1 h1 and the dose increased in 25 g kg1 h1 increments 4 hourly to a maximum of 200 g kg1 h1. The infusion rate was maintained at 50 mL/h. Haemodynamic indices were
Vol 348 • November 2, 1996
Placebo Pulmonary blood pressure: systolic (mm Hg) Pulmonary blood pressure: diastolic (mm Hg) Mean pulmonary pressure (mm Hg) Pulmonary vascular resistance Pulmonary wedge pressure (mm Hg) Arterial oxygen saturation (%) Pulse rate (per min) Right atrial pressure (mm Hg) Cardiac output (L/min) Cardiac index (L min1m2) Systemic blood pressure (mm Hg) Systolic Diastolic Systemic vascular resistance
88 (6) 37 (5) 52·6 (3·85) 10·28 4·85 (1) 91 (2·45) 81 (8·9) 2 (2·3) 4·96 (0·53) 2·65 (0·27) 152 (21) 87 (10) 21·48
Infusion 55 41 48 8·05 5 93 102 2 5·59 2·88 166 97 21·08
Results shown are for the mean (SD) (n 6 observations) during placebo phase and maximum values obtained during the active infusion (at 200 g kg 1 h1). The rate of infusion was constant throughout at 50 mL/h. Rechallenge produced the same effect.
Table: Infusion of BIM26226 to one patient with pulmonary hypertension
measured every half hour (table). At a dose of 25 g kg1 h1 pulmonary systolic pressure began to fall from 88 mm Hg, continuing in a dose-dependent fashion to 54 mm Hg at 200 g kg1 h1. This was associated with a slight rise in diastolic pressure from 37 to 44 mm Hg which was not dose dependent but limited the impact on the mean pulmonary arterial pressure. The heart rate rose as did the cardiac output with a marginal increase in cardiac index. The right atrial pressure and systemic blood pressure were unaltered. 8 min after discontinuation of BIM26226, reflecting the plasma half-life, the pulmonary systolic pressure returned to the preinfusion level. Rechallenge produced the same effect. The mechanism for this effect on pulmonary systolic pressure of BIM26226 is uncertain. The drug may compromise right ventricular function, but since the right atrial pressure did not alter and cardiac output rose (with the increased heart rate), albeit slightly, a purely negative inotropic effect does not seem to provide an explanation. Alternatively, chronic exposure to supraphysiological pulmonary pressures may have led to an increased baroceptor threshold and the acute decrease in the pulmonary systolic pressure, caused by the drug, has led to a compensatory pulmonary venoconstriction with consequent rise in diastolic pressure. If the drug had been continued for a longer period the baroceptors may have reset to a lower level. This preliminary study suggests that these peptides have acute haemodynamic effects in the pulmonary vasculature. Although the function of BLPs in pulmonary development and maintenance is uncertain they have also been implicated in the development of oat-cell carcinoma and smoking-related lung diseases.5 BLP antagonists may have a role in the treatment of primary pulmonary hypertension and other lung diseases. Further studies are required. *S J Hurel, M Main, A Gasgoigne, A Batchelor, P C Adams Departments of *Medicine and Anaesthetics, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4HH, UK; and Ipsen International, London
1 2
3
4
5
Wagenvoort CA. Plexogenic arteriopathy. Thorax 1994; 49 (suppl): S39–45. Heath D, Yacoub M, Gosney JR, Madden B, Caslin AW, Smith P. Pulmonary endocrine cells in hypertensive pulmonary vascular disease. Histopathology 1990; 16: 21–28. Hildebrand P, Possi L, Meyer M, Mossi S, Ketterer S, Beglinger C. Effect of BIM26226, a potent and specific bombesin GRP receptor antagonist, on gastrointestinal functions in man. Gastroenterology 1993; 104: A104. Hildebrand P, Peng FP, Ketterer S, Berthold R, Serrano Y, Beglinger C. Blockade of GRP receptors potently inhibits gastric emptying and gallbladder contraction in man. Gastroenterology 1995; 108: A613. Aguayo SM. Determinants of susceptibility to cigarette smoke. Am J Respir Crit Care Med 1994; 149: 1693–98.
