YOUR PARTNER in SPORTS NUTRITION the STRONG BRAND for SPORTS NUTRITION Inside BODY ATTACK

BODY ATTACK - YOUR PARTNER IN SPORTS NUTRITION THE STRONG BRAND FOR SPORTS NUTRITION Inside BODY ATTACK

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1996 2007 2009 2013 Launch: Online-Shop Product portfolio Launch of Premium Store Move into new diversiﬁcation model & franchise model headquarters/warehouse

1994 2005 2008 2010 2017 Establishment of Start of B2B distribution Ofﬁcial nutrition partner Worldwide Market leader with 38 Body Attack into gyms, stores, pharmacies of HSV (football premier league) distribution network Premium Stores in Germany

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For professional strength athletes, Muscle building, performance improvement, For recreational athletes, persons interested Peak ATP: Studies / Clinical tests Beta TOR: Studies / Clinical tests bodybuilders and athletes deﬁnition, competition diet in ﬁtness and team sport athletes Perfectly aligned formulas Supplements and boosters with the High-quality products with an highest possible dosage optimum composition

1404 J. C. Fuller et al. Rathmacher et al. Journal of the International Society of Sports Nutrition 2012, 9:48 Highly active ingredient dosage http://www.jissn.com/content/9/1/48 in offspring of sows fed HMB for the final 2 weeks of preg- HPLC analysis, and were given with 355 ml of water. Although nancy; increased bone density and plasma amino acid con- the pH of the free acid itself is <3, this is similar to the pH of the centrations in pigs with fundectomy-induced osteopaenia(23); stomach. For the treatments used in this study, the free acid and improved somatotrophic axis and accelerated bone meta- was given either in capsule form, a buffered gel form or as a SHORT REPORT Open Access bolism in lambs fed HMB for the first 21 d after birth(24). The dilute solution in water. In contrast, the Ca-HMB is neutral to β-Hydroxy-β-methylbutyric acid clearance 1405 !" # $!% # & &''((() * )' ' improvement in somatotrophic axis function was further slightly alkaline when in solution. None of the participants During intensive training stages Supplements for perfect sports- demonstrated in rats when chronic HMB administration was reported any oesophagealStatistical or gastrointestinal analysis and irritations calculations with any Table 1. Subject descriptors (25) (Mean values with their standard errors) shown to stimulate the GH/IGF-1 axis . Recently, HMB sup- of the treatment formsThe of AUC HMB. was For calculated the capsule for each treatments, subject using the trapezoidal Adenosine-5'-triphosphate (ATP) supplementation plementation was shown to enhance the exercise-stimulated samples of the capsules were sent to an independent laboratory (29) method that sums the area above the baseline . The following Mean SEM % * + , &+& !-"# increase in GH and IGF-1 response in humans, similar to what and tested for dissolution times (Eurofins). Because of the Highest raw material quality equations were used in the calculation of the half-life of improves low peak muscle torque and torque the previous studies in animals had demonstrated(26). nature of the various treatments, the study could not be fully Sex (n) * + ++"+ .+-"/0 +1 plasma HMB: Male/female 5/5 The pharmacokinetics of orally ingested Ca-HMB in blinded. Age (years) 25·11·0 related support ln C ln C (14) peak À trough ; Journal of Strength and Conditioning Research Publish Ahead of Print capsules were originally described by Vukovich et al. Kel (1) Body weight (kg) fatigue during repeated high intensity exercise ¼ T -Hydroxy- -methylbutyric acid clearance 1407 2+ 3. 4 51 * " DOI: 10.1519/JSC.0000000000002198 and showed a time to peak plasma level of HMB of 2 h after ÀÁinterval ÀÁ All 69·13·1 β β (15) Female 64·33·0 a 1 g dosage. Recently, Fuller et al. demonstrated that Study design 0 693 6 ( 7& *& 8 t Á : (2) Male 73·84·9 sets 1=2 (a) HMB-FA gel form increased plasma HMB concentrations 2 that similar amounts of HMB given as either Ca-HMB or ¼ Kel BMI (kg/m ) 300 Best possible nutrient supply All studies were conducted after a 10- to 12-h overnight fast. in a shorter period of time (30–40 min) with a greater All 23·00·8 HMB-FA resulted in the Ca-HMB having greater peak blood 1,2* 2 2 3 4 4 Subjects arrived at the laboratory in the morning, and an John A Rathmacher , John C Fuller Jr , Shawn M Baier , Naji N Abumrad , Hector F Angus and Rick L Sharp The peak plasma concentration was the highest HMB Female 21·90·8 250 HMB concentrations. There are several concerns with com- blood clearance rate of HMB compared with the Ca-HMB HMB-FA capsule Ca-HMB capsule A SINGLE DOSE OF ORAL ATP SUPPLEMENTATION IMPROVES (27) intravenous catheterconcentration was inserted into at a a measured forearm time vein point using for each subject and Male 24·21·3 2 "& "91 )7 "912 (:) &2175 capsule. A recent 12-week exercise study by Wilson et al. Mean SEM Mean SEM P parison with the rodent study; the most notable is the concern sterile procedures. A preingestion blood sample, of approxi- 200 Original Article ")/(521;0 ) *+2152)" 21 42)< + "9 used these favourable advantages to test the efficacy of was used for Cpeak. Trough concentrations, Ctrough, were the Half-life (h) 2.15 0.07 3.02 0.24 0.0003 related to species differences. For example, the half-life of HMB mately 7 ml, was drawn. The treatment was then consumed fi Clearance PERFORMANCE AND PHYSIOLOGICAL RESPONSE DURING LOWER concentrations measured at 12 h, which were not signi cantly 74.8 4.0 54.5 3.2 0.0001 in blood after Ca-HMB dosing is reported as approximately 1, 2 Abstract BODY HMB-FA administered 30 min before exercise in a periodised 150 (ml/min) =7 >"9128 (33–35) over approximately adifferent 2 min period, from baselineand additional concentrations. blood sam- The Tpeak was the time training programme and showed increased strength, lean body AUC and 3 h for the rat, pig and sheep, respectively , compared https://doi.org/10.12965/jer.1836256.128 Journal of Exercise Rehabilitation 2018;14(4):671-679 53.8 2.7 48.8 3.7 0.16 Background: Intracellular concentrations of adenosine-5’-triphosphate (ATP) are many times greater than ples (7 ml) were takenat at which 2, 5, 10,C 15, 25,was 35, measured 45, 60, 90, for 120, each 180, subject and T was 100 (µmol/l × 1440 min) RESISTANCE EXERCISE IN RECREATIONAL RESISTANCE TRAINED MALES mass gain and muscle power in a highly trained athlete peak interval by treatment interactions for any of the pharmacokinetic para- with humans, with a half-life of 2·4 to 3·2 h for a 1 g dosage of extracellular concentrations (1–10 mM versus 10–100 nM, respectively) and cellular release of ATP is tightly (27) 360 (6 h), 720 (12 h) and 1440 (24 h) min after the ingestion of fl Plasma HMB ( µ mol/l) 24h urine HMB (14,15) population , demonstrating the importance of dosage timing 12 h (time at Ctrough) minus Tpeak. The extracellular uid meters measured, even though all subjects were administered 21.0 3.0 20.3 3.2 0.65 Ca-HMB . Other concerns relate to the experimental - + the supplement; 24 h urine collection was also obtained. Plasma 50 (% initial dose) controlled. Transient rises in extracellular ATP and its metabolite adenosine have important signaling roles; and and peak levels of HMB for maximisation of exercise compartment was assumed to be 20 % of body weight. Vd was the same HMB dose. design, and the analytical methods used, as well as methodo- !" #$ " % &'( and urine samples were stored at −80°C until later analyses(30) of acting through purinergic receptors, can increase blood flow and oxygenation of tissues; and act as benefits. The current human study was thus designed to calculated using equation (3) below . The plasma clearance 0 logical differences related to the accuracy of HMB intake. For )*+,-./01 ! " 23 " *4 /! " 5 "" "6 "4 HMB. Serum and blood samples at times 0 and 1440 min were fl 0 6 12 18 24 neurotransmitters. Increased blood flow not only increases substrate availability but may also aid in recovery Short title: ATP supplementation and performance in compare the pharmacokinetics of the current commercially of HMB was calculated by multiplying the extracellular uid example, in the rodent study, there is no mention of the Oral adenosine 5ƍ-triphosphate supplementation improved resistance trained males. analysed by a commercial laboratory (LabCorp.) for glucose, Time (h) through removal of metabolic waste products allowing muscles to accomplish more work with less fatigue. The " " 76 # ! & 8 ( ! ) available delivery form of Ca-HMB in a capsule and compared compartment, Vd, by the elimination constant, Kel, as shown in Free acid form of β-hydroxy-β-methylbutyrate gel kinetics methodology for the administration of the oral forms in the (31) objective of the present study was to determine if supplemental ATP would improve muscle torque, power, work, & 9 (&: 150-,-,;,<,.=-2.+>+,-?-+>?@;@ uric acid, blood urea nitrogen,equation creatinine, (4) . Na, K, Cl, Ca, CO2, P, methods section of the paper; hence, the method and accuracy hemodynamic and autonomic parameters after exercise this with the newly designed delivery form of HMB-FA in a The HMB-FA gel treatment in the present study showed (b) 1 protein, albumin, globulin, total bilirubin, alkaline phosphatase, 1406 J. C. Fuller et al. 300 or fatigue during repeated bouts of high intensity resistance exercise. 2 1 3 gelcap. Our results confirmed the previous findings of Fuller Vd Body weight 0 20 ; (3) (15) of the amount given is in question. In addition, both forms of Marcelo C. Freitas, Jason M. Cholewa, fi ¼ ðÞÁ similar pharmacokinetics as we had previously shown . - ? + 0<+,-?-+>?@;@ Jose Gerosa-Neto, Daniela C. Gonçalves, Erico C. (15) estimated glomerular ltration rate (eGFR), creatine kinase, HMB were dissolved in solutions containing carboxy- Methods: Sixteen participants (8 male and 8 female; ages: 21–34 years) were enrolled in a double-blinded, et al. and showed that HMB-FA had superior bioavailability HMB-FA in a gel had no comparator in the current study. The 250 in hypertensive women 4 1 *5 lactate dehydrogenase, aspartate aminotransferase,Clearance V alanined Kel : (4) Caperuto, Fábio S. Lira, Fabrício E. Rossi in humans as assessed by blood levels, and improved ¼ ðÞ (a) HMB-FA water Ca-HMB water methylcellulose and Tween 80 with the pH adjusted to 4·5. This placebo-controlled study using a crossover design. The participants received either supplemental ATP (400 mg/d . Cpeak was 261·7(SEM 15·0) µmol/l at 35·5(SEM 4·0) min post- 300 aminotransferase, γ-glutamyl transpeptidase, Fe, TAG, HDL, 200 Mean SEM Mean SEM P clearance. The data for comparable treatments were analysed using a type of solution is likely to affect the bioavailability of the divided into 2 daily doses) or placebo for 15 d. After an overnight fast, participants underwent strength and fatigue LDL, VLDL and cholesterol; a complete blood count was also administration. The half-life of HMB delivered in the gel form was Half-life (h) 2.23 0.10 2.30 0.10 0.47 1,2 3 1 4 3 crossover design with the general linear models (GLM) proce- Ca-HMB by increasing its ionisation, dissociation and absorp- Marcelo Conrado de Freitas , Ana Laura Ricci-Vitor , Renan Valero Freire , Erico Chagas Caperuto , Luiz Carlos Marques Vanderlei , SEM · · SEM · µ × 250 150 Clearance testing, consisting of 3 sets of 50 maximal knee extensions performed on a Biodex® leg dynamometer. D performed. Subjects completed a(32) brief health questionnaire to 2.24 ( 0 10) h and the AUC was 54 1( 3 1) mol/l 1440 *** 72.0 3.2 70.7 4.4 0.69 5 6, dure in SAS . A priori power analysis (G*Power, version 3.1.7) *** (ml/min) tion, thus leading to overestimates of the true pharmacokinetic Fábio Santos Lira , Fabrício Eduardo Rossi * A+,-.4 *"/ # "! # "! 