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SK500492010A3 - Use of beta-D-glucane for decreasing undesirable effect of depression of immune response to excessive physical strain - Google Patents

Use of beta-D-glucane for decreasing undesirable effect of depression of immune response to excessive physical strain Download PDF

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SK500492010A3
SK500492010A3 SK50049-2010A SK500492010A SK500492010A3 SK 500492010 A3 SK500492010 A3 SK 500492010A3 SK 500492010 A SK500492010 A SK 500492010A SK 500492010 A3 SK500492010 A3 SK 500492010A3
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glucan
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Jan Gabriz
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/716Glucans
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    • A23V2002/00Food compositions, function of food ingredients or processes for food or foodstuffs

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Abstract

The use of ß-D-Glucan as an immunomodulator results in the reduction of adverse immune response depression resulting from excessive physical exercise in individuals who routinely engage in this type of exercise. The ß-D-Glucan described here is fungal ß(1,3/1,6)-D-Glucan prepared from the oyster mushroom and is administered orally at a maximum of 200 mg per dose, always prior to excessive physical exercise. The evaluation of the immune response is based on the assessment of NK cell activity, which is performed before excessive physical exercise, within 10 minutes after exercise, and between 50 and 70 minutes after exercise.

Description

Použitie β-D-glukánu na zníženie nežiaduceho efektu depresie imunitnej odpovede na nadmernú fyzickú záťažUse of β-D-Glucan to reduce the adverse effect of immune response depression on excessive physical exercise

Oblasť technikyTechnical field

Vynález sa týka použitia β-D-glukánu na zníženie nežiaduceho efektu depresie imunitnej odpovede na nadmernú fyzickú záťaž - imunitného systému navodenú stresujúcou vyčerpávajúcou fyzickou záťažou, najmä u vrcholových športovcov.The invention relates to the use of β-D-glucan to reduce the undesired effect of depression of the immune response on excessive physical exercise - the immune system induced by stressful exhausting physical exercise, particularly in athletes.

Doterajší stav technikyBACKGROUND OF THE INVENTION

Je známe, že nadmerná a vyčerpávajúca fyzická záťaž produkuje depresiu v imunitnom systéme. Predpokladá sa, že potravinové doplnky (nápoje) obohatené o sacharidy (cukry) podporujú imunitné funkcie v odpovedi na okamžitú fyzickú záťaž. Príjem takýchto sacharidov vplýva na bunkovú distribúciu, proliferáciu lymfocytov, na prirodzenú bunkami sprostredkovanú cytotoxicitu a na distribúciu cytokínov cez hladinu glukózy v krvi a hormonálnu interakciu (Nieman, D.C. 1998, Exerc. Immunol. Rev. 4: 64-76; Bishop, N.C., Walsh, N.P., Haines, D.L., Richards, E.E., and Gleeson, M. 2001, Int. J. Šport Nutr. Exerc. Metabol. 11: 490-502; Gleeson, M. 2006, Nutr. Rev. 64: 119-131). Na druhej strane, nápoje bohaté na sacharidy nemenia aktivitu NK buniek, ktorá charakterizuje stav imunitných funkcií, po nadmernej fyzickej záťaži (Nieman, D.C. 1994, Int. J. Sports Med. 15: S131-141; Braun, W.A., Flynn, M.G., Jacks, D.E., McLoughlin, T., Sowash, J., Lambert, C.P., et al. 1999, Diagn. Immunol. 3: 197-204; Flynn, M.G., Fahlman, M., Braun, W.A., Lambert, C.P., Bouillon, L.E., Brolinson, P.G., et al. 1999, J. Appl. Physiol. 86: 1905-1913; McFarlin, B.K., Flynn, M.G., Phillips, M.D., Stewart, L.K., and Timmerman, K.L. 2004, J. Appl. Physiol. 96: 271-275).It is known that excessive and exhaustive physical stress produces depression in the immune system. Dietary supplements (beverages) enriched with carbohydrates (sugars) are believed to support immune function in response to immediate physical stress. The uptake of such carbohydrates affects cell distribution, lymphocyte proliferation, natural cell-mediated cytotoxicity, and cytokine distribution through blood glucose levels and hormonal interaction (Nieman, DC 1998, Exerc. Immunol. Rev. 4: 64-76; Bishop, NC, Walsh, NP, Haines, DL, Richards, EE, and Gleeson, M. 2001, Int. J. Sport Nutr. Exerc. Metabol. 11: 490-502; Gleeson, M. 2006, Nutr. Rev. 64: 119- 131). On the other hand, carbohydrate-rich beverages do not alter NK cell activity, which characterizes the state of immune function, after excessive physical exercise (Nieman, DC 1994, Int. J. Sports Med. 15: S131-141; Braun, WA, Flynn, MG, Jacks, DE, McLoughlin, T., Sowash, J., Lambert, CP, et al., 1999, Diagn Immunol. 3: 197-204; Flynn, MG, Fahlman, M., Braun, WA, Lambert, CP, Bouillon, LE, Brolinson, PG, et al 1999, J. Appl Physiol 86: 1905-1913, McFarlin, BK, Flynn, MG, Phillips, MD, Stewart, LK, and Timmerman, KL 2004, J. Appl. Physiol 96: 271-275).