1243
AML-M2. After one cycle of amsacrine and high dose of cytosar, blast cells disappeared from her bone marrow, and there was a questionable decrease in the size of the chest wall mass. No further decrease in the size of the chest wall mass occurred after a second course of chemotherapy with etoposide and mitoxantrone. 4 months after the diagnosis of recurrent breast cancer and AML, she underwent uneventful allogeneic PBSCT from a fully HLA-matched brother. 10 weeks after transplantation she was treated with donor blood lymphocyte infusion at a cell dose equivalent to 105 T cells/kg. 20 weeks after transplantation, a higher dose of donor blood lymphocytes, 0·6106 T cells/kg was given. At 29 weeks, a maculopapular skin rash was noted in the upper trunk. A skin biopsy specimen showed an allergic reaction, possible secondary to co-trimoxazole; however, graft-versushost disease (GVHD) could not be excluded. After low-dose prednisone the skin lesions gradually disappeared. 12 months after transplantation, no chest wall mass was seen and the patient was event free with no evidence of either breast cancer or AML. No evidence of chronic GVHD developed. We suggest that graft-versus-tumour effect, similarly to GVL in leukaemia, might have played a part in achieving and maintaining a complete response of breast cancer recurrence. *R Ben-Yosef, R Or, A Nagler, S Slavin Department of Bone Marrow Transplantation & The Cancer Immunobiology Research Laboratory, Hadassah-Hebrew University School of Medicine, Jerusalem, 91120, Israel
1
2 3
Salvin S, Naparstek E, Nagler A. Allogeneic cell therapy for relapsed leukemia following bone marrow transplantation with donor peripheral blood lymphocytes. Exp Hematol 1995; 23: 1553–62. Horowitz M, Gale R, Sondel P, et al. Graft versus leukemia reactions after bone marrow transplantation. Blood 1990; 75: 555–62. Ebil B, Schwaighhofer H, Nachbaur D, et al. Evidence of graft versus tumor effect in a patient treated with marrow ablative chemotherapy and allogeneic bone marrow transplantation for breast cancer. Blood 1006; 88: 1501–08.
Treatment of pulmonary hypertension with bombesin antagonist SIR—Plexogenic arteriopathy is a histological subtype of primary pulmonary hypertension found in some cases of portal hypertension and cirrhosis. Treatment options are limited. The pulmonary neuroendocrine system secretes bombesin-like peptides (BLPs) including gastrin-releasing peptide (GRP). These are growth factors for bronchial epithelium, trigger cytokine release from alveolar macrophages, and may have vasoactive properties within the pulmonary endothelium.1 Several studies have described increased density of BLP-staining cells and raised concentrations of BLPs in plexogenic arteriopathy.2 We therefore hypothesised that a BLP antagonist may have a beneficial effect. GRP stimulates gastric acid secretion prompting the development of specific antagonists. One antagonist BIM26226 has been infused into normal volunteers at 5–500 g kg1 h1 without adverse effects and maximum acid suppression at 500 g kg1 h1.3,4 We administered an infusion of BIM26226 to a man aged 44 with pulmonary hypertension and liver disease. A previous trial of diltiazem (360 mg daily) had no effect. He had not received any other agents. After insertion of a pulmonary artery flow catheter and arterial line he received a 24 h placebo infusion of normal saline at 50 mL/h. BIM26226, reconstituted in saline, was then infused initially at 5 g kg1 h1 and the dose increased in 25 g kg1 h1 increments 4 hourly to a maximum of 200 g kg1 h1. The infusion rate was maintained at 50 mL/h. Haemodynamic indices were
Vol 348 • November 2, 1996
Placebo Pulmonary blood pressure: systolic (mm Hg) Pulmonary blood pressure: diastolic (mm Hg) Mean pulmonary pressure (mm Hg) Pulmonary vascular resistance Pulmonary wedge pressure (mm Hg) Arterial oxygen saturation (%) Pulse rate (per min) Right atrial pressure (mm Hg) Cardiac output (L/min) Cardiac index (L min1m2) Systemic blood pressure (mm Hg) Systolic Diastolic Systemic vascular resistance
88 (6) 37 (5) 52·6 (3·85) 10·28 4·85 (1) 91 (2·45) 81 (8·9) 2 (2·3) 4·96 (0·53) 2·65 (0·27) 152 (21) 87 (10) 21·48
Infusion 55 41 48 8·05 5 93 102 2 5·59 2·88 166 97 21·08
Results shown are for the mean (SD) (n 6 observations) during placebo phase and maximum values obtained during the active infusion (at 200 g kg 1 h1). The rate of infusion was constant throughout at 50 mL/h. Rechallenge produced the same effect.