0-+ +,-. report any physical symptoms (such as nausea, headache and min. The clearance from plasma was 71·7(SEM 3·6) ml/min, and *** *** Results: No differences were detected in high peak torque, power, or total work with ATP supplementation; Methods was completed based on our previously published pharmaco- 200 100 AUC 52.3 3.4 54.6 3.3 0.65 parameters measured. Last, but not least, there is concern "#4 %8 "A · SEM · *** (µmol/l × 1440 min) 1 1 so on) they may have experienced(15) during the experiment. 24 6( 4 4) % of the dosage was excreted in urine over the

however, low peak torque in set 2 was significantly improved Skeletal Muscle (p Assessment < 0.01).Additionally, Laboratory (LABSIM), inset São 3,Paulo a trendState University was detected (UNESP), School of Technology and Sciences, Department of Physical Education, Presidente Plasma HMB ( µ mol/l) 24h Urine HMB related to the accuracy of the measured plasma HMB levels. Exercise and Immunometabolism Research Group, Depar tment of Physical Education, São kinetic study . Assuming a similar degree of variability, a 20.0 3.3 21.6 3.0 0.77 Human subjects After the 180 min blood sampling, each subject was provided 24 h study. * 50 (% initial dose) for less torque fatigue with ATP supplementation (pPrudente, < 0.10). Brazil !" power analysis indicated that ten subjects were required to 150 The authors used warfarin, which is structurally different from 2Department of Nutrition, São Paulo Western University-UNOESTE, Presidente Prudente, Brazil Paulo State University (UNESP), Presidente Prudente E with a standardised lunch (1673·6–2092 kJ (400–500 kcal)), #$ " &'( , SP, Brazil. We performed a randomised crossover study consisting of detect a P value of 0·05 at a power of 0·90 in a crossover 0 the natural HMB form, as an internal standard for the LC-MS/MS Conclusions: Supplementation with 400 mg ATP/d3 for 15 days tended to reduce muscle fatigue and improved a Wilson et al. Nutrition & Metabolism 2013, 10:57 # "B "02@ Department of Physiotherapy, São Paulo State University (UNESP), Presidente Prudente, Brazil ﬁ ﬁ which was consumed at approximately 240 min postingestion; 100 HMB-FA capsule Ca-HMB capsule 0 6 12 18 24 measurements, in contrast to our use of a similar HMB

– Plasma HMB ( µ mol/l) ’ 4 http://www.nutritionandmetabolism.com/content/10/1/57 ve men and ve women (aged 21 32 years). The study was designed study. A repeated-measures polynomial model was participant s ability to maintain a higher force outputUniversity at the São end Judas of anTadeu, exhaustive São Paulo, Brazil exercise bout. the subjects returned to the laboratory for the 720 min blood Acute β-hydroxy-β-methylbutyrate kinetics for capsule and Mean SEM Mean SEM P Time (h) (36) 5 conducted according to the guidelines laid down in the used for the timed sampling of plasma HMB, and the model C (µmol/l) 270.2 17.8 153.9 17.9 0.006 compound, namely d6-HMB, as an internal standard . Exercise and Immunometabolism Research Group, Department of Physical Education, São Paulo State University (UNESP), Presidente Prudente, Brazil 2 water administration 50 *** peak Keywords: ATP, Adenosine-5’-triphosphate, Muscle strength, Muscle fatigue sample. Each subject was then instructed to eat a normal eve- T (min) 44.5 5.5 133.5 29.2 0.009 6 Department of Kinesiology, Recreation, and Sport S tudies, Coastal Carolina University, Declaration of Helsinki, and all procedures involving human– included subject, treatment order, treatment main effects and peak Fig. 2. (a) The 24 h plasma levels of β-hydroxy-β-methylbutyrate (HMB) after To reconcile any potential1408 differences attributed to the J. C. Fuller et al. Immunometabolism of Skeletal Muscle and Exercise Research Group, Department of Physical Education, Federal University of Piauí (UFPI), Teresina, Brazil T British Journal of Nutrition (2015), 114, 1403 1409 doi:10.1017/S0007114515003050 AUC (µmol/l × 180 min) 28.3 1.4 16.2 1.8 0.001 ning meal before 22.00 hours. Subjects were also instructed to C ! " C 9""D! subjects were© The approved Authors2015 by the Iowa State University time by treatment interaction where appropriate. For other The 3 h plasma HMB pharmacokinetics for subjects adminis- 0 administration of either free acid form of HMB (HMB-FA) gelcaps (-●-) or Ca delivery forms, we carried out a head-to-head comparison of an refrain from any strenuous physical activity or exercise during 0123 salt of HMB (Ca-HMB) capsule (- -○-). (b) The 24 h plasma levels of HMB after Conway, SC, USA. Institutional Review Board. Written informed consent was parameters, Proc GLM was used with subject, treatment order tered the HMB-FA and Ca-HMB capsule treatments are shown oral dose of HMB-FA andAcknowledgements Ca-HMB given mixed in water instead 11. Wilkinson DJ, Hossain T, Hill DS, et al. (2013) Effects of Background pain perception [4]. Additionally, ATP is often referred RESEARCH Open Access each testing period, and diet and activity patterns were to be Time (h) administration of either HMB-FA mixed in water (-●-) or Ca-HMB mixed in water fi obtained from all subjects before participation. The study was and treatment main effects included in the model, and the in Fig. 1(a). Compared with Ca-HMB capsules, HMB-FA (- -○-). All treatments contained 0·8 g of HMB. See Fig. 1 for significant of in capsule form. The data from the