The impact of acute and chronic administration of short-acting β2-agonists on urinary pharmacokinetics and athletic performance

Exercise Induced Bronchoconstriction (EIB) is common amongst elite athletes. Short-acting β2-agonists represent the first-line treatment of EIB, however; limited data currently exists examining the ergogenic and pharmacokinetic impact of chronic short-acting β2-agonist administration. Furthermore, the ergogenic impact of acute and chronic administration of short-acting β2-agonists in asthmatic individuals is unknown. Whilst the short-acting β2-agonist salbutamol is permitted in and out of competition due to a known pharmacokinetic response, no urinary threshold has been established for the use of the alternative short-acting β2-agonist terbutaline. The purpose of study 1 was to investigate the ergogenic potential of the WADA upper daily limit of 1600 μg·day-1 salbutamol every day for 6 weeks versus placebo, alongside combined resistance and endurance training. Findings highlighted improvements in; 1 repetition maximum (1RM) bench press (Baseline: 65.6 ± 5.4 kg vs. 64.3 ± 4.9 kg – 6 weeks: 70.3 ± 4.9 vs. 72.5 ± 5.4 kg) and leg press (Baseline: 250 ± 26.9 vs. 217.9 ± 19 kg – 6 weeks: 282.5 ± 22.5 vs. 282.8 ± 18.3 kg); vertical jump test (Baseline: 53.5 ± 4.1 vs. 50.4 ± 2.1 cm – 6 weeks: 55 ± 3.5 vs. 52.4 ± 1.7 cm); 3 km running time-trial performance (Baseline: 988.7 ± 68.7 vs. 1040.5 ± 66.3 s – 6 weeks: 947.5 ± 54.9 vs. 1004.3 ± 70.5 s); isokinetic dynamometry (Baseline: 196.1 ± 47.3 vs. 184.6 ± 35.0 n.m. – 6 weeks: 179.5 ± 48.9 vs. 195.2 ± 28.9 n.m.); and body composition (Baseline: 32.1 ± 13.9 vs. 34.9 ± 10.4 mm – 6 weeks: 32.4 ± 14.5 vs. 34.5 ± 10 mm) for both the salbutamol group and the placebo group, respectively, over the 6 week period, with no difference observed between groups, indicating long-term therapeutic use of salbutamol at the WADA upper daily limit has no ergogenic effect. Of note, one participant exceeded the urinary threshold, presenting with an adverse analytical finding (AAF) showing that the upper daily limit can lead to AAF’s in susceptible individuals. Athletes who respond poorly to salbutamol treatment are able to apply for the use of the short-acting β2-agonist terbutaline via a therapeutic use exemption (TUE) certificate. Urinary upper limits are unknown for terbutaline and as such it is prohibited at all times without the presentation of a TUE. The purpose of study 2 was to investigate the urinary excretion of terbutaline following single and repeated use of inhaled or oral terbutaline. The aim of the study was to establish a differential distinction between routes of administration which could assist the WADA with regard to anti-doping policy and procedure. Results demonstrated a significant difference in urine concentration of terbutaline between inhaled and oral administration for female Caucasian (670.1 ± 128.3 vs. 361.8 ± 43.8 ng·ml-1; P=0.019; 680.8 ± 91 vs. 369.9 ± 41.9 ng·ml-1; P=0.006), male Afro-Caribbean (343.18 ± 45 vs. 231.3 ± 32.95 ng·ml-1; P=0.044; 389.73 ± 67.4 vs. 212.4 ± 50.3 ng·ml-1; P=0.008) and male Asian (266.4 ± 23.7 vs. 143.3 ± 22 ng·ml-1; P=0.004; 379.5 ± 50.4 vs. 197.5 ± 38.6 ng·ml-1; P=0.000) groups for single (5 mg oral vs. 2 mg inhaled) and repeated (4 x 5 mg oral vs. 8 x 1 mg inhaled) administration trials, respectively. No difference was observed in male Caucasians. High intra- and inter-individual variability between samples meant that a clear distinction between routes of administration could not be established. The study was able to identify an upper urinary threshold following inhaled administration of 1284.3 ng·ml-1 and an upper urinary threshold following oral use of 2376.3 ng·ml-1 which may inform the process of distinguishing between inhaled and oral use. Athletes are permitted to use inhaled terbutaline therapeutically through the TUE process. The purpose of study 3 was to investigate the ergogenic effect of terbutaline at high (2 mg and 4 mg) therapeutic inhaled doses on 3 km running time-trial performance in males and females. The study found that inhaled terbutaline, when used at the highest therapeutic dose, has no impact upon 3 km time-trial performance in males (956.3 s vs. 982 s) and females (1249 s vs. 1214.7 s) for placebo vs. 4 mg inhaled terbutaline, respectively. The majority of studies investigating the ergogenic potential of salbutamol have been in healthy individuals. It is not yet understood whether the exercise response differs in asthmatic individuals. The purpose of study 4 was to investigate the use of inhaled salbutamol (400 μg) during a 3 km running time-trial in eucapnic voluntary hyperpnoea positive (EVH+ve) and negative (EVH-ve) individuals, in a low humidity environment. Results demonstrated increased FEV1 in both groups following salbutamol inhalation, which did not translate to improved performance. No performance differences were found between salbutamol and placebo (Sal: 1012.7 ± 50 vs. 962.1 ± 37.5 s – Pla: 1002.4 ± 46.5 vs. 962 ± 28.8 s) in the EVH+ve group vs. the EVH-ve group, respectively. This thesis is the first to investigate the effects of long-term use of salbutamol at the WADA upper daily limit on exercise performance. It is also the first study to establish upper urinary thresholds for terbutaline use, and the effects of therapeutic inhaled terbutaline on exercise performance. The effect of salbutamol on exercise performance at low humidity in asthmatic individuals has also never previously been investigated. Overall, the findings from this thesis support previous research that inhaled β2-agonist use does not provide any ergogenic potential. With β2-agonists being an essential therapy for the treatment of EIB their current position on the WADA List of Prohibited Substances and Methods is appropriate. Further research is warranted to fully elucidate the upper urinary threshold for terbutaline to inform WADA and support the re-introduction of terbutaline as a therapeutic tool in the treatment of EIB in athletes