β-D-glukány (funkčné polysacharidy) patria do skupiny modifikátorov biologických odpovedí a podieľajú sa na zlepšovaní imunitných funkcií (Sherwood, E.R., Williams, D.L., and DiLuzio, N.R. 1986, J. Biol. Response Mod. 5: 504-526; Browder, W., Williams, D., Pretus, H., Olivero, G., Enrichens, F., Mao, P., et al. 1990, Ann. Surg. 211: 605-613; Pretus, H.A., Ensley, H.E., McNamee, R.B., Jones, E.L., Browder, I.W., and Williams, D.L. 1991, J. Pharmacol. Exp. Ther. 257: 500-510; Williams, J.D., Mueller, A., and Browder, W. 1996, Clin. Immunother. 5: 392-399).β-D-glucans (functional polysaccharides) belong to the class of biological response modifiers and are involved in improving immune functions (Sherwood, ER, Williams, DL, and DiLuzio, NR 1986, J. Biol. Response Mod. 5: 504-526; Browder, W., Williams, D., Pretus, H., Olivero, G., Enrichens, F., Mao, P., et al., 1990, Ann. Surg., 211: 605-613; Pretus, HA, Ensley , HE, McNamee, RB, Jones, EL, Browder, IW, and Williams, DL 1991, J. Pharmacol., Exp Ther. 257: 500-510; Williams, JD, Mueller, A., and Browder, W. 1996 Clin Clin Immunother 5: 392-399).

Účinok β-D-glukánu na zmeny v imunitnom systéme vyvolané fyzickou aktivitou nebol doposiaľ podrobne popísaný. Nieman et al (Nieman, D.C., Henson, D.A., McMahon, M., Wrieden, J.L., Davis, J.M., Murphy, E.A., et al. 2008, Med. Sci. Sports Exerc. 40: 14631471) zistil, že podávanie rozpustného β-D-glukánu u športovcov neviedlo k obnoveniu znížených imunitných funkcií po nadmernej fyzickej záťaži. Na druhej strane pravidelné užívanie nerozpustného β-D-glukánu u ľudí s nadmernou fyzickou aktivitou zabraňuje vzniku respiračných infekcií (Talbott, S., and Talbott, J., 2009, J. Sports Sci. Med. 8: 509515).The effect of β-D-glucan on changes in the immune system induced by physical activity has not been described in detail. Nieman et al (Nieman, DC, Henson, DA, McMahon, M., Wrieden, JL, Davis, JM, Murphy, EA, et al. 2008, Med. Sci. Sports Exerc. 40: 14631471) found that administration of soluble β-D-glucan in athletes did not lead to the restoration of reduced immune functions after excessive physical exercise. On the other hand, regular use of insoluble β-D-glucan in people with excessive physical activity prevents respiratory infections (Talbott, S., and Talbott, J., 2009, J. Sports Sci. Med. 8: 509515).

Williams, J.D., Mueller, A., and Browder, W. 1996. Glucan-based macrophage stimulators. A review of their anti-infective potential. Clin. Immunother. 5: 392-399).Williams, J.D., Mueller, A., and Browder, W. 1996. Glucan-based macrophage stimulators. A review of their anti-infective potential. Clin. Immunother. 5: 392-399).

