Current Medical Research and Opinion
ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20
The effect of oxpentifylline (Trental') on fibrinolytic activity and plasma fibrinogen levels Paul E. M. Jarrett, Marian Moreland & Norman L. Browse To cite this article: Paul E. M. Jarrett, Marian Moreland & Norman L. Browse (1977) The effect of oxpentifylline (Trental') on fibrinolytic activity and plasma fibrinogen levels, Current Medical Research and Opinion, 4:7, 492-495, DOI: 10.1185/03007997709109338 To link to this article: http://dx.doi.org/10.1185/03007997709109338
Published online: 07 Aug 2008.
Submit your article to this journal
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Citing articles: 5 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=icmo20 Download by: [Deakin University Library]
Date: 05 November 2015, At: 14:06
Current Medical Research and Opinion
Vol. 4, No. 7, 1977
The effect of oxpentifylline (‘Trental’) on fibrinolytic activity and plasma fibrinogen levels
Paul E. M. Jarrett, M.A.,F.R.C.S,. Marian Moreland, B.Sc., and
Norman L. Browse, M.D., F.R.C.S.
Downloaded by [Deakin University Library] at 14:06 05 November 2015
Department of Surgery, St. Thomas’s Hospital Medical School, London,England
Curr. Med. Res. Opin., (1977), 4,492.
Received: 10th November 1976
Summary Twenty healthy volunteers were treated for 3 months with oxpentifylline (200 mg 3-times a day) or a placebo in a controlled double-blind randomized trial. The volunteers taking the oxpentifylline showed a signijicant increase in their jibrinolytic activity, as assessed by the dilute blood clot lysis time andfibrin plate lysis area, and a significant reduction in their plasma fibrinogen levels. No change was found in the control group. Thesejindings suggest that oxpentifyfline may be valuable in the treatment of small vessel occlusive disease associated with loweredfibrinolytic activity and raisedfibrinogen levels. Key words: Pentoxifylline -3brinogen -fibrinolytic agents -fibrinolysis
Introduction Oxpentifylline* (‘Trental’ t) is the recently introduced xanthine derivative 3,7 dimethyl-1-(5-oxohexyl) xanthine. Clinical studies suggest that oxpentifylline has a beneficial therapeutic effect on peripheral vascular disease, relieving intermittent claudication and increasing walking distance, as well as promoting the healing of ischaemic ulcers.3,11-17 The use of oxpentifylline in cerebrovascular disease1,13,1 6*1*,21,22 and circulatory diseases involving the eye*slo and ear14 has also been reported. Attempts have been made to define the mode of action of this drug. Based upon work by S t e f a n o v i ~ h , ~Ehrly5s6 3 , ~ ~ has claimed that the drug reduces red cell rigidity thereby improving microcirculatory flow. Others have shown that oxpentifylline causes a reduction in blood viscosity.9,12Whole blood viscosity is one factor which affects the flow properties of blood in peripheral vascular d i ~ e a s e . 4 , ~ ~ Changes in plasma fibrinogen concentration are known to affect whole blood vis~osity.~,~9,25,26 Microthrombi and the resulting obstructions of the microcirculation are known to further complicate peripheral vascular disease. This study was designed to ascertain whether plasma fibrinogen levels and the fibrinolytic activity of the blood are affected by the administration of oxpentifylline in normal healthy volunteers. ~~
~~~
~
*Oxpentifyllineis the generic name in the U.K. for pentoxifylline. 492
~
ttrade mark,Hoechst
Paul E. M. Jarrett, M. Moreland and Norman L. Browse
Downloaded by [Deakin University Library] at 14:06 05 November 2015
Methods and materials Twenty healthy volunteers, 10 men and 10 women, with a mean age of 28.1 years (range 20 to 38 years) were paired for age and sex. No volunteer was taking any other medication. Normal fibrinolytic activity and normal fibrinogen levels were confirmed in all subjects before inclusion into the study. One volunteer in each pair received oxpentifylline in a dosage of 200 mg (2 tablets) 3-times a day, and the other, placebo tablets of identical appearance in the same dosage schedule. The study was double-blind ;treatment being aIlocated by means of a random code, and continued for 3 months. Fibrinolytic activity was measured by the dilute blood clot lysis time (DBCLT)’ and the fibrin plate lysis area (FPLA).2 The FPLA test was modified by using human instead of bovine fibrinogen. Plasma fibrinogen levels were assessed by the clot weight method of Ingram.15 Packed cell volume (PCV) was measured using a Coulter S machine. The above measurements were performed on 7.5 ml of blood, withdrawn without venous stasis, from fasting volunteers between 09.30 and 10.30 hours, 8 days and 1 day before treatment was started and after 3 months of treatment. Another blood sample was taken from those who had been receiving oxpentifylline 4 weeks after the trial period.