current study con rm our leucine and its metabolite beta-hydroxy-beta-methylbutyrate The intracellular role of ATP as the energy source for to as a cotransmitter that affects local tissue changes in replicated for each treatment testing period. Subjects reported (15) The present study was funded by Metabolic Technologies, Inc., The aim of this study was to verify the autonomic modulation and blood ence during recovery, with higher RMSSD for ATP compared to placebo listed on ClinicalTrials.gov (NCT01914952, https://clinicaltrials. P values are reported for the treatment main effect. Although administration in capsules resulted in significantly greater(b) differences in plasma HMB concentrations in the initial 3 h. Values are means previous findings and demonstrate that even when delivered on human skeletal muscle protein metabolism. J Physiol 591, tissues has long been recognized [1]. However, the extra- neurotransmission and neuromodulation by acting upon P back to the laboratory the following morning for the fasted 300 pressure after adenosine-5’-triphosphate (ATP) supplementation asso- (rest= 16.4± 8.5 vs. placebo= 11.6± 4.0; ATP= 18.5± 9.7 msec; P= 0.020). gov). The subjects were not currently taking amino acid, protein the study was neither designed nor powered to detect sex plasma levels at all time points from 15 to 120 min after with their standard error of means for five men and five women. The inset table mixed in water HMB-FA isAmes, still superior IA. to Ca-HMB in delivering 2911–2923. cellular metabolic functions of ATP have only recently both peripheral and central nervous systems [5,6]. Comparison of availability and plasma1440 min blood clearance sample. Urine rates collection of containers were pro- shows the half-life, clearance, 24 h AUC and 24 h urinary excretion of HMB. The authors’ contributions were as follows: J. A. R. designed 12. Wilson JM, Kim JS, Lee SR, et al. (2009) Acute and timing ciated to acute aerobic exercise in hypertensive women. Eleven hyper- When analyzing the delta (recovery minus rest), the RMSSD (ATP= 2.1± 3 or HMB supplements. differences, sex by treatment interaction was determined by administration (P < 0·001 at 15, 25, 35, 45, 60 and 90 min and * HMB, albeit to lesser degree than when both forms are deliv- Effects of oral adenosine-5′-triphosphate vided, and subjects collected all urine produced during the 24 h 250 *** The P value indicated is for differences between the treatment means. effects of beta-hydroxy-beta-methylbutyrate (HMB) on indir- been investigated, and primary to this function is thetensive womenWhereas (age, 61.8± intracellular 5.0 years) completed concentrations a randomized, of ATP double are rela-7.2 msec vs. placebo= -4.7± 7.5 msec; P= 0.009), LF (ATP= -19.8± 122.7 Biosciences Department, universidade Federal de São Paulo, UNIFESP, Santos, SP, Brazil. GLM. In addition, the main effects of Ca-HMB and HMB-FA P < 0·05 at 120 min). The 180 min AUC was 75 % greater ** ered in capsules. This wasthe quite research. evident J. within A. R.,the H. F.first A., hour P. Y. of K. and R. L. S. conducted β-hydroxy-β-methylbutyrate deliveryexperimental in the period. free The urine acid was and stored calcium refrigerated when ect markers of skeletal muscle damage. Nutr Metab (Lond) role of ATP in signal transduction through purinergicblind trial:tively ATP supplement high (1-10 conditionmM), (ATP= extracellular 400 mg) or placebo. concentrations After 30 arevs. placebo= -94.1± 200.2 msec2; P= 0.02), and SDNN (ATP= -2.8± 12.2 when given in water and by capsule were determined using (P < 0·001) for the HMB-FA in capsule form. In addition, the absorptive period (Fig.the 1(b)). research In including addition, sample we noted analysis. no J. C. F. Jr analysed the receptors found in most cell types [2]. Extracellular tightly regulated at very low levels (10-100 nM) [7,8]. supplementation on athletic performance, E Treatments salt forms possible. 200 data and wrote the paper. J. A. R. had primary responsibility for 6, 6. min of supplementation or placebo intake, the subjects performed 30 msec vs. placebo= -10.6± 10.5 msec; P= 0.010) were higher for ATP than GLM and least square means, and these data are shown in administration of HMB-FA in capsule form resulted in 76 % for the gel form, which was equivalent to the levels, 262 and difference in 24 h urinary excretion of HMB (Fig. 2(b)), 13. Wilson JM, Lowery RP, Joy JM, et al. (2013) ) β-Hydroxy- final content. All authors read and approved the final manuscript. functions of ATP include vasodilation [3] and reducedmin of aerobicWhen exercise ATP is (70%–75% infused intoof maximum the arterial heart rate). blood The flow auto- of mus-placebo. Furthermore, there was a greater postexercise hypotension at The treatments were given to each subject in random order with online Supplementary Table S3. Statistical significance was greater peak levels (P < 0·006) in one-third the time (P < 0·009). 