446
Contrary to the assertion of Miles, the impact of the continuous infusion schedule is not on the frequency of toxicity, which remains unaltered, but on its severity and the fact that it can be more easily managed by slowing, interrupting, or even discontinuing the infusion completely.3 Since Miles et al provide no evidence about the work of West and colleagues that the toxicity observations of West may be due to reduced bioavailability, the most reasonable explanation for the change in toxicity with the continuous infusion schedule is the reduced daily dose of rIL-2 received by the patient. rIL-2 dose and toxicity are correlated.l,2,4 There are no published reports that efficacy is significantly reduced by the continuous schedule--indeed, response rates do not seem to differ in respect of route or schedule,1,2,4 provided treatment intensity is optima1.5 Miles and colleagues’ own observations are interesting and merit further evaluation. The potential for proteins to adhere to some plastics is well known. In the circumstances, the recommendation that albumin be used in low concentrations when further diluting rIL-2 is reasonable, and is in line with the established recommendation of the company. EuroCetus, 1105 BJ Amsterdam-ZO, Netherlands
C. R. FRANKS
1. West WH, Tauer KW, Yannelli JR, et al. Constant infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Eng J Med 1987; 316: 898-905. 2. Rosenberg SA, Lotze MT, Yang JC, et al. Experience with the use of high dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg 1989; 210: 474-85. 3. Hamblin TJ. Interleukin-2: side-effects are acceptable. Br Med J 1990; 300: 275-76. 4. Atzpodien J, Korfer A, Franks CR, et al Home therapy with recombinant interleukin-2 and interferon &agr;-2b in advanced human malignancies. Lancet 1990; 335: 1509-12. 5. Bradley EC, Louie AC, Paradise CM, et al. Antitumour response m patients with metastatic renal cell carcinoma is dependent upon regimen intensity. ASCO 1989; 519: 133.
SiR,—In our phase I/II clinical study of continuous rIL-2 infusions on an outpatient basis at doses ranging from 180 000 to 18 000 000 IUjnr daily, patients were given every week seven syringes loaded with rIL-2 which were stored at - 20oC; every day one syringe was thawed and placed in a mechanical infusion pump. The infusion device consisted of a 10 ml plastic syringe, a 200 cm polyethylene catheter (1-5 mm), and a central venous access (’Vascuport’; Viggo) consisting of a titanium injection portal with an 11-5 mm silicone membrane connected with a 60 cm polyurethane catheter (1-2 mm). The polyethylene catheter was changed every week. rIL-2 (’Proleukin’; Eurocetus) was reconstituted with 1-2 ml sterile water and diluted in 0-9% saline. The stability of this solution had been tested at concentrations ranging from 30 000 to 3000 000 lU/ml after storage at 37, 20, 4, and - 20°C for 24 h, and at - 20°C for 8 days. The solutions, stored for 24 h at 4°C and - 20°C, had been passed quickly through the infusion device at room temperature. No loss of bioactivity had been noted with any of these solutions in a standard bioassay based on 3H-thymidine incorporation into DNA of the CTLL-2 cell line. No toxicity was seen in any treated patient up to doses of 18 000 000 IU jm2 daily when rIL-2 was given via continuous infusion through the pump. However, continuous infusion of 18 000 000 IUjm2 in 500 ml 5% glucose via a peripheral vein resulted in typical rIL-2 side-effects within 12 h. Subsequently we assayed the bioactivity of solutions of rIL-2 dissolved in 10 ml 0-9% saline, which had been passed through the infusion device over 24 h at 30°C. We found almost complete loss of bioactivity at concentrations ranging from 180 000 to 3000 000
given
IU/ml : Bioactivity of solution before and after passage through infusion Concentration of rlL-2 in 09% saline (lulml) 3000 000 1800000 1000000 180000
device in 24 h Before After 100 100 100 100
3 01 05-1 1-2
Dr Miles and colleagues noted about 75% loss of bioactivity for rIL-2 dissolved in 50 ml 5 % glucose. The greater loss of bioactivity observed by us may be the result of the smaller volume of solution
used, leading to a slower infusion rate and longer exposure of the solution to the infusion device. However, factors other than adsorption of the cytokine may be involved; when 1000 000 IU,iml rIL-2 was dissolved in water alone or in water with 2 % albumin and passed through the infusion device over 24 h no significant loss of bioactivity was observed. rIL-2 manufactured by Hoffmann-La Roche or Cetus differ slightly from each other and from native IL-2 in respect of aminoacid sequence. In contrast to the Cetus product rIL-2 provided by Hoffmann-La Roche contains 25 mg albumin per 1000 000 units. In reported clinical studies rIL-2 was dissolved in various volumes of solvents with or without the addition of albumin. Our data and those of Miles et al may help to explain the differences in reported toxicity and efficacy seen with both continuous infusion and bolus injection.1 L. THOMAS VLASVELD ELAINE M. RANKIN
SJOERD RODENHUIS Department of Medical Oncology, Division of Immunology, and Pharmacy, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands
1. Parkinson DR. Interleukin-2 10-26.
in cancer
WIM M. J. VUIST JOS H. BEIJNEN ANNE M. HILTON RIA DUBBELMAN ANNEMARIE HEKMAN therapy. J. Clin Oncol 1988; 15 (suppl 6).