Results Four of the 10 volunteers taking oxpentifylline (1 male and 3 females) withdrew from the study because of nausea and vomiting. Prior to commencing therapy there was no significant difference in fibrinolytic activity, fibrinogen levels and packed cell volume between those who received active or placebo treatment. However, after 3 months of treatment the volunteers who had taken oxpentifylline showed a statistically significant decrease in DBCLT (p < 0.05), increase in FPLA (p < 0.05),and decrease in fibrinogen levels (p < 0.05) as shown in Table I. The levels in those taking placebo therapy did not change (Table I). At the end of the treatment period, the DBCLT, FPLA and fibrinogen levels of the two Table I. Results in healthy volunteers after 3-months’ treatment with placebo or oxpentifylline Group
Placebo (n = 10) Pre-treatment Post-treatment Oxpentifylline (n =6) Pre-treatment Post-treatment 4 weeks after end of treatment
DBCLT (min)
( m 2 )
FPLA
Plasma PCV fibrinogen (%I (mg/100 ml plasma)
284 245
3 58 390
310 323
40 40
256 163* 243
319 413* 376
319 262* 195
42 42 41
‘denotes a significant change from previous value in table (p 0.05) or in those taking the placebo (p > 0.05). After oxpentifylline had been discontinued for 4 weeks the fibrinogen levels continued to fall, although the change from the level after 3-months’ treatment was not significant. The fibrinolytic activity had, however, by this time, reverted to the pre-treatment level.
Discussion Four volunteers on active therapy withdrew from the study at an early stage because of side-effects. This was possibly because they failed to observe the instructions to take the tablets with food. Under clinical conditions we have observed that this precaution coupled with a gradual increase in dosage to therapeutic levels prevents vomiting in all patients, and nausea, if it does occur, is only transient. The improved fibrinolytic activity and lowered fibrinogen levels in the volunteers taking oxpentifylline, without a change in packed cell volume, suggests a possible mechanism for the reduction in blood viscosity which has been noted in other studies with this drug.9.12 A reduction in fibrinogen levels has been associated with a reduction in red cell aggregation and red cell flexibility.20 Depending upon the fall in fibrinogen levels, the beneficial reduction in red cell aggregation in the peripheral circulation is, to a greater or lesser extent, offset by the reduced red cell flexibility. However, other pharmacological studies with oxpentifylline have suggested that this drug, unlike others that lower fibrinogen levels, increases red cell flexibility.5-6 If in vivo studies with oxpentifylline confirm the in vitro hdings of increased red cell flexibility then the drug would have a valuable place in the treatment of small vessel occlusive disease associated with raised fibrinogen levels and lowered fibrinolytic activity.
Acknowledgement We thank Hoechst Pharmaceuticals for supplying the oxpentifylline (‘Trental’) and identical placebo tablets.