270 µmol/l for the gel and gelcap, respectively, in the current suggesting an earlier and greater tissue availability of HMB β-methylbutyrate free acid reduces markers of exercise- 4 150 J. C. F. Jr and J. A. R. are employed by Metabolic Technolo- nomic modulationcle, the half-life was assessed has beenby heart shown rate variability to be <1 during second rest [9] as20 min for ATP (SBP:skeletal ATP= -13.2± 8.4 mmHg muscle vs. placebo= -6.1± 9.9hypertrophy mmHg; and recovery in University São Judas Tadeu. São Paulo, SP, Brazil. at least a 48 h washout period between treatments. The treat- determined for P < 0·05. The dissolution time of the capsules could not account for these * study. Similarly, the times to peak HMB level previously deter- when given in the free acid form. induced muscle damage and improves recovery in ATP is rapidly degraded to adenosine by several surface- 1 2 Plasma and2 urine β-hydroxy-2 β-methylbutyrate analysis 1,3 results; it was 13 min for the HMB-FA capsules and 5 min for the mined for Ca-HMB administration were 120(14), 122(15) and 135 Our study has few limitations,gies Inc., albeit Ames, minor IA. in nature.R. L. S. The receivedfirst funds from Metabolic resistance-trained men. Br J Nutr 110, 538–544. and recovery (postexercise until 30 min of recovery), the square root of P= 0.006). Acute ATP supplementation promoted greater postexercise ments were asJohn follows: C. Fuller (1) Ca-HMB Jr , Rick in a commercialL. Sharp , gelatin Hector F. Angus , Paul Y. Khoo and John A. Rathmacher * 100 HMB-FA water Ca-HMB water * Correspondence: [email protected] (15) Ca-HMB capsules, thus favouring the release of Ca-HMB fromPlasma HMB ( µ mol/l) min , which are comparable to the 134 min in the current study. limitation relates to the fewTechnologies number of tosubjects conduct studied the study. (n 10); H. F. A. and P. Y. K. had no 14. Vukovich MD, Slater G, Macchi MB, et al. (2001) ) β-Hydroxy- 1 the meanexpressed squared difference and soluble between enzymesadjacent RR ofintervals the (RMSSD), ectonucleoside hypotension forresistance-trained systolic blood pressure and induced faster recovery of men C capsule (Optimum1 Nutrition); (2) HMB-FA capsule (gelcap) The plasma and urine HMB were analysed as previously Mean SEM Mean SEM P Department of Animal Science, Iowa State University, Ames, IA 50010, USA Metabolic Technologies Inc., Iowa State University Research Park, Ames, IA 50010, USA fl !" (15) (28) conflicts of interest to declare. β-methylbutyrate (HMB) kinetics and the in uence of glucose 2 families [10]. ATP in blood is primarily carried by erythro- 2 Results fl the capsules. C (µmol/l) 274.4 24.6 247.4 15.2 0.11 When HMB-FA was administered in a gel, the times to peak levels this limitation, however, is countered by the use of the subjects Metabolic Technologies Inc, Iowa State University Research Park, Ames, IAstandard deviation of successive values (SDNN), low frequency (LF) heart rate variability in hypertensive women. (Capsugel); (3)Department HMB-FA as of aKinesiology, gel as previously Iowa described State University,; Ames,described IA 50010, using GC/MS USA . Brie y, HMB in the free acid form is 50 peak – 1* 1 1 2 3 % . . . . . (15) (15) ingestion in humans. J Nutr Biochem 12, 631 639. ! !" # $ fi Tpeak (min) 36 0 2 8 42 5 4 1 0 23 50010, USA and highcytes frequency [8]. (HF) Therefore, were measured. measurement The blood pressure of circulating (systolic free Jacob M Wilson , Jordan M Joy , Ryan P Lowery , Michael D Roberts , Christopher M Lockwood , (4) Ca-HMB mixed3 in water or (5) HMB-FA mixed in water. quanti ed from standards using d6-HMB as an internal standard. Fig. 1(b) shows the 3 h plasma HMB pharmacokinetics were 33 and 42 min , and in the current study the times to as their own control in a crossover design. Another theoretical Department of Animal Science, Iowa State University, Ames, IA 50010,Subject USA characteristics . . . . . 15. Fuller JC Jr, Sharp RL, Angus HF, et al. (2011) Free acid gel Full list of author information is available at the end of the article 4 5 6 5 7 5 Immunometabolism% % of Skeletal Muscle and Exercise( Re search (Group, Department of fi for the administration of HMB-FA and Ca-HMB when mixed in AUC (µmol/l × 60 min) 10 9 0 9 9 1 0 9 0 03 peak level for HMB-FA as a gel and gelcap were 36 and 45 min, limitation may relate to our calculation of the amount of HMB blood pressure [SBP] and diastolic blood pressure, mmHg) were re- Anssi H Manninen , John C Fuller Jr. , Eduardo O De Souza , Shawn M Baier , Stephanie MC Wilson & " ! ' ) * "+ " , All treatments delivered 0·8 g of HMB orally, con rmed by This method has a CV of approximately 4·1 %. 0 Supplementary material form of β-hydroxy-β-methylbutyrate (HMB) improves HMB # * fi fi 0123 © 2012 Rathmacher et al.; licensee BioMedcorded Central at rest, Ltd. Thisimmediately is an Open postexercise, Access article distributed post-10, underpost-20, the termsand post-30 of the Keywords: Aerobic exercise, ATP supplementation,5,8 Nutrition, Autonom- $%& ' & ()' (' + & ,'-!&.%" ' (Submitted 22 February 2015 – Final revision received 14 July 2015 – Accepted 17 July 2015Subject– First characteristics published online of 16 the Septemberve male 2015) and ve female subjects water. Administration of HMB-FA in water resulted in greater respectively. Urinary losses were similar across all studies and available for tissue utilisation, as the difference between the clearance from plasma in humans compared to the calcium and John A Rathmacher /") !'0',$% 1' ' 'C 2((-'*#/3(&% '" 1'4 Time (h) Creative Commons Attribution Licensemin (http://creativecommons.org/licenses/by/2.0), after exercise. For RMSSD, there was which statistically permits unrestricted significant use, differ- ic nervous system, Hypertension Physical Education, Federal University of Piauí (UFPI), Teresina, PI, Brazil. are shown Table 1. The average age of the subjects was plasma HMB levels at 15, 25, 35 and 45 min (P < 0·05, 0·001, dosage forms, and including our present study were between 14 amount consumed minus theFor amount supplementary excreted material/s in the urine. referred This to in this article, please HMB salt. Br J Nutr 105, 367–372. distribution, and reproduction in any medium, provided the original work is properly cited. (14,15) fi 25·1(SEM 1·0) years and the average weight and BMI were 0·004, and P < 0·05, respectively).Fig. 1. (a) The The inset 3 h plasma shows levels that of HMB-FAβ-hydroxy-β-methylbutyrate (HMB) after administration of either free acid form of HMB (HMB-FA) gelcaps (-●-) or Caand salt 25 of % HMB of the dosage . The ndings have several practical assumption would be accuratevisit http://dx.doi.org/doi:10.1017/S0007114515003050 with additional measurement of 16. Dreyer HC, Fujita S, Cadenas JG, et al. (2006) Resistance 8 4"%9 ! "&"" ! " #& ! 