Cieľom vynálezu je dosiahnuť zníženie nežiaduceho efektu depresie imunitného systému vyvolaného stresujúcou vyčerpávajúcou fyzickou záťažou.It is an object of the present invention to reduce the undesirable effect of depression of the immune system induced by stressful exhausting physical stress.

Podstata vynálezuSUMMARY OF THE INVENTION

Tento cieľ sa dosiahol pomocou použitia β-D-glukánu podľa vynálezu, ktorého podstata spočíva v tom, že sa použije β-D-glukán ako imunomodulátor na zníženie nežiaducej depresie imunitnej odpovede na nadmernú fyzickú záťaž u jedincov podrobených tejto záťaži.This object has been achieved by the use of the β-D-glucan of the invention, which is based on the use of β-D-glucan as an immunomodulator to reduce unwanted depression of the immune response to excessive physical exercise in individuals subjected to this exercise.

β-D-glukán je fungálny β(1,3/1,6)-ϋ^1ι±έη, pripravený z hlivy ustricovej.β-D-glucan is a fungal β (1,3 / 1,6) -ϋ ^ 1 1 ± έη, prepared from oyster mushroom.

Zistilo sa, že je výhodné, keď sa β-D-glukan podáva perorálne v množstve najviac 200 mg vždy pred nadmernou fyzickou záťažou.It has been found to be advantageous to administer β-D-glucan orally in an amount of not more than 200 mg each before excessive physical exercise.

Vyhodnotenie imunitnej odpovede organizmu jedincov sa uskutočňuje stanovením aktivity NK buniek, a to tesne pred nadmernou fyzickou záťažou, do 10 minút po nej a následne po relaxácii od 50 do 70 minút po nadmernej fyzickej záťaži.Evaluation of an individual's immune response is performed by determining NK cell activity, just before, or within 10 minutes of, and after relaxation from 50 to 70 minutes after excessive physical exercise.

Podávanie β-D-glukánu významne znižuje nežiaduci efekt depresie imunitného systému vyvolaný stresujúcou vyčerpávajúcou fyzickou záťažou, pretože hodnota aktivity NK buniek po 50 až 70 minútovej relaxácii po nadmernej fyzickej záťaži je významne vyššia u jedincov užívajúcich β-D-glukán oproti hodnote získanej u jedincov užívajúcich placebo, a je približne rovnaká, ako hodnota získaná pred nadmernou fyzickou záťažou. Pokles hodnoty aktivity NK buniek po 50 až 70 minútovej relaxácii po nadmernej fyzickej záťaži v porovnaní s hodnotou zistenou pred fyzickou záťažou je u jedincov užívajúcich β-D-glukán v priemere o 3,5 %, zatiaľ čo u jedincov užívajúcich placebo je to priemerne o 29 %. Teda hodnota aktivity NK buniek po 50 až 70 minútovej relaxácii po nadmernej fyzickej záťaži u jedincov užívajúcich β-D-glukán sa dostane prakticky na úroveň pred fyzickou záťažou.Administration of β-D-glucan significantly reduces the adverse effect of immune system depression induced by stressful exhausting physical exercise, since the value of NK cell activity after 50-70 minutes of relaxation after excessive physical exercise is significantly higher in subjects taking β-D-glucan compared to that obtained in individuals. using placebo, and is approximately the same as the value obtained prior to excessive physical exercise. The decrease in NK cell activity values after 50-70 minutes of relaxation after excessive physical exercise compared to pre-exercise levels is on average 3.5% in subjects taking β-D-glucan, while those receiving placebo on average 29%. Thus, the value of NK cell activity after 50-70 minutes of relaxation after excessive physical exercise in individuals taking β-D-glucan will reach virtually pre-physical exercise levels.

Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION

V príkladnej štúdii bol použitý β-D-glukán vo forme komerčného prípravku Imunoglukán vyrobeného z hlivy ústricovej.In an exemplary study, β-D-glucan was used as a commercial preparation of Immunoglucan made from oyster mushroom.

