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Codergocrine-mesylate is of no brain protective effect after exercise in moderate hypoxia at moderate altitude
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Archives of Gerontology and Geriatrics 21 (1995) 215-218
ARCHIVES OF GERONTOLOGY AND GERIATRICS
L e t t e r to the E d i t o r
Codergocrine-mesylate is of no brain protective effect after exercise in moderate hypoxia at moderate altitude G. R o e g g l a , H. R o e g g l a , R. F r e y , M. Binder, M. Muellner, M. R o e g g l a Department of Emergency Medicine, University of Vienna, Vienna, Austria Received 25 July 1994; revision received 3 February 1995; accepted 12 February 1995
Dear Editor, Saletu et al. (1994) proved codergocrine-mesylate (CDM) to be an effective drug for brain protection in a hypoxic environment (normobaric hypoxia simulating 6000 m altitude). The cost to the central nervous system of climbing to high altitude has been a target of interest and of frequent research (Hornbein et al., 1989). The aim of our contribution was to evaluate if the findings of Saletu and co-workers may help prevent a decline of cognitive function in moderate hypoxia at moderate altitude in alpinists. The study was performed in the Austrian Alps at two altitude levels as a randomised, cross-over, placebo-controlled trial. Five healthy male volunteers, age 20-22 years, took part after informed consent. All subjects were healthy non-smokers and took no medication. All were lowland dwellers, but experienced leisure time alpinists. Physical fitness was not measured, but could be reckoned to be good to excellent. Subjects were randomised to 5 mg CDM (Hydergine®) or placebo before exercise (4 h of fast walking at a constant pulse rate of 120 beats/rain) at 800-1000 m altitude and, after a 3-day interval, to exercise of equal length and intensity at 2900-3100 m altitude. The same procedure was performed after an interval of 1 week, when subjects crossed to the other study branch. Sleeping altitude was in the lowland at 500 m altitude throughout the study, subjects were brought to exercising altitude by car and cable car. Pulse rate was measured continuously (Polar sport tester, Gro/~ 0167-4943/95/$09.50 © 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0167-4943(95)00627-W
G. Roeggla et aL / Arch. Gerontol. Geriatr. 21 (1995) 215-218
216
Gerau, Germany). Ability to concentrate and attention was tested with the d 2 test before exercise and after a 30-rain rest after exercise (Brickenkamp, 1967). Arterial oxygen saturation (Sao2) was measured by pulse oxymetrie (~-Ox Pulsoxymeter, MCC, Kadsruhe, Germany) after a 30-rain rest after exercise. Barometric pressure was 670 mmHg at 1000 m altitude and 520 mmHg at 3100 m altitude, otherwise setting and procedures were comparable at both altitudes.
Statisties Direct comparison of the differences of d 2 test scores before and after exercise at both test conditions and at both altitudes as well as SaO2 comparison was performed by the t-test (Hills and Armitage, 1979). P < 0.05 was considered significant.
Results Sao2 was significantly decreased at 3100 m altitude compared to 1000 m altitude in both test conditions (Placebo: 91.8 ± 0.84% vs. 98.4 -t- 0.55%, difference 6.6, 95%CI 5.57-7.63, P < 0.01; CDM: 91.4 4- 1.14% vs. 98.4 4- 0.55%, difference 7.0, 95% CI 5.7-8.3, P < 0.01), no significant difference between both test conditions was found at 1000 m altitude (Placebo: 98.4 4- 0.55%; CDM: 98.4 4- 0.55% difference 0.0, 95% C1-0.8-0.8, P = n.s.) and at 3100 m altitude (Placebo: 91.8 -t- 0.84%; CDM: 91.4 4- 1.14%, difference 0.4, 95% CI -1.06-1.86, P = n.s.), d 2 scores are shown in detail in Table 1. After 4 h of exercise at 1000 m altitude, the decline of scores was significantly lower than at 3100 m altitude in both test conditions (Placebo: 99.20 ± 12.28 vs. 170.60 ± 9.61, difference -71.40, 95% CI -87.48--55.32, P < 0.01; CDM: 89.0 4- 13.32 vs. 185.6 4- 7.0, difference -96.6, 95% CI -112.13--81.07, P < 0.01). Direct comparison of the differences o f d 2-test scores before and after exercise at 1000 m altitude shows no significant difference between placebo and CDM (99.20 4- 12.28 vs. 89.0 4- 13.32, difference 10.20, 95% CI -8.48-28.88, P = n.s.). At 3100 m altitude, the decline of scores was significantly
Table ! Results of the d 2 test (attention and concentration) before and after 4 h of exercise at A: 1000 m altitude before, B: after placebo, C: 1000 m altitude before, D: after codergocrine-mesylate E: 3100 m altitude before, F: after placebo, G: 3100 m altitude before, H: after Codergocrine-mesylate No.