69·1(SEM 3·1) kg and 23·0(SEM 0·8) kg, respectively. The male administered in water had a(Ca-HMB) significantly capsule greater (- -○-). AUC (b) The during 3 h plasma the levels of HMB after administration of either HMB-FA mixed in water (-●-) or Ca-HMB mixed in water (- -○-).implications All treatments for the average athlete. Although both forms of HMB HMB oxidation rates, which were not examined in this study. exercise increases AMPK activity and reduces 4E-BP1 phos- Abstract Abstract 0<< !& < H populations. 9 -. +,-.0-=0>> (gelcap). The current study was conducted to compare the bioavailability of HMB using the two commercially available capsule forms of HMB-FA and 1. Nissen S, Sharp R, Ray M, et al. (1996) Effect of the leucine protein synthesis and breakdown after resistance exercise ? $ 3 " @ $ " exercise, thus achieving better outcomes, as was recently con- dose, suggestive of enhanced utilisation of HMB by human demonstrated that hypertensive subjects have several dysfunctions *Corresponding ! " Author Ca-HMB. We also compared the pharmacokinetics of each form when administered mixed in water. Ten human subjects (five male and five female) metabolite β-hydroxy β-methylbutyrate on muscle metabo- in humans. Am J Physiol 273, E99–E107. Therefore, we investigated the effects of 12 weeks of 400 mg per day of oral ATP on muscular adaptations in .((# #+$ 3" firmed by Wilson et al.(27). muscle following intake of HMB-FA. High blood pressure has been associated with cardiovascular on the autonomic nervous system (ANS) and vascular tissue # # $ were studied in a randomised crossover design. There was no significant sex by treatment interaction for any of the pharmacokinetic parameters lism during resistance-exercise training. J Appl Physiol 81, 18. Kerksick C, Harvey T, Stout J, et al. (2008) International trained individuals. We also sought to determine the effects of ATP on muscle protein breakdown, cortisol, and Society of Sports Nutrition Position Stand: nutrient timing. J Int Fabrício E. Rossi. *2( / $ 3 measured. HMB-FA administered in capsules was more efficient than Ca-HMB capsule at HMB delivery with a 37 % increase in plasma clearance rate HMB-FA in water, whereas the Tpeak level was not different Blood chemistry and haematology Our human data differ considerably from the recently pub- In conclusion, the use of the2095 commercially–2104. available forms of risk and mortality (Heidenreich et al., 2011; Mozaffarian et al., (Grassi and Ram,performance 2016; Kario during et al., an1997), overreaching generating cycle.the in- # # (33) Soc Sports Nutr 5, 17. +"."9" + : (74·8(SEM 4·0) v. 54·5(SEM 3·2) ml/min, P < 0·0001) and a 76 % increase in peak plasma HMB concentration (270·2(SEM 17·8) v. 153·9(SEM 17·9) mol/l, between the HMB-FA and Ca-HMB treatments. lished data in rodents , which reported that Ca-HMB had HMB as either the HMB-FA2. or Panton Ca-HMB LB, resulted Rathmacher in earlier JA, Baier and S, et al. (2000) Nutritional $ ## # μ There were no untoward effects of the treatments on blood 19. American College of Sports Medicine, American Dietetic 2015), and this disease is considered a major public health prob- crease of blood Methods:pressure. OnThe the studyother washand, a regular 3-phase exercise randomized, has double-blind, and placebo- and diet-controlled intervention. Phase Department of Physical # $ $ Education, Federal Universit y of Piauí (UFPI), “Ministro P < 0·006), which was reached in one-third the time (P < 0·009). When HMB-FA and Ca-HMB were administered in water, the differences still favoured better availability as measured by peak blood levels when increased plasma concentrations,supplementation with increased of the clearance leucine metabolite β-hydroxy # $ # $ chemistries or haematology and the data are presented in β-methylbutyrate (HMB)fi during resistance training. Nutr 16, Association & Dieticians of Canada (2000) Joint position lem, with worldwide prevalence rate around one billion and in- been effective in1 waspreventing a periodized this disease resistance-training and is strongly recom program.- Phase 2 consisted of a two week overreaching cycle in which # 3 )( HMB-FA, albeit to a lesser degree. Plasma HMB with HMB-FA administered in water was greater during the early phase of absorption (up to 45 min compared with HMB-FA. In that study, the investigators com- rates, when the HMB was given as HMB-FA. This nding can be 24 h β-hydroxy-β-methylbutyrate kinetics for capsule and online Supplementary Tables S1 and S2. 