Perforation of colon in distal intestinal syndrome of cystic fibrosis SIR,-In their patient with cystic fibrosis Dr Hassan and Dr Keaney (May 19, p 1225) attribute perforation of the colon to mebeverine. It is unlikely that mebeverine was related to this event. Mebeverine reduces smooth-muscle spasm and is effective in conditions where spasm is implicated, such as irritable bowel syndrome. Investigations have not shown that mebeverine produces atony or bowel stasis ’l-3 and such an effect has not been reported either in clinical trials or during 25 years of clinical
practice. The case described is complicated, but I would suggest that the constipation and distal intestinal syndrome (DIS) developed concomitantly, and together predisposed to the stercoral ulceration. Hassan and Keaney’s point about the importance of early active management in DIS is certainly very important. Duphar Laboratories Limited, Gaters Hill West End, Southampton SO3 3JD, UK
A. M. WHITEHEAD
A, Selzer H, Claassen V, Gans P, Offringa OR, Zwagemakers JMA. Pharmacological properties of mebeverine, a smooth muscle relaxant. Arch Int Pharmacodyn 1963; 145: 378-95. 2 Connell AM. Physiological and clinical assessment of the effect of the musculotropic agent mebeverine on the human colon. Br Med J 1965; ii: 848-51. 3. Den Hertog A, Van Den Akker J. Modification of a receptor-operated channels by mebeverine in smooth muscle cells of guinea-pig taenia caeci. Eur J Pharmacol 1. Lindner
1987, 138: 367-74.
Phrenic
nerve
stimulation in
quadriplegia
SiR,—Your July 14 editorial on phrenic nerve pacing states that the Finnish stimulator works on a similar principle to that of the Vienna device. The similarity, however, is restricted to the fact that both devices, in contrast to the New Haven device, use several electrode loops or buttons instead of one for each nerve. The devices differ in the mode of nerve stimulation they provide. Physiologically, contractions for continuous muscle use, such as for breathing at rest, are provided by slow twitch fatigue-resistant motor units (SFR). 50-60% of fibres in the diaphragm are SFR Axons which control SFR physiologically fire at 8-20 Hz. For energy supply SFR depend on oxidation (ie, capillary blood flow). Axons fire at random over time and in space, but overlapping in time. This results in a fusion frequency of muscles of 30-200 Hz.’ During electrical stimulation all axons within the stimulation compa 2ment are excited synchronously. Fatigue during electrical
Contrary to the assertion of Miles, the impact of the continuous infusion schedule is not on the frequency of toxicity, which remains unaltered, but on its severity and the fact that it can be more easily managed by slowing, interrupting, or even discontinuing the infusion completely.3 Since Miles et al provide no evidence about the work of West and colleagues that the toxicity observations of West may be due to reduced bioavailability, the most reasonable explanation for the change in toxicity with the continuous infusion schedule is the reduced daily dose of rIL-2 received by the patient. rIL-2 dose and toxicity are correlated.l,2,4 There are no published reports that efficacy is significantly reduced by the continuous schedule--indeed, response rates do not seem to differ in respect of route or schedule,1,2,4 provided treatment intensity is optima1.5 Miles and colleagues’ own observations are interesting and merit further evaluation. The potential for proteins to adhere to some plastics is well known. In the circumstances, the recommendation that albumin be used in low concentrations when further diluting rIL-2 is reasonable, and is in line with the established recommendation of the company. EuroCetus, 1105 BJ Amsterdam-ZO, Netherlands
C. R. FRANKS
1. West WH, Tauer KW, Yannelli JR, et al. Constant infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Eng J Med 1987; 316: 898-905. 2. Rosenberg SA, Lotze MT, Yang JC, et al. Experience with the use of high dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg 1989; 210: 474-85. 3. Hamblin TJ. Interleukin-2: side-effects are acceptable. Br Med J 1990; 300: 275-76. 4. Atzpodien J, Korfer A, Franks CR, et al Home therapy with recombinant interleukin-2 and interferon &agr;-2b in advanced human malignancies. Lancet 1990; 335: 1509-12. 5. Bradley EC, Louie AC, Paradise CM, et al. Antitumour response m patients with metastatic renal cell carcinoma is dependent upon regimen intensity. ASCO 1989; 519: 133.