A
B
C
D
E
F
G
H
I 2 3 4 5 mean 4. S.D.
422 464 503 422 527 467.6 47.3
324 382 409 311 416 368.4 48.4
433 439 511 430 502 463.0 39.6
352 362 407 350 399 374.0 27.0
411 455 503 419 507 459.0 45.2
250 275 330 240 347 288.4 47.9
422 453 516 430 519 468.0 46.6
240 257 333 252 330 282.4 45.3
Figures are total scores minus errors.
G. Roeggla et ai./Arch. Gerontol. Geriatr. 21 (1995) 215-218
217
lower after placebo than after CDM (170.60 ± 9.61 vs. 185.6 4- 7.0, difference -15, 95% CI -27.26 to -2.74, P < 0.05). The possibility of any effect of test order or treatment carry-over was tested using the baseline readings of each period and group (Hills and Armitage, 1979). No significant effects were found. D~Oll
The d 2 test was performed after a 30-min rest after exercise at both investigation altitudes at stable conditions. Sa02 was significantly decreased at 3100 m altitude, but no impairment of the ability to concentrate or attention was detected at rest. d 2 test scores decreased significantly after physical exercise due to exhaustion (mean minus at 1000 m altitude: 20%), hypoxia at moderate altitude adds to this decrease (mean minus at 3100 m altitude: 38%). After exercise at 3100 m altitude, d 2 test scores decreased significantly less after placebo. This could possibly be due to hemodynamic effects of CDM at high altitude. CDM was of no cerebroprotective effect in our trial. Saletu and co-workers' laboratory model to expose subjects to normobaric hypoxia is an established method to evaluate the pharmacodynamic properties of nootropic drugs. We do not agree with the authors, that this model simulates the situation at high altitude. In high altitude, the fraction of inspired oxygen concentration (FiO2) is 0.21 as in the low lands, but the pressure of inspired oxygen (PO2) decreases due to the reduction of barometric pressure. Saletu's model, on the contrary, leaves barometric pressure unchanged and reduces F~02. In an animal model, the effects of normobaric to hypobaric hypoxia on the brain were proved to be different (Lassanova and Tursky, 1991). Furthermore, alpinists at 6000 m altitude are normally not at rest, but at exhausting exercise. Our data unfortunately do not support the hypotheses, that CDM could be of protective effect on cerebral functions and could be a possible emergency preventive measure in alpinists at moderate altitude. R d m Brickenkamp, R. (1967): Test d 2. Hogrefe, G6ttingen. Hills, M. and Armitage, P. (1979): The two period cross over clinical trial. Br. J. Clin. Pharmacol., 8, 7-20. Horabein, T.F., Townes, B.D., Schoene, R.B., Sutton, J.R. and Houston, C.S. 0989): The cost to the central nervous system of climbing to extremely high altitude. N. Engl. J. Med., 321, 1714-1719. Lassanova, M. and Tursky, T. (1991): The influence of hypoxia on the formation of amino acids from oxidized substrates in the rat brain in vivo. Physiol. Res., 40, 403-411. Saletu, B., Cm3nberger, J., Anderer, P., Linzmayer, L., Pakesch, G. and Zyhlarz, G. (1994): Effect-kinetics on brain protection of two codergocrine-mesylate preparations (Aramexate retard® and Hydergine °) by EEG mapping and psychometry under bypoxia. Arch. Gerontoi. Geriatrics, 18, 81-99.
