allopurinol does not reduce exercise induced muscle damage
TRANSCRIPT
Allopurinol does not reduce
exercise induced muscle damage
in ultra-marathon runners.
DR PAUL R. MASON
MBBS (HONS), B. PHYSIO, MASTERS OCC. HEALTH
DR JONATHAN KING
FACSEP, FRACGP, MSC SPORT SCIENCE
Exercise induced muscle
damage. novel or unaccustomed exercise
soreness and swelling
reduced power
reduces ability to perform
subsequent bouts of exercise
Mechanisms of exercise
induced muscle damage.
Mechanical
muscle contraction
shock impulses
Reactive oxygen species
unbalanced valence shell
oxidise amino acids
oxidise cell membrane
damage of DNA / RNA
Biopsy findings in exercise
induced muscle damage. Structural changes
Cell necrosis
Serology of exercise
induced muscle damage. released intra-cellular elements
• Creatine Kinase
• Lactate Dehydrogenase
• Aspartate Aminotransferase
oxidised cell membranes
• Lipid peroxidation
• Produces malondialdehyde
Production of reactive oxygen species (1/2)
• ~2% of oxygen in ETC forms ROS
• by-product of oxygen
metabolism
Production of reactive oxygen species (2/2)
• Xanthine oxidase activity
• Purine metabolism
• Produces ROS
• Found in many tissues
• liver
• intestines
• endothelium
• lungs
• relative hypoxia
increases activity
Allopurinol
Active metabolite
oxypurinol• Inhibits xanthine oxidase
• Half life 23.3 +/- 6.0 hours
• Reduces ROS
production
Past research
Allopurinol and Markers of Muscle
Damage Among Participants in the
Tour de France
Significant differences
(placebo vs allopurinol)• CK (P=0.03)
• AST (P=0.02)
• Malondialdehyde (P=0.009)
Gómez-Cabrera, M.-C., Pallardó, F. V., Sastre, J., Viña, J., & García-del-Moral, L. (2003).
JAMA, 289(19), 2503–2504.
Allopurinol prevents cardiac and skeletal muscle damage in professional soccer players.
Significant differences (placebo vs
allopurinol)
CK (P<0.05)
LDH (P<0.05)
AST (P<0.05)
Myoglobin (P<0.05)
Malondialdehyde (P<0.05)
Sanchis-Gomar, F., Pareja-Galeano, H., Gomez-Cabrera, M. C., Candel, J., Lippi, G., Salvagno,
G. L., Viña, J. (2015). Scandinavian Journal of Medicine & Science in Sports, 25(1), e110–115.
Oxidative stress in marathon
runners: interest of antioxidant
supplementation. Placebo: increase in malondialdehyde (P<0.05)
Allopurinol: no significant change in malondialdehyde
Between group: no significant difference
Gomez-Cabrera, M.-C., Martínez, A., Santangelo, G., Pallardó, F. V., Sastre, J., & Viña, J.
(2006). The British Journal of Nutrition, 96 Suppl 1, S31–33.
Hypothesis
Prophylactic allopurinol may lead to
reduced exercise induced muscle damage
by reducing oxidative stress in ultra-
marathon runners.
Ultra-marathons
>42km
Often extreme conditions
>3,000 ultra-marathons annually
globally
Great North Walk 100’s
103.7 km
3,800m ascent/descent
22 hour limit
175.3 km
6,200m ascent/descent
36 hour limit
Check points ~25km apart
(eat, drink and rest)
Methodology
Recruitment via email
13 runners (8 male, 5 female)
Pre-event blood test
baseline renal/hepatic function
baseline uric acid levels
Test dose 300mg allopurinol/placebo
Dose night before event (300mg)
Dose on morning of event (300mg)
Post event blood test 48 hours post event
Results (1/2)
SexDistance
(km)Time Group
CK
(pre)
CK
(post)
LDH
(pre)
LDH
(post)
AST
(pre)
AST
(post)
Male 81.6 13:57:00 allopurinol 169 530 166 205 26 43
Male 175.3 35:37:00 allopurinol 205 1225 204 350 26 77
Male 103.7 16:07:00 allopurinol 159 601 183 268 23 40
Male 52.5 7:19:00 allopurinol 150 325 153 204 22 43
Female 175.3 35:41:00 allopurinol 175 1161 171 377 23 110
Female 28.6 6:15:00 allopurinol 133 146 193 205 22 22
Male 103.7 17:04:00 placebo 96 956 181 306 24 133
Male 85 15:00:00 placebo 96 191 181 189 24 33
Male 175.3 20:42:00 placebo 297 863 173 236 23 44
Male 175.3 35:15:00 placebo 110 773 174 233 25 54
Female 103.7 15:02:00 placebo 92 171 161 230 17 27