734–739. statement: nutrition and athletic performance. Med Sci Sports volume and frequency were increased followed by a 2-week taper (Phase 3). Muscle mass, strength, and power postadministration, P < 0·05); this resulted in increased AUC during the first 60 min after administration, when compared with Ca-HMB mixed in water pared Ca-HMB with HMB-FA administration both orally in a used favourably by athletes to gauge their intake of HMB before Exerc 32, 2130–2145. creasing direct healthcare costs (Kearney et al., 2005; Mills et al., mended for hypertension treatment (Besnier et al., 2017; Corne- Petrônio Portella” Campus, # " (")" 2 # 64049-550, Teresina-PI, Brazil. Telephone: (86)3215-5525, water administration (33) 3. Knitter AE, Panton L, Rathmacher(27) JA, et al. (2000) Effects of liquid suspension and by intravenous injection, and showed an exercise bout, as recently observed by Wilson et al. . were examined at weeks 0, 4, 8, and 12 to assess the chronic effects of ATP; assessment performance variables also (P < 0·03). In conclusion, HMB-FA in capsule form improves clearance rate and availability of HMB compared with Ca-HMB in capsule form. β-hydroxy-β-methylbutyrate on muscle damage following a 20. Coyle EF, Coggan AR, Hemmert MK, et al. (1985) Substrate " " Fig. 2(a) shows the 24 h plasma HMB levels in subjects given – usage during prolonged exercise following a preexercise occurred at the end of weeks 9 and 10, corresponding to the mid and endpoints of the overreaching cycle. Fax (86)3215-55264391. e-mail: [email protected] Discussion prolonged run. J Appl Physiol 89, 1340 1344. *Corresponding author: Fabrício Eduardo Rossi is is an Open Access article distributed under the terms of the Creative Commons At- %& ' $ # Key words: β-Hydroxy-β-methylbutyrate: Free acid form of hydroxy-β-methylbutyrate: Calcium salt of hydroxy-β-methylbutyrate: either Ca-HMB or HMB-FA in capsule form. As shown in the 4. Wilson GJ, Wilson JM & Manninen AH (2008) Effects meal. J Appl Physiol (1985) 59, 429–433. https://orcid.org/0000-0002-0594-2529 tribution Non-CommercialResults: LicenseThere (http://creativecommons.org/licenses/by-nc/4.0/) were time (p < 0.001), and group x time effects for increased total body strength (+55.3 ± 6.0 kg 21. Tatara MR (2009) Effect of beta-hydroxy-beta-methylbutyrate ( (()*+((" , "-./"( (+ Gelcaps: Capsules: Clearance inset, the HMB-FA capsule administration resulted in a 37 % In this study, we tested the human pharmacokinetics of the two of beta-hydroxy-beta-methylbutyrate (HMB) on exercise Department of Physical Education, Federal University of Piauí (UFPI), which permits unrestrictedATP vs.non-commercial + 22.4 ± 7.1use, distribution, kg placebo, and reproductionp < 0.001); in any increased vertical jump power (+ 796 ± 75 ATP vs. 614 ± 52 watts Copyright performance and body composition across varying levels of (HMB) administration on volumetric bone mineral density, medium, provided the original work is properly cited. ª 2017 5 %A # ( National Strength and ()+*+(((/ Conditioning Association increased clearance of HMB from plasma (P < 0·0001), resulting commercially available forms of HMB, used for the promotion “Ministro Petrônio Portella” Campus, 64049-550, Teresina-PI, Brazil *.(("-./"( ()+*+"((("-0/"( (.1 and morphometric and mechanical properties of tibia in male placebo, p < 0.001); and greater ultrasound determined muscle thickness (+4.9 ± 1.0 ATP vs. (2.5 ± 0.6 mm placebo, # $*B/ # $ in a 29 % decrease in half-life (P < 0·0003). The 24 h AUC for of muscular strength and mass. Our results demonstrate that, age, sex, and training experience: a review. Nutr Metab Tel: +86-3215-5525, Fax: +86-3215-55264391, E-mail: [email protected] p < 0.02) with ATP supplementation. During the overreaching cycle, there were group x time effects for strength *+"2(( " -0/ # The leucine metabolite β-hydroxy-β-methylbutyrate (HMB) has a it can persist for up to 48 h postexercise(17). These (Lond) 5, 1. turkeys. J Anim Physiol Anim Nutr (Berl) 93, 669–677. Received: May 13, 2018 / Accepted: July 14, 2018 :; *B)/ ;C ' HMB and for urinary excretion rates were the same for both irrespective of the capsule delivery form used, HMB-FA is more 22. Tatara MR, Krupski W, Tymczyna B, et al. (2012) Effects of and power, which decreased to a greater extent in the placebo group. Protein breakdown was also lower in the * 3 4" 56" & " &/7 *-0/ long history of use as a nutritional supplement for enhancing anabolic events are also accompanied by depletion of muscle 5. Wilson JM, Fitschen PJ, Campbell B, et al. (2013) International $ ## " forms. readily available and has a higher clearance rate than Ca-HMB combined maternal administration with alpha-ketoglutarate Copyright © 2018 Korean Society of Exercise Rehabilitation 671 http://www.e-jer.org pISSN 2288-176X # $ $ # recovery, and for increasing strength, power, aerobic performance energy stores in the form of glycogen, resulting in decreased Society of Sports Nutrition Position Stand: beta-hydroxy-beta- FUNCTIONAL ATP group. fi eISSN 2288-1778 # ( ()+*+"(((/ (1–5) Similarly, Fig. 2(b) shows the 24 h plasma HMB levels in (Fig. 2(a)), indicative of higher ef ciency and faster utilisation. methylbutyrate (HMB). J Int Soc Sports Nutr 10, 6. (AKG) and beta-hydroxy-beta-methylbutyrate (HMB) on pre- ACTIVE # $ and lean body mass with exercise . HMB improves muscle exercise intensity, and associated with increased muscle Conclusions: Our results suggest oral ATP supplementation may enhance muscular adaptations following 12-weeks – subjects given either Ca-HMB or HMB-FA mixed in water. We All human studies to date have consistently demonstrated the 6. Eley HL, Russell ST & Tisdale MJ (2008) Mechanism of natal programming of skeletal properties in the offspring. Nutr # $ > protein balance by decreasing muscle protein breakdown and by damage(18 20). The changes have been attributed to increased # 3 # noted significant differences in plasma HMB levels during the superiority of the HMB-FA form to reach a higher HMB plasma attenuation of muscle protein degradation induced by tumor Metab (Lond) 9, 39. of resistance training, and prevent decrements in performance following overreaching. No statistically or clinically %$ 3+"9" + $ # ## (6–11) increasing muscle protein synthesis , resulting in reduced skeletal muscle AMP-activated protein kinase activity and fi necrosis factor alpha and angiotensin II by beta-hydroxy- 23. Tatara MR, Sliwa E, Krupski W, et al. (2008) 3-Hydroxy-3- significant changes in blood chemistry or hematology were observed. (3,12,13) rst