Reply Dear Editor, The Letter to the Editor of G. Roeggla, H. Roeggla, R. Frey, M. Binder and M. Roeggla is in many ways inconclusive. First of all, too many variables are ignored
218
G. Roeggla et al./Arch. GerontoL Geriatr. 21 (1995) 215-218
in the experimental design (velocity and duration of mountain hiking, beverage intake, water and electrolyte balance, etc). In comparison to the well-defined conditions of the trial of Saletu and coworkers (Arch. Gerontol. Geriatr. 18:81-99;1994) the major lack of the authors trial is the missing design of their experiment. The conclusions would be much better if an experienced physician, qualified in sports medicine, had supervised the trial. Independent from these formal inconsistencies, the authors are obviously not familiar with the pharmacology of codergocrine mesylate. The sympathicolytic effect of codergocrine disqualifies the compound from physical excercise. The antiadrenergic effect was the first pharmacological action described by Rothlin (Schweiz. Akad. Med. Wiss. 2:249-272;1946/7; see also for ref.: Handb. Exp. Pharmacol. 49;1978). With reference to the a-receptor-blocking action, codergocrine mesylate (dehydroergotoxine mesylate was the former generic name) was launched in 1949 as a drug against elevated blood pressure. Any a-receptor blocker lowers the capacity of physical performance and disqualifies these compounds as adjuvant for mountain climbing and competitive sports. The data of Saletu and coworkers establish experimental observations of Gygax et al. (Acta Med. Scand. Suppl. 678:29-36;1982; Int. Res. Commun. Syst. 11-161;1973) and Wiernsperger et al. (Arzneim. Forsch. 28:768-770; 1978), which observed that codergocrine mesylate causes an activation of nerve cells after temporary ischemia and hypovelmic shock. In summary codergocrine mesylate is not a doping compound for competitive sports but one of the best pharmocological and clinical-investigated psychogeriatric drugs. Prof. Dr. W. Meier-Ruge Gcrontol. Brain Research, Institute of Pathology, University of Basel SSDI 0167-4943(95)00628-X
Archives of Gerontology and Geriatrics 21 (1995) 215-218
ARCHIVES OF GERONTOLOGY AND GERIATRICS
L e t t e r to the E d i t o r
Codergocrine-mesylate is of no brain protective effect after exercise in moderate hypoxia at moderate altitude G. R o e g g l a , H. R o e g g l a , R. F r e y , M. Binder, M. Muellner, M. R o e g g l a Department of Emergency Medicine, University of Vienna, Vienna, Austria Received 25 July 1994; revision received 3 February 1995; accepted 12 February 1995
Dear Editor, Saletu et al. (1994) proved codergocrine-mesylate (CDM) to be an effective drug for brain protection in a hypoxic environment (normobaric hypoxia simulating 6000 m altitude). The cost to the central nervous system of climbing to high altitude has been a target of interest and of frequent research (Hornbein et al., 1989). The aim of our contribution was to evaluate if the findings of Saletu and co-workers may help prevent a decline of cognitive function in moderate hypoxia at moderate altitude in alpinists. The study was performed in the Austrian Alps at two altitude levels as a randomised, cross-over, placebo-controlled trial. Five healthy male volunteers, age 20-22 years, took part after informed consent. All subjects were healthy non-smokers and took no medication. All were lowland dwellers, but experienced leisure time alpinists. Physical fitness was not measured, but could be reckoned to be good to excellent. Subjects were randomised to 5 mg CDM (Hydergine®) or placebo before exercise (4 h of fast walking at a constant pulse rate of 120 beats/rain) at 800-1000 m altitude and, after a 3-day interval, to exercise of equal length and intensity at 2900-3100 m altitude. The same procedure was performed after an interval of 1 week, when subjects crossed to the other study branch. Sleeping altitude was in the lowland at 500 m altitude throughout the study, subjects were brought to exercising altitude by car and cable car. Pulse rate was measured continuously (Polar sport tester, Gro/~ 0167-4943/95/$09.50 © 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0167-4943(95)00627-W
G. Roeggla et aL / Arch. Gerontol. Geriatr. 21 (1995) 215-218
216
Gerau, Germany). Ability to concentrate and attention was tested with the d 2 test before exercise and after a 30-rain rest after exercise (Brickenkamp, 1967). Arterial oxygen saturation (Sao2) was measured by pulse oxymetrie (~-Ox Pulsoxymeter, MCC, Kadsruhe, Germany) after a 30-rain rest after exercise. Barometric pressure was 670 mmHg at 1000 m altitude and 520 mmHg at 3100 m altitude, otherwise setting and procedures were comparable at both altitudes.
