• In the clinic, all oral antiplatelet medicines have a risk of bleeding complications.• We present an antidote for ticagrelor that reverses its antiplatelet effect in human platelet-rich plasma and its bleeding effect in mice.Ticagrelor is a direct-acting reversibly binding P2Y 12 antagonist and is widely used as an antiplatelet therapy for the prevention of cardiovascular events in acute coronary syndrome patients. However, antiplatelet therapy can be associated with an increased risk of bleeding. Here, we present data on the identification and the in vitro and in vivo pharmacology of an antigen-binding fragment (Fab) antidote for ticagrelor. The Fab has a 20 pM affinity for ticagrelor, which is 100 times stronger than ticagrelor's affinity for its target, P2Y 12 . Despite ticagrelor's structural similarities to adenosine, the Fab is highly specific and does not bind to adenosine, adenosine triphosphate, adenosine 59-diphosphate, or structurally related drugs. The antidote concentration-dependently neutralized the free fraction of ticagrelor and reversed its antiplatelet activity both in vitro in human platelet-rich plasma and in vivo in mice. Lastly, the antidote proved effective in normalizing ticagrelor-dependent bleeding in a mouse model of acute surgery. This specific antidote for ticagrelor may prove valuable as an agent for patients who require emergency procedures. (Blood. 2015;125(22):3484-3490)

We examined the effects of physical training in 10 predialytic uremic patients (7 men, 3 women, mean age 47 ± 8 years) with an average glomerular filtration (GFR) of 15 ± 7 ml/min × 1,73 m². All 10 patients participated in an exercise programme 3 times/week for 3 months and were compared to a control group of 9 patients with comparable baseline variables. The exercise group increased its maximal exercise capacity measured by standardized exercise test on a bicycle ergometer, from an average 159 ± 49 to 174 ± 57 W (p < 0.01). They also showed a decrease in heart rate at equal load (138 ± 29–123 ± 18 beats/min, p < 0.05). The control group did not change its exercise capacity (171 ± 60 and 171 ± 65 W, respectively, NS), nor its heart rate at equal load (124 ± 24 and 123 ± 24 beats/min, respectively, NS). Thigh muscular function assessed by static endurance increased from a median 77 s (range 27–197) to 113 s (range 66–201), p < 0.002. Dynamic muscular endurance increased from a median number of 41 movements (range 28–105) to 93 movements (range 45–139), p < 0.001. The corresponding figures for the controls were: static endurance 60 (range 20–209) and 47 s (range 9–203), respectively, NS; dynamic endurance 53 (range 19–190) and 43 movements (range 10–126), respectively, NS. Total hemoglobin, blood volume, GFR, blood pressure and echocardiographic variables remained unchanged during the observation period. We conclude that in predialytic uremic patients, physical training improves exercise capacity mainly due to an improved muscular function.

We examined 58 patients (38 men, 20 women; mean age: 45 ± 12 years; body mass index: 24 ± 4 kg/m²) with a glomerular filtration rate (GFR) ranging from 3 to 32 ml/min, in order to determine the effects of a progressive decline in renal function on total hemoglobin (THb) and exercise capacity. The THb ranged from 185 to 759 g and the hemoglobin concentration ranged from 66 to 151 g/l. Maximal exercise capacity ranged from 50 to 260 W (40-143% of the expected norm). Nearly all the patients interrupted their exercise tests due to general fatigue, leg tiredness or a combination of these factors. There was a sigificant partial correlation between THb and GFR after sex and age had been accounted for (r = 0.39; p < 0.005). Maximal exercise capacity and THb showed a significant partial correlation after sex, age and GFR had been accounted for (r = 0.27; p < 0.05). Maximal exercise capacity showed a significant partial correlation with GFR after sex, age and THb had been accounted for (r = 0.30; p < 0.05). In conclusion, there is a gradual decline in THb and maximal exercise capacity as uremia progresses. Anemia appears to be a contributory cause responsible for the decrease in maximal exercise capacity along with other factors pertinent to uremia per se.

Abstract. Pehrsson SK, Linnersjö A, Hammar N