Príklad 1Example 1

Do štúdie bolo po informovanom súhlase zaradených 22 športovcov z Vrcholového strediska zimných športov ŠKP Štrbské Pleso ( 23 ± 6 rokov ). Počas štúdie prebiehala v stredisku letná príprava a športovci absolvovali tréning minimálne 3 krát týždenne s minimálnym zaťažením viac ako 60% ich VO2 max po dobu 1 hod a viac. Skupina pozostávala zo športovcov venujúcich sa vytrvalostnému behu na lyžiach (n=9, L) rýchlokorčuľovaniu (n=6, K) a sánkárskym športom (n=7, S). Pred vstupným testom boli športovci náhodne rozdelení do dvoch skupín s pravidelným zastúpením spomínaných disciplín v každej skupine. V štúdii bola aplikovaná záťaž vo forme stupňovitého bicyklového testu až do vyčerpania. Boli vykonané vyšetrenia nasledovných parametrov: krvný obraz, subpopulácie lymfocytov- v relatívnom i absolútnom počte, s dôrazom na NK bunky, subpopulácie NK buniek CD16±/CD8±/CD56±, aktivity NK buniek, IgA, IgM, IgG,C3,C4 a kortizolu. Parametre boli vyšetrované pred záťažou, 5 minút po záťaži a po hodinovej relaxácii od záťaže. Športovci boli rozdelení na dve terapeutické skupiny. Jedna skupina (nazveme ju „Glukán“) užívala každé ráno pre záťažou nalačno 100 mg Imunoglukánu +100 mg vitamínu C, druhá skupina (nazveme ju „Placebo“) užívala vtom istom režime placebo (100 mg fruktózy a 100 mg vitamínu C) počas doby 2 mesiacov pri súčasne prebiehajúcej letnej tréningovej príprave. Z osobných dôvodov štúdiu nedokončili dvaja športovci: lyžiar a krasokorčuliar, obaja zo skupiny „Glukán“.After informed consent, 22 athletes from the SKP Strbske Pleso Winter Sports Center (23 ± 6 years) were included in the study. During the study, summer training took place at the center and athletes underwent training at least 3 times a week with a minimum load of more than 60% of their VO2 max for 1 hour or more. The group consisted of athletes engaged in endurance cross-country skiing (n = 9, L), speed skating (n = 6, K) and sledding (n = 7, S). Before the entrance test, the athletes were randomly divided into two groups with regular representation of the above mentioned disciplines in each group. The study applied a stepped bicycle test load to exhaustion. The following parameters were examined: blood count, lymphocyte subpopulations - in relative and absolute numbers, with emphasis on NK cells, NK cell subpopulations CD16 ± / CD8 ± / CD56 ±, NK cell activities, IgA, IgM, IgG, C3, C4 and cortisol. Parameters were examined before exercise, 5 minutes after exercise and after one hour of relaxation from exercise. Athletes were divided into two therapeutic groups. One group (called “Glucan”) took 100 mg of Imunoglucan + 100 mg of vitamin C each morning for a fasting load, the other group (called “Placebo”) took the same placebo regimen (100 mg fructose and 100 mg vitamin C) for the same time 2 months with summer training at the same time. For personal reasons, two athletes did not complete the study: a skier and a figure skater, both from the Glucan group.

Stanovenie výsledkov štúdie sa uskutočňovalo nasledovne: Ráno pred absolvovaním fyzickej záťaže bol urobený odber venóznej krvi do odberového systému Vacutainer na nasledovné vyšetrenia: krvný obraz, subpopulácie leukocytov a lymfocytov (4ml, K3EDTA). NK aktivita bola vyšetrená z heparínovej krvi (7 ml, Na2Heparín). Výsledky týchto vyšetrení slúžili ako bazálne hodnoty. Druhý odber na rovnaké vyšetrenia bol urobený 5 minút po absolvovaní záťaže a tretí odber po 1 hodine relaxácie od absolvovania záťaže.The results of the study were determined as follows: In the morning before exercise, venous blood was collected into the Vacutainer collection system for the following examinations: blood count, leukocyte and lymphocyte subpopulations (4ml, K3EDTA). NK activity was examined from heparin blood (7 ml, Na2Heparin). The results of these examinations served as basal values. The second sampling for the same examinations was made 5 minutes after the exercise and the third sampling after 1 hour of relaxation from the exercise.