The Effect of 400 µg Inhaled Salbutamol on 3 km Time Trial Performance in a Low Humidity Environment.

The Objectives of the study were to investigate whether 400 µg inhaled salbutamol influences 3 km running time-trial performance and lung function in eucapnic voluntary hyperpnoea positive (EVH+ve) and negative (EVH-ve) individuals. Fourteen male participants (22.4 ± 1.6yrs; 76.4 ± 8.7kg; 1.80 ± 0.07 m); (7 EVH+ve; 7 EVH-ve) were recruited following written informed consent. All participants undertook an EVH challenge to identify either EVH+ve (↓FEV1>10%) or EVH-ve (↓FEV110% from baseline) in FEV1 following any time-trial. Administration of 400µg inhaled salbutamol does not improve 3 km time-trial performance in either mild EVH+ve or EVH-ve individuals despite significantly increased HR and FEV1

The influence of environmental and core temperature on cyclooxygenase and PGE2 in healthy humans.

Whether cyclooxygenase (COX)/prostaglandin E2 (PGE2) thermoregulatory pathways, observed in rodents, present in humans? Participants (n = 9) were exposed to three environments; cold (20 °C), thermoneutral (30 °C) and hot (40 °C) for 120 min. Core (Tc)/skin temperature and thermal perception were recorded every 15 min, with COX/PGE2 concentrations determined at baseline, 60 and 120 min. Linear mixed models identified differences between and within subjects/conditions. Random coefficient models determined relationships between Tc and COX/PGE2. Tc [mean (range)] increased in hot [+ 0.8 (0.4-1.2) °C; p < 0.0001; effect size (ES): 2.9], decreased in cold [- 0.5 (- 0.8 to - 0.2) °C; p < 0.0001; ES 2.6] and was unchanged in thermoneutral [+ 0.1 (- 0.2 to 0.4) °C; p = 0.3502]. A relationship between COX2/PGE2 in cold (p = 0.0012) and cold/thermoneutral [collapsed, condition and time (p = 0.0243)] was seen, with higher PGE2 associated with higher Tc. A within condition relationship between Tc/PGE2 was observed in thermoneutral (p = 0.0202) and cold/thermoneutral [collapsed, condition and time (p = 0.0079)] but not cold (p = 0.0631). The data suggests a thermogenic response of the COX/PGE2 pathway insufficient to defend Tc in cold. Further human in vivo research which manipulates COX/PGE2 bioavailability and participant acclimation/acclimatization are warranted to elucidate the influence of COX/PGE2 on Tc

Eucapnic Voluntary Hyperpnea Testing in Asymptomatic Athletes.

Letter to the Edito

The Effect of 400 µg Inhaled Salbutamol on 3 km Time Trial Performance in a Low Humidity Environment

The Objectives of the study were to investigate whether 400 µg inhaled salbutamol influences 3 km running time-trial performance and lung function in eucapnic voluntary hyperpnoea positive (EVH+ve) and negative (EVH-ve) individuals. Fourteen male participants (22.4 ± 1.6yrs; 76.4 ± 8.7kg; 1.80 ± 0.07 m); (7 EVH+ve; 7 EVH-ve) were recruited following written informed consent. All participants undertook an EVH challenge to identify either EVH+ve (?FEV1>10%) or EVH-ve (?FEV110% from baseline) in FEV1 following any time-trial. Administration of 400µg inhaled salbutamol does not improve 3 km time-trial performance in either mild EVH+ve or EVH–ve individuals despite significantly increased HR and FEV1

The influence of environmental and core temperature on cyclooxygenase and PGE2 in healthy humans