References 1 . Aschkar, D., Dorazil, E., and Sigl, H., (1972). Zur klinischen Anwendung des neuen Vasotherapeutikums BL 191 bei peripheren und zerebralen Durchblutungsstorungen. Therupiewoche, 22. 3646. 2. Astrup, T., and Mullertz, S., (1952). Fibrin plate method for estimating fibrinolytic activity. Arch. Biol., 40,346. 3. Bossong, W., (1972). Klinische Erfahrung mit dem Vasotherapeutikum Trental in der Dermatologie.Z . Huut-Geschl. Kr., 46,711. 4. Dormandy, J. A., Boare, E., Colley, J., Arrowsmith, D. E., and Dormandy, T. L., (1973). Clinical haemodynamic, rheological and biochemical findings in 126 patients with intermittent claudication. Br. Med. J., 4, 576. 494
Downloaded by [Deakin University Library] at 14:06 05 November 2015
Paul E. M. Jarrett, M. Moreland and Norman L. Browse
5. Ehrly, A. M., (1975). The effect of pentoxifylline on the flow properties of hyperosmolar blood. I.R.C.S., 3,465. 6. Ehrly, A. M.,(1975). Beeinfiussing der Verformbarkeit der Erythrozyten durch Pentoxifyllin. Med. Welt, 26, 2300. 7. Fearnley, G.R., Balmforth, G. V., and Feamley, E., (1957).Evidence of a diurnal fibrinolytic rhythm; with a simple method of measuring natural fibrinolysis. Clin. Sci., 16,645. 8 . Fellner, R., and Simon, A., (1972). Untersuchungen iiber die durchblutungsverbessernde Wirkung von BL 191 auf die Chorioidea des menschlichen Auges. Klin. Monatsbl. Augenheilkd., 161,439. 9. Heidrich, H., and Ott, M., (1974). Vasodilatantien und Blutviskositat. Herz-Kreislauf, 6,542. 10. Heinsius, F., and Flamm, P., (1973). Ophthalmologische Erfahrungen rnit dem neuen Xanthinkorper. BL 191.Med. Klin., 68, 1540. 11. Herger, R., (1972). Erfahrungen mit dem neuen Vasotherapeutikum Trental in der dermatologishen Fachpraxis. Fortschr. Med., 90.865. 12. Hess, H., Franke, I., and Jauch, M., (1973). Medikamentose Verbesserung der Fliesseigenschaften des Blutes. Fortsch. Med., 91,743. 13. Hirsch, H., and Woschee, G. J., (1971). Erfahrungen mit einem Xanthinderivat bei zentralen und peripheren Durchblutungsstorungen. Ther. Ggw., 11,1668. 14. Huppertz, M.,(1973). Clinical experience with a new xanthine derivative in the treatment of acute impairment of hearing and in deafness. Therapiewoche,51,5008. 15. Ingram, G. I. C., (1952). Determination of plasma fibrinogen by clot-weight method. J. Biochem., 51,583. 16. JovanoviC, U. J., (1972).Polygraphische Registrierungen nach parenteraler Applikation von 3,7-D~methyl-l-(5-oxohexyl)-xanthin (BL 191). Arzneim. Forsch., 22,994. 17. Jiinger, H.,(1974). Klinische Erfahrungen rnit Pentoxifyllin (BL 191) bei der Ulcus-crurisBehandlung. Wein. Med. Wochenschr.,9, 134. 18. Mansfeld, H. G., (1972). Therpieerfahrungen rnit einen neuen Xanthinderivat bei Peripheren unt Zentralen Durchblutungsstorungen. Dtsch. Med. J., 23,49. 19. Merrill, E. W., (1969). Rheology of blood. Physiol. Rev., 49,863. 20. Rampling, M., and Sirs, J. A., (1972). The interactions of fibrinogen and dextrans with erythrocytes. J. Physiol., 223, 199. 21. Schafk, M. K.,(1973).Erfahrungen mit Trental bei peripheren Durchblutungsstorungen und zerebrovaskularer Insuffizienz. Munch. Med. Wochenschr.,115,1745. 22. Spriet, A., and Mesuret, A., (1973). Un critere clinique objectif dans la thkrapeutique l'insuffisance circulatoire chronique. Gaz. Med. Fr., 80,3657. 23. Stefanovich, V., (1975). Effect of pentoxifylline on erythrocyte adenine nucleotide levels in rats. I.R.C.S. Med. Sci., 3,91. 24. Stefanovich, V., (1975). Beeinflussing des ATP-Gehaltes der Erythrozyten durch Pentoxifyllin. Med. Welt, 26, 1882. 25. Stormer, B., Horsch, R., Kleinschmidt, F., Loose, D., Broster, H., and Kremer, K., (1974). Blood viscosity in patients with peripheral vascular diseases in the area of low shear rates. J. Cardiovasc. Surg., 15,577. 26. Weaver, J. P. A., Evans, A., and Walder, D. N., (1969). The effect of increased fibrinogen content on the viscosity of blood. Clin. Sci., 36,l.