SiR,—In our phase I/II clinical study of continuous rIL-2 infusions on an outpatient basis at doses ranging from 180 000 to 18 000 000 IUjnr daily, patients were given every week seven syringes loaded with rIL-2 which were stored at - 20oC; every day one syringe was thawed and placed in a mechanical infusion pump. The infusion device consisted of a 10 ml plastic syringe, a 200 cm polyethylene catheter (1-5 mm), and a central venous access (’Vascuport’; Viggo) consisting of a titanium injection portal with an 11-5 mm silicone membrane connected with a 60 cm polyurethane catheter (1-2 mm). The polyethylene catheter was changed every week. rIL-2 (’Proleukin’; Eurocetus) was reconstituted with 1-2 ml sterile water and diluted in 0-9% saline. The stability of this solution had been tested at concentrations ranging from 30 000 to 3000 000 lU/ml after storage at 37, 20, 4, and - 20°C for 24 h, and at - 20°C for 8 days. The solutions, stored for 24 h at 4°C and - 20°C, had been passed quickly through the infusion device at room temperature. No loss of bioactivity had been noted with any of these solutions in a standard bioassay based on 3H-thymidine incorporation into DNA of the CTLL-2 cell line. No toxicity was seen in any treated patient up to doses of 18 000 000 IU jm2 daily when rIL-2 was given via continuous infusion through the pump. However, continuous infusion of 18 000 000 IUjm2 in 500 ml 5% glucose via a peripheral vein resulted in typical rIL-2 side-effects within 12 h. Subsequently we assayed the bioactivity of solutions of rIL-2 dissolved in 10 ml 0-9% saline, which had been passed through the infusion device over 24 h at 30°C. We found almost complete loss of bioactivity at concentrations ranging from 180 000 to 3000 000
given
IU/ml : Bioactivity of solution before and after passage through infusion Concentration of rlL-2 in 09% saline (lulml) 3000 000 1800000 1000000 180000
device in 24 h Before After 100 100 100 100
3 01 05-1 1-2
Dr Miles and colleagues noted about 75% loss of bioactivity for rIL-2 dissolved in 50 ml 5 % glucose. The greater loss of bioactivity observed by us may be the result of the smaller volume of solution
used, leading to a slower infusion rate and longer exposure of the solution to the infusion device. However, factors other than adsorption of the cytokine may be involved; when 1000 000 IU,iml rIL-2 was dissolved in water alone or in water with 2 % albumin and passed through the infusion device over 24 h no significant loss of bioactivity was observed. rIL-2 manufactured by Hoffmann-La Roche or Cetus differ slightly from each other and from native IL-2 in respect of aminoacid sequence. In contrast to the Cetus product rIL-2 provided by Hoffmann-La Roche contains 25 mg albumin per 1000 000 units. In reported clinical studies rIL-2 was dissolved in various volumes of solvents with or without the addition of albumin. Our data and those of Miles et al may help to explain the differences in reported toxicity and efficacy seen with both continuous infusion and bolus injection.1 L. THOMAS VLASVELD ELAINE M. RANKIN
SJOERD RODENHUIS Department of Medical Oncology, Division of Immunology, and Pharmacy, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands
1. Parkinson DR. Interleukin-2 10-26.
in cancer
WIM M. J. VUIST JOS H. BEIJNEN ANNE M. HILTON RIA DUBBELMAN ANNEMARIE HEKMAN therapy. J. Clin Oncol 1988; 15 (suppl 6).
Perforation of colon in distal intestinal syndrome of cystic fibrosis SIR,-In their patient with cystic fibrosis Dr Hassan and Dr Keaney (May 19, p 1225) attribute perforation of the colon to mebeverine. It is unlikely that mebeverine was related to this event. Mebeverine reduces smooth-muscle spasm and is effective in conditions where spasm is implicated, such as irritable bowel syndrome. Investigations have not shown that mebeverine produces atony or bowel stasis ’l-3 and such an effect has not been reported either in clinical trials or during 25 years of clinical
practice. The case described is complicated, but I would suggest that the constipation and distal intestinal syndrome (DIS) developed concomitantly, and together predisposed to the stercoral ulceration. Hassan and Keaney’s point about the importance of early active management in DIS is certainly very important. Duphar Laboratories Limited, Gaters Hill West End, Southampton SO3 3JD, UK
A. M. WHITEHEAD
A, Selzer H, Claassen V, Gans P, Offringa OR, Zwagemakers JMA. Pharmacological properties of mebeverine, a smooth muscle relaxant. Arch Int Pharmacodyn 1963; 145: 378-95. 2 Connell AM. Physiological and clinical assessment of the effect of the musculotropic agent mebeverine on the human colon. Br Med J 1965; ii: 848-51. 3. Den Hertog A, Van Den Akker J. Modification of a receptor-operated channels by mebeverine in smooth muscle cells of guinea-pig taenia caeci. Eur J Pharmacol 1. Lindner
1987, 138: 367-74.
Phrenic
nerve
stimulation in
quadriplegia
SiR,—Your July 14 editorial on phrenic nerve pacing states that the Finnish stimulator works on a similar principle to that of the Vienna device. The similarity, however, is restricted to the fact that both devices, in contrast to the New Haven device, use several electrode loops or buttons instead of one for each nerve. The devices differ in the mode of nerve stimulation they provide. Physiologically, contractions for continuous muscle use, such as for breathing at rest, are provided by slow twitch fatigue-resistant motor units (SFR). 50-60% of fibres in the diaphragm are SFR Axons which control SFR physiologically fire at 8-20 Hz. For energy supply SFR depend on oxidation (ie, capillary blood flow). Axons fire at random over time and in space, but overlapping in time. This results in a fusion frequency of muscles of 30-200 Hz.’ During electrical stimulation all axons within the stimulation compa 2ment are excited synchronously. Fatigue during electrical