Whether cyclooxygenase (COX)/prostaglandin E2 (PGE2) thermoregulatory pathways, observed in rodents, present in humans? Participants (n = 9) were exposed to three environments; cold (20 °C), thermoneutral (30 °C) and hot (40 °C) for 120 min. Core (Tc)/skin temperature and thermal perception were recorded every 15 min, with COX/PGE2 concentrations determined at baseline, 60 and 120 min. Linear mixed models identified differences between and within subjects/conditions. Random coefficient models determined relationships between Tc and COX/PGE2. Tc [mean (range)] increased in hot [+ 0.8 (0.4–1.2) °C; p < 0.0001; effect size (ES): 2.9], decreased in cold [− 0.5 (− 0.8 to − 0.2) °C; p < 0.0001; ES 2.6] and was unchanged in thermoneutral [+ 0.1 (− 0.2 to 0.4) °C; p = 0.3502]. A relationship between COX2/PGE2 in cold (p = 0.0012) and cold/thermoneutral [collapsed, condition and time (p = 0.0243)] was seen, with higher PGE2 associated with higher Tc. A within condition relationship between Tc/PGE2 was observed in thermoneutral (p = 0.0202) and cold/thermoneutral [collapsed, condition and time (p = 0.0079)] but not cold (p = 0.0631). The data suggests a thermogenic response of the COX/PGE2 pathway insufficient to defend Tc in cold. Further human in vivo research which manipulates COX/PGE2 bioavailability and participant acclimation/acclimatization are warranted to elucidate the influence of COX/PGE2 on Tc

Eucapnic Voluntary Hyperpnea: Gold Standard for Diagnosing Exercise-Induced Bronchoconstriction in Athletes?

In athletes, a secure diagnos is of exercise-induced bronchoconstriction (EIB) is dependent on objective testing. Evaluating spirometric indices of airflow before and following an exercise bout is intuitively the optimal means for the diagnosis; however, this approach is recognized as having several key limitations. Accordingly, alternative indirect bronchoprovocation tests have been recommended as surrogate means for obtaining a diagnosis of EIB. Of these tests, it is often argued that the eucapnic voluntary hyperpnea (EVH) challenge represents the ‘gold standard’. This article provides a state-of-the-art review of EVH, including an overview of the test methodology and its interpretation. We also address the performance of EVH against the other functional and clinical approaches commonly adopted for the diagnosis of EIB. The published evidence supports a key role for EVH in the diagnostic algorithm for EIB testing in athletes. However, its wide sensitivity and specificity and poor repeatability preclude EVH from being termed a ‘gold standard’ test for EIB

Prevalence of bronchoconstriction induced by eucapnic voluntary hyperpnoea in recreationally active individuals.

OBJECTIVE Exercise-induced bronchoconstriction (EIB) is more prevalent in elite athletes than in the general population. Many of these athletes provide a positive eucapnic voluntary hyperpnoea (EVH) challenge without previous diagnosis of EIB. It is unknown whether this is specific to elite athletes or whether the same risk applies to recreationally active individuals. The purpose of this study was to investigate the prevalence of a positive EVH challenge in a population of recreationally active individuals. METHODS 136 recreationally active individuals (Age: 21.9?±?3.7 years; Height: 175?±?9?cm; Weight: 70.9?±?10.0?kg) without previous history of asthma or EIB, volunteered to take part in the study. All participants completed an EVH challenge, which was deemed positive if FEV1 fell ?10% from baseline at two consecutive time points, and was reversible following inhalation of a short acting ?2-agonist. RESULTS 18 of 136 (13.2%) participants had a positive EVH challenge. Of the 18 individuals, the fall in FEV1 from baseline ranged from -12% to -50%. At baseline, percentage predicted FEV1 (97.5?±?12.5% versus 104.9?±?10%; p?<?0.01), FEV1/FVC ratio (79.5?±?6.9% versus 87.8?±?5.5%; p?<?0.01), FEF25-75 (3.73?±?1.00 versus 4.73?±?1.00?l/s; p?<?0.01) and predicted PEF (89.4?±?8.8% versus 97.5?±?13.6%; p?<?0.05) values for EVH positive participants were significantly lower than EVH negative participants respectively. CONCLUSIONS Overall, 13.2% of recreationally active individuals with no previous history of asthma presented with a positive EVH challenge. Individuals who are recreationally active may benefit from an objective bronchial provocation challenge, given that self-reported symptoms alone only provide a supportive role towards a valid EIB diagnosis

The Effect of 400 µg Inhaled Salbutamol on 3 km Time Trial Performance in a Low Humidity Environment

The Objectives of the study were to investigate whether 400 µg inhaled salbutamol influences 3 km running time-trial performance and lung function in eucapnic voluntary hyperpnoea positive (EVH+ve) and negative (EVH-ve) individuals. Fourteen male participants (22.4 ± 1.6yrs; 76.4 ± 8.7kg; 1.80 ± 0.07 m); (7 EVH+ve; 7 EVH-ve) were recruited following written informed consent. All participants undertook an EVH challenge to identify either EVH+ve (↓FEV1>10%) or EVH-ve (↓FEV110% from baseline) in FEV1 following any time-trial. Administration of 400µg inhaled salbutamol does not improve 3 km time-trial performance in either mild EVH+ve or EVH–ve individuals despite significantly increased HR and FEV1