495
ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20
The effect of oxpentifylline (Trental') on fibrinolytic activity and plasma fibrinogen levels Paul E. M. Jarrett, Marian Moreland & Norman L. Browse To cite this article: Paul E. M. Jarrett, Marian Moreland & Norman L. Browse (1977) The effect of oxpentifylline (Trental') on fibrinolytic activity and plasma fibrinogen levels, Current Medical Research and Opinion, 4:7, 492-495, DOI: 10.1185/03007997709109338 To link to this article: http://dx.doi.org/10.1185/03007997709109338
Published online: 07 Aug 2008.
Submit your article to this journal
Article views: 3
View related articles
Citing articles: 5 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=icmo20 Download by: [Deakin University Library]
Date: 05 November 2015, At: 14:06
Current Medical Research and Opinion
Vol. 4, No. 7, 1977
The effect of oxpentifylline (‘Trental’) on fibrinolytic activity and plasma fibrinogen levels
Paul E. M. Jarrett, M.A.,F.R.C.S,. Marian Moreland, B.Sc., and
Norman L. Browse, M.D., F.R.C.S.
Downloaded by [Deakin University Library] at 14:06 05 November 2015
Department of Surgery, St. Thomas’s Hospital Medical School, London,England
Curr. Med. Res. Opin., (1977), 4,492.
Received: 10th November 1976
Summary Twenty healthy volunteers were treated for 3 months with oxpentifylline (200 mg 3-times a day) or a placebo in a controlled double-blind randomized trial. The volunteers taking the oxpentifylline showed a signijicant increase in their jibrinolytic activity, as assessed by the dilute blood clot lysis time andfibrin plate lysis area, and a significant reduction in their plasma fibrinogen levels. No change was found in the control group. Thesejindings suggest that oxpentifyfline may be valuable in the treatment of small vessel occlusive disease associated with loweredfibrinolytic activity and raisedfibrinogen levels. Key words: Pentoxifylline -3brinogen -fibrinolytic agents -fibrinolysis
Introduction Oxpentifylline* (‘Trental’ t) is the recently introduced xanthine derivative 3,7 dimethyl-1-(5-oxohexyl) xanthine. Clinical studies suggest that oxpentifylline has a beneficial therapeutic effect on peripheral vascular disease, relieving intermittent claudication and increasing walking distance, as well as promoting the healing of ischaemic ulcers.3,11-17 The use of oxpentifylline in cerebrovascular disease1,13,1 6*1*,21,22 and circulatory diseases involving the eye*slo and ear14 has also been reported. Attempts have been made to define the mode of action of this drug. Based upon work by S t e f a n o v i ~ h , ~Ehrly5s6 3 , ~ ~ has claimed that the drug reduces red cell rigidity thereby improving microcirculatory flow. Others have shown that oxpentifylline causes a reduction in blood viscosity.9,12Whole blood viscosity is one factor which affects the flow properties of blood in peripheral vascular d i ~ e a s e . 4 , ~ ~ Changes in plasma fibrinogen concentration are known to affect whole blood vis~osity.~,~9,25,26 Microthrombi and the resulting obstructions of the microcirculation are known to further complicate peripheral vascular disease. This study was designed to ascertain whether plasma fibrinogen levels and the fibrinolytic activity of the blood are affected by the administration of oxpentifylline in normal healthy volunteers. ~~
~~~
~
*Oxpentifyllineis the generic name in the U.K. for pentoxifylline. 492
~
ttrade mark,Hoechst
Paul E. M. Jarrett, M. Moreland and Norman L. Browse
Downloaded by [Deakin University Library] at 14:06 05 November 2015
Methods and materials Twenty healthy volunteers, 10 men and 10 women, with a mean age of 28.1 years (range 20 to 38 years) were paired for age and sex. No volunteer was taking any other medication. Normal fibrinolytic activity and normal fibrinogen levels were confirmed in all subjects before inclusion into the study. One volunteer in each pair received oxpentifylline in a dosage of 200 mg (2 tablets) 3-times a day, and the other, placebo tablets of identical appearance in the same dosage schedule. The study was double-blind ;treatment being aIlocated by means of a random code, and continued for 3 months. Fibrinolytic activity was measured by the dilute blood clot lysis time (DBCLT)’ and the fibrin plate lysis area (FPLA).2 The FPLA test was modified by using human instead of bovine fibrinogen. Plasma fibrinogen levels were assessed by the clot weight method of Ingram.15 Packed cell volume (PCV) was measured using a Coulter S machine. The above measurements were performed on 7.5 ml of blood, withdrawn without venous stasis, from fasting volunteers between 09.30 and 10.30 hours, 8 days and 1 day before treatment was started and after 3 months of treatment. Another blood sample was taken from those who had been receiving oxpentifylline 4 weeks after the trial period.