Stanovenie aktivity NK buniek sa uskutočnilo testom na prietokovom cytometri, pričom hodnoty aktivity NK buniek sa stanovujú v lyrických jednotkách LU, teda počte efektorov potrebných na 20% -tnú lýzu 10000 terčových buniek, a vyjadrujú ako počet LU v obsiahnutých v 107 buniek (LU20/I07 efektorov).Determination of NK cell activity was performed by flow cytometry assay, with NK cell activity values determined in lyric units of LU, the number of effectors required for 20% lysis of 10,000 target cells, and expressed as the number of LUs contained in 10 7 cells (LU20). / I0 7 effectors).

Aktivita NK buniek je jediným parametrom, u ktorého bola pozorovaná štatisticky signifikantná diferencia medzi oboma terapeutickými skupinami (obr.l). Rozdiel bol zaznamenaný aj v celkovom počte NK buniek, ktorý však nebol štatisticky významný.NK cell activity is the only parameter in which a statistically significant difference was observed between the two treatment groups (Fig. 1). The difference was also noted in the total number of NK cells, but this was not statistically significant.

Na obr. 1 sú znázornené hodnoty aktivity NK buniek vyjadrené v lyrických jednotkách pre obidve skupiny „Glukán“ i „Placebo“, Bazálne hodnoty aktivity NK buniek vyjadrenej v lyrických jednotkách (priemer 48 LU), 5 minút po záťaži stúpajú vysoko signifíkantne (priemer 100 LU) v priemere o 115 percent Vo fáze relaxácie dochádza k depresii pod bazálnu hodnotu v priemere o 28 percent u „Placebo“ terapeutickej skupiny. Teda depresiu počtu NK buniek vo fáze relaxácie po predchádzajúcom fyzickom strese sprevádza i funkčný pokles v aktivite NK buniek. U skupiny užívajúcej β-D-glukán sme po relaxácii nezaznamenali pokles aktivity NK buniek pod bazálnu hodnotu.In FIG. Fig. 1 shows the values of NK cell activity expressed in lyric units for both the Glucan and Placebo groups. Basal values of NK cell activity expressed in lyric units (mean 48 LU), 5 minutes after the load, increase very significantly (mean 100 LU) in an average of 115 percent In the relaxation phase, depression is below baseline by an average of 28 percent in the "Placebo" therapeutic group. Thus, depression of NK cell numbers in the relaxation phase after previous physical stress is accompanied by a functional decrease in NK cell activity. In the β-D-glucan group, there was no decrease in NK cell activity below baseline after relaxation.

Z výsledkov v obr. 1 vidíme, že zmena hodnoty aktivity NK buniek po 50 až 70 minútovej relaxácii po nadmernej fyzickej záťaži v porovnaní s hodnotou zistenou pred fyzickou záťažou je nasledovná;From the results in FIG. 1 shows that the change in the value of NK cell activity after 50-70 minutes of relaxation after excessive physical exercise compared to that observed prior to physical exercise is as follows;

skupina „B-D-glukán“ - vzostup o 1,8 %group "B-D-glucan" - increase by 1.8%

- skupina „Placebo“ - pokles o 28 %- "Placebo" group - decrease by 28%

Zmena hodnoty aktivity NK buniek po 50 až 70 minútovej relaxácii po nadmernej fyzickej záťaži v porovnaní s hodnotou zistenou pred fyzickou záťažou u jedincov užívajúcich β-D-glukán predstavuje vzostup v priemere o 1,8 %, zatiaľ čo u jedincov užívajúcich placebo je to pokles priemerne o 28 %. Teda hodnota aktivity NK buniek po 50 až 70 minútovej relaxácii po nadmernej fyzickej záťaži u jedincov užívajúcich β-D-glukán sa dostane prakticky na úroveň pred fyzickou záťažou.The change in NK cell activity value after 50-70 minutes of relaxation after excessive physical exercise compared to the pre-exercise value in individuals taking β-D-glucan represents an increase of 1.8% on average, whereas in patients taking placebo it is a decrease an average of 28%. Thus, the value of NK cell activity after 50-70 minutes of relaxation after excessive physical exercise in individuals taking β-D-glucan will reach virtually pre-physical exercise levels.