Table: Infusion of BIM26226 to one patient with pulmonary hypertension
measured every half hour (table). At a dose of 25 g kg1 h1 pulmonary systolic pressure began to fall from 88 mm Hg, continuing in a dose-dependent fashion to 54 mm Hg at 200 g kg1 h1. This was associated with a slight rise in diastolic pressure from 37 to 44 mm Hg which was not dose dependent but limited the impact on the mean pulmonary arterial pressure. The heart rate rose as did the cardiac output with a marginal increase in cardiac index. The right atrial pressure and systemic blood pressure were unaltered. 8 min after discontinuation of BIM26226, reflecting the plasma half-life, the pulmonary systolic pressure returned to the preinfusion level. Rechallenge produced the same effect. The mechanism for this effect on pulmonary systolic pressure of BIM26226 is uncertain. The drug may compromise right ventricular function, but since the right atrial pressure did not alter and cardiac output rose (with the increased heart rate), albeit slightly, a purely negative inotropic effect does not seem to provide an explanation. Alternatively, chronic exposure to supraphysiological pulmonary pressures may have led to an increased baroceptor threshold and the acute decrease in the pulmonary systolic pressure, caused by the drug, has led to a compensatory pulmonary venoconstriction with consequent rise in diastolic pressure. If the drug had been continued for a longer period the baroceptors may have reset to a lower level. This preliminary study suggests that these peptides have acute haemodynamic effects in the pulmonary vasculature. Although the function of BLPs in pulmonary development and maintenance is uncertain they have also been implicated in the development of oat-cell carcinoma and smoking-related lung diseases.5 BLP antagonists may have a role in the treatment of primary pulmonary hypertension and other lung diseases. Further studies are required. *S J Hurel, M Main, A Gasgoigne, A Batchelor, P C Adams Departments of *Medicine and Anaesthetics, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4HH, UK; and Ipsen International, London
1 2
3
4
5
Wagenvoort CA. Plexogenic arteriopathy. Thorax 1994; 49 (suppl): S39–45. Heath D, Yacoub M, Gosney JR, Madden B, Caslin AW, Smith P. Pulmonary endocrine cells in hypertensive pulmonary vascular disease. Histopathology 1990; 16: 21–28. Hildebrand P, Possi L, Meyer M, Mossi S, Ketterer S, Beglinger C. Effect of BIM26226, a potent and specific bombesin GRP receptor antagonist, on gastrointestinal functions in man. Gastroenterology 1993; 104: A104. Hildebrand P, Peng FP, Ketterer S, Berthold R, Serrano Y, Beglinger C. Blockade of GRP receptors potently inhibits gastric emptying and gallbladder contraction in man. Gastroenterology 1995; 108: A613. Aguayo SM. Determinants of susceptibility to cigarette smoke. Am J Respir Crit Care Med 1994; 149: 1693–98.
1243