Female 175.3 33:42:00 placebo 69 355 159 266 22 59
Results (2/2)
Control (n = 6) Allopurinol (n = 6) Allopurinol vs. Control
Pre Post ∆ Pre Post ∆
Between-
condition changes
(Cohen’s d)
% Chances
Benefical/
Trivial/Harmful
CK
(U/L)
126.7
(57.2-196.2)
551.5
(261.1-841.9)
424.8
(161.2-688.5)
165.2
(145-185.3)
664.7
(302.9-1026.4)
499.5
(155.9-843.1)
-0.47
(-2.12 - 1.17)
24/15/62
LDH
(U/L)
171.5
(163.6-179.4)
243.3
(211-275.7)
71.8
(38.1-105.5)
178.3
(163-193.7)
268.2
(203.8-332.6)
89.8
(29.6-150.1)
0.43
(-2.25 - 3.11)
56/10/34
AST
(U/L)
22.5
(20.1-24.9)
58.3
(26.6-90)
35.8
(5-66.6)
23.7
(22.1-25.2)
55.8
(29.5-82.1)
32.2
(6.2-58.1)
-0.72
(-5.27 - 3.83)
36/6/58
Discussion
Shock impulses vs muscle contraction
Running vs. skiing
Event duration vs oxypurinol half life
4 runners >30 hours
Re-analysis did not change results
Conclusion
Premature to discount benefits of prophylactic allopurinol in
reducing oxidative stress
Malondialdehyde useful to assess oxidative stress directly
Future research should focus on
Low impact activities
Event duration <17 hours
Questions.
Assumpção, C. de O., Lima, L. C. R., Oliveira, F. B. D., Greco, C. C., & Denadai, B. S. (2013). Exercise-Induced Muscle Damage and
Running Economy in Humans. The Scientific World Journal, 2013. https://doi.org/10.1155/2013/189149
Brancaccio, P., Lippi, G., & Maffulli, N. (2010). Biochemical markers of muscular damage. Clinical Chemistry and Laboratory Medicine,
48(6), 757–767. https://doi.org/10.1515/CCLM.2010.179
Day, R. O., Graham, G. G., Hicks, M., McLachlan, A. J., Stocker, S. L., & Williams, K. M. (2007). Clinical pharmacokinetics and
pharmacodynamics of allopurinol and oxypurinol. Clinical Pharmacokinetics, 46(8), 623–644. https://doi.org/10.2165/00003088-
200746080-00001
Gomez-Cabrera, M.-C., Martínez, A., Santangelo, G., Pallardó, F. V., Sastre, J., & Viña, J. (2006). Oxidative stress in marathon runners:
interest of antioxidant supplementation. The British Journal of Nutrition, 96 Suppl 1, S31–33.
Gómez-Cabrera, M.-C., Pallardó, F. V., Sastre, J., Viña, J., & García-del-Moral, L. (2003). Allopurinol and markers of muscle damage
among participants in the Tour de France. JAMA, 289(19), 2503–2504. https://doi.org/10.1001/jama.289.19.2503-b
Grobler, L. A., Collins, M., Lambert, M. I., Sinclair-Smith, C., Derman, W., St Clair Gibson, A., & Noakes, T. D. (2004). Skeletal muscle
pathology in endurance athletes with acquired training intolerance. British Journal of Sports Medicine, 38(6), 697–703.
https://doi.org/10.1136/bjsm.2003.006502
Hill, J. A., Howatson, G., van Someren, K. A., Walshe, I., & Pedlar, C. R. (2014). Influence of compression garments on recovery after
marathon running. Journal of Strength and Conditioning Research / National Strength & Conditioning Association, 28(8), 2228–2235.
https://doi.org/10.1519/JSC.0000000000000469
Hopkins, W. G., Marshall, S. W., Batterham, A. M., & Hanin, J. (2009). Progressive statistics for studies in sports medicine and exercise
science. Medicine and Science in Sports and Exercise, 41(1), 3–13. https://doi.org/10.1249/MSS.0b013e31818cb278
Sanchis-Gomar, F., Pareja-Galeano, H., Gomez-Cabrera, M. C., Candel, J., Lippi, G., Salvagno, G. L., … Viña, J. (2015). Allopurinol
prevents cardiac and skeletal muscle damage in professional soccer players. Scandinavian Journal of Medicine & Science in Sports,
25(1), e110–115. https://doi.org/10.1111/sms.12213
Sastre, J., Asensi, M., Gascó, E., Pallardó, F. V., Ferrero, J. A., Furukawa, T., & Viña, J. (1992). Exhaustive physical exercise causes
oxidation of glutathione status in blood: prevention by antioxidant administration. The American Journal of Physiology, 263(5 Pt 2),
R992–995.
Worldwide 2016 – 2017 Ultramarathon Calendar. (2016, November 4). Retrieved April 11, 2016, from
http://marathons.ahotu.com/calendar/ultramarathon