Príklad 2Example 2

Postupovalo sa rovnako ako v príklade 1 stým rozdielom, že jedincom bolo podávané 180 mg β-D-glukánu. Hodnota aktivity NK buniek po 50 až 70 minútovej relaxácii po nadmernej fyzickej záťaži u jedincov užívajúcich β-D-glukán sa dostane prakticky na úroveň pred fyzickou záťažou.The procedure of Example 1 was followed except that 180 mg of β-D-glucan was administered to the subjects. The value of NK cell activity after 50-70 minutes of relaxation after excessive physical exercise in subjects taking β-D-glucan is virtually at pre-physical exercise levels.

Výsledky štúdie preukázali že počas intenzívneho opakovaného cvičenia dochádza k mobilizácii a redistribúcii buniek imunitného systému v súvislosti so stresom, ktoré môžu viesť k nežiaducemu efektu depresie imunitnej odpovede. Z pozorovaných údajov je možné usúdiť, že niektoré nežiaduce efekty najmä v oblasti funkcie buniek je možné modulovať. Práve v tejto oblasti sa ako sľubným ukazuje pozitívny protektívny vplyv fungálneho β( 1,3/1,6)-D-glukánu resp. Imunoglukánu, na aktivitu NK buniek.The results of the study showed that during intensive repetitive exercise, the immune system cells are mobilized and redistributed in connection with stress, which can lead to an adverse effect of depression of the immune response. From the observed data it can be concluded that some adverse effects, especially in the field of cell function, can be modulated. It is in this area that promising positive protective effect of fungal β (1,3 / 1,6) -D-glucan resp. Immunoglucan, for NK cell activity.

Priemyselná využiteľnosťIndustrial usability

Vynález možno využívať najmä v oblasti športu, a to pre vrcholových športovcov.The invention can be used, in particular, in the field of sports, for top athletes.

Claims (7)

PATENTOVÉ NÁROKYPATENT CLAIMS 1. Použitie β-D-glukánu ako imunomodulátora na zníženie nežiaducej depresie imunitnej odpovede na nadmernú fyzickú záťaž u jedincov podrobených tejto záťaži.Use of β-D-glucan as an immunomodulator to reduce unwanted depression of the immune response to excessive physical exercise in individuals subjected to this exercise. 2. Použitie podľa nároku 1, vyznačujúce sa tým, že β-D-glukan je fungálny β(1,3/1,6)D-glukán.Use according to claim 1, characterized in that the β-D-glucan is a fungal β (1,3 / 1,6) D-glucan. 3. Použitie podľa nároku 1 a 2, vyznačujúce sa tým, že fungálny β(1,3/1,6)-ϋ^1χύάίη je pripravený z hlivy ustricovej.Use according to claim 1 or 2, characterized in that the fungal β (1,3 / 1,6) -ϋϋ 1ύύύίίηη is prepared from oyster mushroom. 4. Použitie podľa nároku 1, vyznačujúce sa tým, že β-D-glukán sa podáva v množstve najviac 200 mg vždy pred nadmernou fyzickou záťažou.Use according to claim 1, characterized in that the β-D-glucan is administered in an amount of not more than 200 mg each before excessive physical exercise. 5. Použitie podľa nároku 1 až 4, vyznačujúce sa tým, že β-D-glukán sa podáva perorálne.Use according to claims 1 to 4, characterized in that the β-D-glucan is administered orally. 6. Použitie podľa nároku 1 až 5, vyznačujúce sa tým, že vyhodnotenie imunitnej odpovede organizmu jedincov sa uskutočňuje stanovením aktivity NK buniek.Use according to claims 1 to 5, characterized in that the evaluation of the immune response of the individual is carried out by determining the activity of NK cells. 7. Použitie podľa nároku 1 až 6, vyznačujúce sa tým, že stanovenie aktivity NK buniek sa uskutočňuje pred nadmernou fyzickou záťažou, do 10 minút po nej a následne od 50 do 70 minút po nadmernej fyzickej záťaži.Use according to claims 1 to 6, characterized in that the determination of NK cell activity is carried out before, within 10 minutes after, and subsequently from 50 to 70 minutes after the excessive physical exercise.
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PCT/SK2011/050016 WO2012060783A1 (en) 2010-11-06 2011-11-05 THE USE OF β-D-GLUCAN TO REDUCE THE ADVERSE EFFECT OF THE IMMUNE RESPONSE DEPRESSION INDUCED BY EXCESSIVE PHYSICAL EXERCISE

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