Statisties Direct comparison of the differences of d 2 test scores before and after exercise at both test conditions and at both altitudes as well as SaO2 comparison was performed by the t-test (Hills and Armitage, 1979). P < 0.05 was considered significant.
Results Sao2 was significantly decreased at 3100 m altitude compared to 1000 m altitude in both test conditions (Placebo: 91.8 ± 0.84% vs. 98.4 -t- 0.55%, difference 6.6, 95%CI 5.57-7.63, P < 0.01; CDM: 91.4 4- 1.14% vs. 98.4 4- 0.55%, difference 7.0, 95% CI 5.7-8.3, P < 0.01), no significant difference between both test conditions was found at 1000 m altitude (Placebo: 98.4 4- 0.55%; CDM: 98.4 4- 0.55% difference 0.0, 95% C1-0.8-0.8, P = n.s.) and at 3100 m altitude (Placebo: 91.8 -t- 0.84%; CDM: 91.4 4- 1.14%, difference 0.4, 95% CI -1.06-1.86, P = n.s.), d 2 scores are shown in detail in Table 1. After 4 h of exercise at 1000 m altitude, the decline of scores was significantly lower than at 3100 m altitude in both test conditions (Placebo: 99.20 ± 12.28 vs. 170.60 ± 9.61, difference -71.40, 95% CI -87.48--55.32, P < 0.01; CDM: 89.0 4- 13.32 vs. 185.6 4- 7.0, difference -96.6, 95% CI -112.13--81.07, P < 0.01). Direct comparison of the differences o f d 2-test scores before and after exercise at 1000 m altitude shows no significant difference between placebo and CDM (99.20 4- 12.28 vs. 89.0 4- 13.32, difference 10.20, 95% CI -8.48-28.88, P = n.s.). At 3100 m altitude, the decline of scores was significantly
Table ! Results of the d 2 test (attention and concentration) before and after 4 h of exercise at A: 1000 m altitude before, B: after placebo, C: 1000 m altitude before, D: after codergocrine-mesylate E: 3100 m altitude before, F: after placebo, G: 3100 m altitude before, H: after Codergocrine-mesylate No.
A
B
C
D
E
F
G
H
I 2 3 4 5 mean 4. S.D.
422 464 503 422 527 467.6 47.3
324 382 409 311 416 368.4 48.4
433 439 511 430 502 463.0 39.6
352 362 407 350 399 374.0 27.0
411 455 503 419 507 459.0 45.2
250 275 330 240 347 288.4 47.9
422 453 516 430 519 468.0 46.6
240 257 333 252 330 282.4 45.3
Figures are total scores minus errors.