hour, with no further observed differences during the 24 h peak in a much shorter time than the Ca-HMB form, with similar # $ (" ) muscle damage and faster and improved recovery . These reduced phosphorylation of 4E-BP1 in the mTOR pathway, (14,15) beta-methylbutyrate. Am J Physiol Endocrinol Metab 295, methylbutyrate administration diminishes fundectomy- (16) measurement period. As seen in the inset, there were also no urinary excretion of HMB . When Ca-HMB was adminis- Trial registration: ClinicalTrials.gov NCT01508338 $ 3*$3( benefits with HMB to improve muscle performance with vigorous as occurs with resistance exercise . HMB supplementation (14) (15) E1417–E1426. induced osteopenia of the lumbar spine in pigs. Nutr 24, differences observed for plasma HMB half-life, clearance rates tered, peak plasma HMB levels were 115 , 131 and 7. Smith HJ, Wyke SM & Tisdale MJ (2004) Mechanism of the 753–760. !/" $# exercise have generally been achieved with the Ca salt of HMB has been shown to increase phosphorylation of 4E-BP1 in (15) Keywords: Adenosine triphosphate, Exercise performance, Power, Strength, Muscle hypertrophy, Sports nutrition or AUC over the 24 h measurement period. In addition, 24 h 131 µmol/l , which were comparable to the 154 µmol/l deter- 24. Tatara MR (2008) Neonatal programming of skeletal develop- (Ca-HMB) administered in capsule form. However, as shown in human muscle(11), prompting us to hypothesise that HMB as attenuation of proteolysis-inducing factor stimulated protein urinary excretion as a percentage of the initial dose was the mined in the current study. Previous studies with HMB-FA found degradation in muscle by beta-hydroxy-beta-methylbutyrate. ment in sheep is mediated by somatotrophic axis function. - previous studies, and confirmed by the findings of the current HMB-FA would offer a more convenient delivery form resulting same for both treatments. the peak plasma HMB levels to be 259(15) and 239 µmol/l(15) Cancer Res 64, 8731–8735. Exp Physiol 93, 763–772. # study, peak plasma levels of HMB are not reached until in an improved anabolic effect of HMB on muscle protein 8. Smith HJ, Mukerji P & Tisdale MJ (2005) Attenuation 25. Gerlinger-Romero F, Guimaraes-Ferreira L, Giannocco G, # $ approximately 120 min after ingestion of Ca-HMB, which makes it synthesis and diminishing protein breakdown. of proteasome-induced proteolysis in skeletal muscle by et al. (2011) Chronic supplementation of beta-hydroxy-beta inconvenient for scheduling exercise sessions to coincide with Other metabolic effects of HMB have been demonstrated β-hydroxy-β-methylbutyrate in cancer-induced muscle loss. methylbutyrate (HMβ) increases the activity of the GH/IGF-I & peak plasma HMB levels(14,15). In this study, we show that the time in animal models. Turkeys fed HMB during the last 15 weeks Cancer Res 65, 277–283. axis and induces hyperinsulinemia in rats. Growth Horm IGF For everyone who pays attention to a to peak HMB level decreased by two-thirds when HMB was of rearing had increased bone density and strength and 9. Eley HL, Russell ST, Baxter JH, et al. (2007) Signaling path- Res 21, 57–62. High-quality vitamin, mineral and DE " *((/ # ways initiated by β-hydroxy-β-methylbutyrate to attenuate the 26. Townsend JR, Hoffman JR, Gonzalez AM, et al. (2015) Effects * Correspondence: [email protected] 3 # $ # delivered as the free acid in capsule form (HMB-FA), thus making an increase in some plasma amino acids including the (21) (22) depression of protein synthesis in skeletal muscle in response of beta-hydroxy-beta-methylbutyrate free acid ingestion and 1Department of Health Sciences and Human Performance, The University of ; "1+*++/"+(.2+(00 it more convenient to time peak HMB level with exercise. branched-chain amino acids . Tatara et al. also demon- to cachectic stimuli. Am J Physiol Endocrinol Metab 293, resistance exercise on the acute endocrine response. Int J Tampa, Tampa FL, USA A " F " *(+/ 0G */ The anabolic stimulus of exercise results in an increase in strated increased growth and bone density, and increased E923–E931. Endocrinol 2015, article ID 856708. Full list of author information is available at the end of the article (16) $ 3 , , # muscle protein synthesis in as little as 1 h postexercise , and growth hormone (GH) and insulin-like growth factor-1 (IGF-1), 10. Eley HL, Russell ST & Tisdale MJ (2008) Attenuation of 27. Wilson JM, Lowery RP, Joy JM, et al. (2014) The effects of F # 6 depression of muscle protein synthesis induced by lipopoly- 12 weeks of beta-hydroxy-beta-methylbutyrate free acid © 2013 Wilson et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative 5 #5! "1*+/"+H healthy and balanced diet Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and saccharide, tumor necrosis factor and angiotensin II by supplementation on muscle mass, strength, and power in diet products reproduction in any medium, provided the original work is properly cited. Abbreviations: Ca-HMB, calcium salt of HMB; HMB, -hydroxy- -methylbutyrate; HMB-FA, free acid form of HMB. 8 # $$ % /2( β β β-hydroxy-β-methylbutyrate. Am J Physiol Endocrinol Metab resistance trained individuals: a randomized, double-blind, 1 ! 295, E1409–E1416. placebo-controlled study. Eur J Appl Physiol 114, 1217–1227. 3 3 *+9( /"/ * Corresponding author: Dr J. A. Rathmacher, fax +1 515 296 0908, email [email protected] $ # #56*:5/" /1(# $ " 6 "& "& " " # $ *:;/ $ $ !<= > 5 % Functional foods with the additional plus To ensure sufficient vitamin and mineral supply Optimised food balance To prevent deficiencies during diet phases Reduced sugar content or sporting activities PROMINENCE & QUALITY Proven Quality since 1994

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