Results Four of the 10 volunteers taking oxpentifylline (1 male and 3 females) withdrew from the study because of nausea and vomiting. Prior to commencing therapy there was no significant difference in fibrinolytic activity, fibrinogen levels and packed cell volume between those who received active or placebo treatment. However, after 3 months of treatment the volunteers who had taken oxpentifylline showed a statistically significant decrease in DBCLT (p < 0.05), increase in FPLA (p < 0.05),and decrease in fibrinogen levels (p < 0.05) as shown in Table I. The levels in those taking placebo therapy did not change (Table I). At the end of the treatment period, the DBCLT, FPLA and fibrinogen levels of the two Table I. Results in healthy volunteers after 3-months’ treatment with placebo or oxpentifylline Group
Placebo (n = 10) Pre-treatment Post-treatment Oxpentifylline (n =6) Pre-treatment Post-treatment 4 weeks after end of treatment
DBCLT (min)
( m 2 )
FPLA
Plasma PCV fibrinogen (%I (mg/100 ml plasma)
284 245
3 58 390
310 323
40 40
256 163* 243
319 413* 376
319 262* 195
42 42 41
‘denotes a significant change from previous value in table (p 0.05) or in those taking the placebo (p > 0.05). After oxpentifylline had been discontinued for 4 weeks the fibrinogen levels continued to fall, although the change from the level after 3-months’ treatment was not significant. The fibrinolytic activity had, however, by this time, reverted to the pre-treatment level.
Discussion Four volunteers on active therapy withdrew from the study at an early stage because of side-effects. This was possibly because they failed to observe the instructions to take the tablets with food. Under clinical conditions we have observed that this precaution coupled with a gradual increase in dosage to therapeutic levels prevents vomiting in all patients, and nausea, if it does occur, is only transient. The improved fibrinolytic activity and lowered fibrinogen levels in the volunteers taking oxpentifylline, without a change in packed cell volume, suggests a possible mechanism for the reduction in blood viscosity which has been noted in other studies with this drug.9.12 A reduction in fibrinogen levels has been associated with a reduction in red cell aggregation and red cell flexibility.20 Depending upon the fall in fibrinogen levels, the beneficial reduction in red cell aggregation in the peripheral circulation is, to a greater or lesser extent, offset by the reduced red cell flexibility. However, other pharmacological studies with oxpentifylline have suggested that this drug, unlike others that lower fibrinogen levels, increases red cell flexibility.5-6 If in vivo studies with oxpentifylline confirm the in vitro hdings of increased red cell flexibility then the drug would have a valuable place in the treatment of small vessel occlusive disease associated with raised fibrinogen levels and lowered fibrinolytic activity.
Acknowledgement We thank Hoechst Pharmaceuticals for supplying the oxpentifylline (‘Trental’) and identical placebo tablets.
