To assess the effects of concurrent strength (S) and endurance (E) training on S and E development, one group (4 young men and 4 young women) trained one leg for S and the other leg for S and E (S+E). A second group (4 men, 4 women) trained one leg for E and the other leg for E and S (E+S). E training consisted of five 3-min bouts on a cycle ergometer at a power output corresponding to that requiring 90-100% of oxygen uptake during maximal exercise (VO2 max). S training consisted of six sets of 15-20 repetitions with the heaviest possible weight on a leg press (combined hip and knee extension) weight machine. Training was done 3 days/wk for 22 wk. Needle biopsy samples from vastus lateralis were taken before and after training and were examined for histochemical, biochemical, and ultrastructural adaptations. The nominal S and E training programs were "hybrids", having more similarities as training stimuli than differences; thus S made increases (P less than 0.05) similar to those of S+E in E-related measures of VO2max (S, S+E: 8%, 8%), repetitions with the pretraining maximal single leg press lift [1 repetition maximum (RM)] (27%, 24%), and percent of slow-twitch fibers (15%, 8%); and S made significant, although smaller, increases in repetitions with 80% 1 RM (81%, 152%) and citrate synthase (CS) activity (22%, 51%). Similarly, E increased knee extensor area [computed tomography (CT) scans] as much as E+S (14%, 21%) and made significant, although smaller, increases in leg press 1 RM (20%, 34%) and thigh girth (3.4%, 4.8%). When a presumably stronger stimulus for an adaptation was added to a weaker one, some additive effects occurred (i.e., increases in 1 RM and thigh girth that were greater in E+S than E; increases in CS activity and repetitions with 80% 1 RM that were greater in S+E than S). When a weaker, although effective, stimulus was added to a stronger one, addition generally did not occur. Concurrent S and E training did not interfere with S or E development in comparison to S or E training alone.
Biosimilars are designed to be highly similar to approved or licensed (reference) biologics and are evaluated based on the totality of evidence from extensive analytical, nonclinical and clinical studies. As part of the stepwise approach recommended by regulatory agencies, the first step in the clinical evaluation of biosimilarity is to conduct a pharmacokinetics similarity study in which the potential biosimilar is compared with the reference product. In the context of biosimilar development, a pharmacokinetics similarity study is not necessarily designed for a comparative assessment of safety. Development of PF-05280014, a potential biosimilar to trastuzumab, illustrates how a numerical imbalance in an adverse event in a small pharmacokinetics study can raise questions on safety that may require additional clinical trials.
618 Background: Trastuzumab, a humanized recombinant monoclonal antibody, targets HER2 and is approved for treatment of HER2-overexpressing breast and gastric cancers. PF-05280014 is being developed as a potential biosimilar to trastuzumab. Similarity of PF-05280014 to trastuzumab sourced from the EU and US (trastuzumab-EU and -US) was assessed using structural and functional, nonclinical pharmacokinetic (PK) and tolerability, and clinical studies; the toxicity of PF-05280014 was also assessed. Methods: Structural similarity was determined by peptide mapping. Functional similarity was measured using an in vitro tumor cell growth inhibition assay. Comparative PK, tolerability, and anti-drug antibody (ADA) responses were evaluated in male CD-1 mice following a single dose; PK and toxicity of PF-05280014 alone were evaluated in CD-1 mice (both sexes) after 5 doses. In a phase I study, 105 healthy male volunteers received a single 6 mg/kg IV dose of PF-05280014, trastuzumab-EU, or trastuzumab-US. Drug concentration-time data were analysed by noncompartmental methods. PK similarity was considered demonstrated for a given test-to-reference comparison if the 90% CI was within 80.00%-125.00%. Results: Peptide mapping showed PF-05280014 was similar to trastuzumab-EU and trastuzumab-US. Dose response curves in the in vitro cell growth inhibition assay were superimposable. In vivo PK profiles were similar in mice and there were no toxicity findings for PF-05280014. In the phase I study, PK similarity was shown between PF-05280014 and trastuzumab-EU and trastuzumab-US, with 90% CI of Cmax, AUCT, and AUC0-∞ within 80.00%–125.00% for each pair-wise comparison. Adverse events were similar across groups; only 1 subject (trastuzumab-EU group) was ADA positive postdose. Conclusions: Evaluation of PF-05280014 thus far supports its development as a potential biosimilar to trastuzumab. An ongoing, phase III, randomized, double-blind clinical trial is comparing PF-05280014 + paclitaxel with trastuzumab-EU + paclitaxel for first-line treatment of patients with HER2+ metastatic breast cancer. A second phase III, randomized, double-blind trial evaluating PF-05280014 in the neoadjuvant setting for breast cancer is ongoing. Clinical trial information: NCT01603264, NCT02187744, and NCT01989676.
The purpose of this study was to examine the effects of ginseng extract ingestion on physiological responses to intense exercise. Subjects performed a control ride (CN) on a cycle ergometer, followed by placebo (PL) and ginseng (GS) treatments. Ginseng was ingested as 8 or 16 mg/kg body weight daily for 7 days prior to trial GS. Venous blood was sampled for FFA, lactate, and glucose analyses. Due to similar findings for both dose groups, the subjects were considered as one group. Lactate, FFA, , , and RPE increased significantly from 10 through 40 min. RER increased during the first 10 min of exercise and then remained stable, with no intertrial differences. Glucose did not vary significantly from 0 to 40 min or among treatments. RPE was significantly greater and time to exhaustion was significantly less during trial CN than PL or GS, while PL and GS trials were similar. The data indicated that with 1 week of pretreatment there is no ergogenic effect of ingesting the ginseng saponin extract.
The first biosimilar of bevacizumab was approved by the US FDA; other potential biosimilars of bevacizumab are in late-stage clinical development. Their availability offers opportunity for increased patient access across a number of oncologic indications. The regulatory pathway for biosimilar approval relies on the totality of evidence that includes a comprehensive analytical assessment, and a clinical comparability study in a relevant disease patient population. Extrapolation of indications for a biosimilar to other eligible indications held by the originator, in the absence of direct clinical comparison, frequently forms part of the regulatory judgment. Herein, we consider the evidence required to demonstrate biosimilarity for bevacizumab biosimilars, with particular focus on the rationale for extrapolation across oncologic indications.
This study was designed to examine the interrelationships among endurance running performance (marathon), the exercise intensity at which the "onset of blood lactate accumulation" (OBLA) occurs training volume, and muscle fiber characteristics. In conjunction with Stockholm's Marathon (1979), 18 male subjects underwent a test to determine the relationship between treadmill running velocity and blood lactate accumulation. The velocity at which a blood lactate accumulation of 4 mmol x l-1 occurred was referred to as the VOBLA. The m. vastus lateralis was biopsied and muscle fiber type distribution (% slow twitch, ST) and capillary density determined. With marathon running velocity (VM) as the dependent variable, multiple regression analysis showed that VOBLA accounted for 92% of the variation in VM, and VOBLA plus training volume prior to the marathon accounted for 96% of this variation. All performance variables were positively correlated to % ST muscle fiber distribution (r = 0.55-0.69) and capillary density (r = 052-0.63). Thus, marathon running performance was closely related to VOBLA and to the ability to run at a pace close to that velocity during the race. These properties were in turn related to % ST, capillary density, and training volume.
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