G. Roeggla et ai./Arch. Gerontol. Geriatr. 21 (1995) 215-218
217
lower after placebo than after CDM (170.60 ± 9.61 vs. 185.6 4- 7.0, difference -15, 95% CI -27.26 to -2.74, P < 0.05). The possibility of any effect of test order or treatment carry-over was tested using the baseline readings of each period and group (Hills and Armitage, 1979). No significant effects were found. D~Oll
The d 2 test was performed after a 30-min rest after exercise at both investigation altitudes at stable conditions. Sa02 was significantly decreased at 3100 m altitude, but no impairment of the ability to concentrate or attention was detected at rest. d 2 test scores decreased significantly after physical exercise due to exhaustion (mean minus at 1000 m altitude: 20%), hypoxia at moderate altitude adds to this decrease (mean minus at 3100 m altitude: 38%). After exercise at 3100 m altitude, d 2 test scores decreased significantly less after placebo. This could possibly be due to hemodynamic effects of CDM at high altitude. CDM was of no cerebroprotective effect in our trial. Saletu and co-workers' laboratory model to expose subjects to normobaric hypoxia is an established method to evaluate the pharmacodynamic properties of nootropic drugs. We do not agree with the authors, that this model simulates the situation at high altitude. In high altitude, the fraction of inspired oxygen concentration (FiO2) is 0.21 as in the low lands, but the pressure of inspired oxygen (PO2) decreases due to the reduction of barometric pressure. Saletu's model, on the contrary, leaves barometric pressure unchanged and reduces F~02. In an animal model, the effects of normobaric to hypobaric hypoxia on the brain were proved to be different (Lassanova and Tursky, 1991). Furthermore, alpinists at 6000 m altitude are normally not at rest, but at exhausting exercise. Our data unfortunately do not support the hypotheses, that CDM could be of protective effect on cerebral functions and could be a possible emergency preventive measure in alpinists at moderate altitude. R d m Brickenkamp, R. (1967): Test d 2. Hogrefe, G6ttingen. Hills, M. and Armitage, P. (1979): The two period cross over clinical trial. Br. J. Clin. Pharmacol., 8, 7-20. Horabein, T.F., Townes, B.D., Schoene, R.B., Sutton, J.R. and Houston, C.S. 0989): The cost to the central nervous system of climbing to extremely high altitude. N. Engl. J. Med., 321, 1714-1719. Lassanova, M. and Tursky, T. (1991): The influence of hypoxia on the formation of amino acids from oxidized substrates in the rat brain in vivo. Physiol. Res., 40, 403-411. Saletu, B., Cm3nberger, J., Anderer, P., Linzmayer, L., Pakesch, G. and Zyhlarz, G. (1994): Effect-kinetics on brain protection of two codergocrine-mesylate preparations (Aramexate retard® and Hydergine °) by EEG mapping and psychometry under bypoxia. Arch. Gerontoi. Geriatrics, 18, 81-99.
Reply Dear Editor, The Letter to the Editor of G. Roeggla, H. Roeggla, R. Frey, M. Binder and M. Roeggla is in many ways inconclusive. First of all, too many variables are ignored
218
G. Roeggla et al./Arch. GerontoL Geriatr. 21 (1995) 215-218
in the experimental design (velocity and duration of mountain hiking, beverage intake, water and electrolyte balance, etc). In comparison to the well-defined conditions of the trial of Saletu and coworkers (Arch. Gerontol. Geriatr. 18:81-99;1994) the major lack of the authors trial is the missing design of their experiment. The conclusions would be much better if an experienced physician, qualified in sports medicine, had supervised the trial. Independent from these formal inconsistencies, the authors are obviously not familiar with the pharmacology of codergocrine mesylate. The sympathicolytic effect of codergocrine disqualifies the compound from physical excercise. The antiadrenergic effect was the first pharmacological action described by Rothlin (Schweiz. Akad. Med. Wiss. 2:249-272;1946/7; see also for ref.: Handb. Exp. Pharmacol. 49;1978). With reference to the a-receptor-blocking action, codergocrine mesylate (dehydroergotoxine mesylate was the former generic name) was launched in 1949 as a drug against elevated blood pressure. Any a-receptor blocker lowers the capacity of physical performance and disqualifies these compounds as adjuvant for mountain climbing and competitive sports. The data of Saletu and coworkers establish experimental observations of Gygax et al. (Acta Med. Scand. Suppl. 678:29-36;1982; Int. Res. Commun. Syst. 11-161;1973) and Wiernsperger et al. (Arzneim. Forsch. 28:768-770; 1978), which observed that codergocrine mesylate causes an activation of nerve cells after temporary ischemia and hypovelmic shock. In summary codergocrine mesylate is not a doping compound for competitive sports but one of the best pharmocological and clinical-investigated psychogeriatric drugs. Prof. Dr. W. Meier-Ruge Gcrontol. Brain Research, Institute of Pathology, University of Basel SSDI 0167-4943(95)00628-X