References 1 . Aschkar, D., Dorazil, E., and Sigl, H., (1972). Zur klinischen Anwendung des neuen Vasotherapeutikums BL 191 bei peripheren und zerebralen Durchblutungsstorungen. Therupiewoche, 22. 3646. 2. Astrup, T., and Mullertz, S., (1952). Fibrin plate method for estimating fibrinolytic activity. Arch. Biol., 40,346. 3. Bossong, W., (1972). Klinische Erfahrung mit dem Vasotherapeutikum Trental in der Dermatologie.Z . Huut-Geschl. Kr., 46,711. 4. Dormandy, J. A., Boare, E., Colley, J., Arrowsmith, D. E., and Dormandy, T. L., (1973). Clinical haemodynamic, rheological and biochemical findings in 126 patients with intermittent claudication. Br. Med. J., 4, 576. 494
Downloaded by [Deakin University Library] at 14:06 05 November 2015
Paul E. M. Jarrett, M. Moreland and Norman L. Browse
5. Ehrly, A. M., (1975). The effect of pentoxifylline on the flow properties of hyperosmolar blood. I.R.C.S., 3,465. 6. Ehrly, A. M.,(1975). Beeinfiussing der Verformbarkeit der Erythrozyten durch Pentoxifyllin. Med. Welt, 26, 2300. 7. Fearnley, G.R., Balmforth, G. V., and Feamley, E., (1957).Evidence of a diurnal fibrinolytic rhythm; with a simple method of measuring natural fibrinolysis. Clin. Sci., 16,645. 8 . Fellner, R., and Simon, A., (1972). Untersuchungen iiber die durchblutungsverbessernde Wirkung von BL 191 auf die Chorioidea des menschlichen Auges. Klin. Monatsbl. Augenheilkd., 161,439. 9. Heidrich, H., and Ott, M., (1974). Vasodilatantien und Blutviskositat. Herz-Kreislauf, 6,542. 10. Heinsius, F., and Flamm, P., (1973). Ophthalmologische Erfahrungen rnit dem neuen Xanthinkorper. BL 191.Med. Klin., 68, 1540. 11. Herger, R., (1972). Erfahrungen mit dem neuen Vasotherapeutikum Trental in der dermatologishen Fachpraxis. Fortschr. Med., 90.865. 12. Hess, H., Franke, I., and Jauch, M., (1973). Medikamentose Verbesserung der Fliesseigenschaften des Blutes. Fortsch. Med., 91,743. 13. Hirsch, H., and Woschee, G. J., (1971). Erfahrungen mit einem Xanthinderivat bei zentralen und peripheren Durchblutungsstorungen. Ther. Ggw., 11,1668. 14. Huppertz, M.,(1973). Clinical experience with a new xanthine derivative in the treatment of acute impairment of hearing and in deafness. Therapiewoche,51,5008. 15. Ingram, G. I. C., (1952). Determination of plasma fibrinogen by clot-weight method. J. Biochem., 51,583. 16. JovanoviC, U. J., (1972).Polygraphische Registrierungen nach parenteraler Applikation von 3,7-D~methyl-l-(5-oxohexyl)-xanthin (BL 191). Arzneim. Forsch., 22,994. 17. Jiinger, H.,(1974). Klinische Erfahrungen rnit Pentoxifyllin (BL 191) bei der Ulcus-crurisBehandlung. Wein. Med. Wochenschr.,9, 134. 18. Mansfeld, H. G., (1972). Therpieerfahrungen rnit einen neuen Xanthinderivat bei Peripheren unt Zentralen Durchblutungsstorungen. Dtsch. Med. J., 23,49. 19. Merrill, E. W., (1969). Rheology of blood. Physiol. Rev., 49,863. 20. Rampling, M., and Sirs, J. A., (1972). The interactions of fibrinogen and dextrans with erythrocytes. J. Physiol., 223, 199. 21. Schafk, M. K.,(1973).Erfahrungen mit Trental bei peripheren Durchblutungsstorungen und zerebrovaskularer Insuffizienz. Munch. Med. Wochenschr.,115,1745. 22. Spriet, A., and Mesuret, A., (1973). Un critere clinique objectif dans la thkrapeutique l'insuffisance circulatoire chronique. Gaz. Med. Fr., 80,3657. 23. Stefanovich, V., (1975). Effect of pentoxifylline on erythrocyte adenine nucleotide levels in rats. I.R.C.S. Med. Sci., 3,91. 24. Stefanovich, V., (1975). Beeinflussing des ATP-Gehaltes der Erythrozyten durch Pentoxifyllin. Med. Welt, 26, 1882. 25. Stormer, B., Horsch, R., Kleinschmidt, F., Loose, D., Broster, H., and Kremer, K., (1974). Blood viscosity in patients with peripheral vascular diseases in the area of low shear rates. J. Cardiovasc. Surg., 15,577. 26. Weaver, J. P. A., Evans, A., and Walder, D. N., (1969). The effect of increased fibrinogen content on the viscosity of blood. Clin. Sci., 36,l.
495
