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New Findings: What is the central question of this study? What are the interactions between sleep and appetite following early evening high-intensity interval exercise (HIIE)? What is the main finding and its importance? HIIE can be performed in the early evening without subsequent sleep disruptions and may favourably alter appetite-related hormone concentrations. Nonetheless, perceived appetite and energy intake do not change with acute HIIE regardless of time of day., Abstract: Despite exercise benefits for sleep and appetite, due to increased time restraints, many adults remain inactive. Methods to improve exercise compliance include preferential time-of-day or engaging in short-duration, high-intensity interval exercise (HIIE). Hence, this study aimed to compare effects of HIIE time-of-day on sleep and appetite. Eleven inactive men undertook sleep monitoring to determine baseline (BASE) sleep stages and exclude sleep disorders. On separate days, participants completed 30 min HIIE (60 s work at 100% V ̇ O 2 peak , 240 s rest at 50% V ̇ O 2 peak ) in (1) the morning (MORN; 06.00-07.00 h), (2) the afternoon (AFT; 14.00-16.00 h) and (3) the early evening (EVEN: 19.00-20.00 h). Measures included appetite-related hormones (acylated ghrelin, leptin, peptide tyrosine tyrosine) and glucose pre-exercise, 30 min post-exercise and the next morning; overnight polysomnography (PSG; sleep stages); and actigraphy, self-reported sleep and food diaries for 48 h post-exercise. There were no between-trial differences for total sleep time (P = 0.46). Greater stage N3 sleep was recorded for MORN (23 ± 7%) compared to BASE (18 ± 7%; P = 0.02); however, no between-trial differences existed (P > 0.05). Rapid eye movement (REM) sleep was lower and non-REM sleep was higher for EVEN compared to BASE (P ≤ 0.05). At 30 min post-exercise, ghrelin was higher for AFT compared to MORN and EVEN (P = 0.01), while glucose was higher for MORN compared to AFT and EVEN (P ≤ 0.02). No between-trial differences were observed for perceived appetite (P ≥ 0.21) or energy intake (P = 0.57). Early evening HIIE can be performed without subsequent sleep disruptions and reduces acylated ghrelin. However, perceived appetite and energy intake appear to be unaffected by HIIE time of day., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

Background: Glutamine has been shown in numerous studies to reduce intestinal permeability which can be increased by chemotherapy. However, there have been few reports that conduct on its clinical effect on gastrointestinal toxicity., Aim: To examine whether prophylactic intravenous alanyl-glutamine dipeptide can ameliorate clinical manifestations of gastrointestinal toxicity induced by chemotherapy., Methods: Forty-four patients with gastric or colorectal cancer developing WHO side-effect grading system of grade 2 or higher were randomized to either control group (n = 22) or Gln group (n = 22) during next cycle of chemotherapy. Patients were crossed over to the alternate treatment during chemotherapy cycle 2. In the control group, the patients received the same chemotherapy regimens as screening cycle and in the Gln group, the patients received chemotherapy and alanyl-glutamine. Prophylactic intravenous 20 g of alanyl-glutamine dipeptide was given for 5 days., Results: Compared with the control group, the plasma glutamine level in the Gln group was significantly higher and the plasma endotoxin level was significantly lower. The scores of nausea/vomiting and diarrhoea decreased significantly., Conclusion: Prophylactic intravenous alanyl-glutamine is effective in preventing intestinal permeability disruption induced by chemotherapy and clinical manifestations of gastrointestinal toxicity.

Objective: To investigate a possible mechanism that could lead to the subsequent development of cardiovascular diseases (CVD) in women with a history of severe pre-eclampsia., Design: Case-control study., Setting: University Medical Centre Nijmegen, The Netherlands., Sample: Non-pregnant women with a history of severe pre-eclampsia (n= 131) and women with an uncomplicated obstetric history (n= 94)., Methods: Total plasma levels of cysteine (tCys), homocysteine (tHcy), cysteinylglycine (tCysGly) and glutathione (tGSH), the free-to-oxidised ratio of these thiols in whole blood, the glucose-6-phosphate dehydrogenase (G6PDH) enzyme activity and antioxidant capacity were assessed at least 6 months following last pregnancy., Main Outcome Measure: Oxidative stress and antioxidant status., Results: Women with a history of severe pre-eclampsia showed higher levels (mean [SD]) of tHcy (13.1 [5.0] versus 11.5 [4.8] micromol/L; P= 0.018) and tCysGly (37.5 [5.6] versus 34.0 [5.8] micromol/L; P= 0.0001) compared with controls, whereas tCys was lower (232 [31] versus 242 [39]; P= 0.029). The lower free-to-oxidised ratio of homocysteine (2.3 [0.8] versus 2.9 [1.0], P= 0.0001) among women with a history of severe pre-eclampsia as compared with control subjects might indicate a higher oxidant status for homocysteine. Previous severe pre-eclamptic patients had also a higher antioxidant capacity as compared with controls (0.79 [0.14] versus 0.74 [0.11] mmol Fe2+/L, P= 0.002)., Conclusion: Since women with a history of severe pre-eclampsia showed elevated total homocysteine levels, which is an independent risk factor for CVD, and higher oxidised homocysteine levels in whole blood, these women may have an enhanced risk for the subsequent development of cardiovascular-related problems in later life.

1. In the present study, the depressor action of the dipeptide Val-Tyr, with an in vivo antihypertensive effect, was investigated in transgenic mice carrying the human renin gene cross-mated with mice bearing the human angiotensinogen gene (Tsukuba Hypertensive Mouse; THM). 2. Single oral administration of Val-Tyr (0.1 mg/g) to 11-week-old THM resulted in a prolonged reduction of blood pressure for up to 9 h. The effect clearly demonstrated that the Val-Tyr absorbed acted on the enhanced human renin-angiotensin system (RAS). 3. After Val-Tyr administration, an approximate eightfold higher increment of plasma Val-Tyr was observed at 1 h (3406 +/- 211 fmol/mL plasma) compared with the level observed at 0 h; plasma concentrations of Val-Tyr returned to baseline levels at 6 h. 4. Transient changes in plasma concentrations of angiotensin (Ang) I and AngII only at 1 h were consistent with plasma Val-Tyr concentrations, suggesting that that the long-lasting reduction in blood pressure was achieved by the latent hypotensive mechanism of Val-Tyr and not by transient suppression of the circulatory RAS. 5. Ageing of the THM greatly affected the depressor action of Val-Tyr, with no significant reduction in blood pressure observed in 18- and 24-week-old THM.

1. Intact absorption of the bioactive dipeptide Val-Tyr (VY), with in vivo antihypertensive ability in normotensive human subjects, was investigated. 2. As a result of a single oral administration of VY, the VY absorption curve occurred maximally over the second hour postprandially; a greater than 10-fold higher increment of VY following a dose of 12 mg was observed in the plasma at 2 h compared with the baseline concentration of VY at 0 h (1934 +/- 145 vs 159 +/- 11 fmol/mL plasma, respectively). 3. Plasma VY levels increased with dose administered (3, 6 and 12 mg), suggesting that exogenous VY could be absorbed intact into the human blood depending on the dose. The elimination half time (t1/2) of VY was estimated to be 3.1 h. The area under the curve for the 12 mg VY dose was 9185 +/- 688 fmol small middle doth/mL plasma.

Serum MK-422 and plasma angiotensin converting enzyme activity were measured during the introduction of enalapril therapy in eight patients with heart failure. In a second study of 16 patients, we recorded exercise tolerance, clinical status and haemodynamics before and after 12 weeks of placebo or enalapril treatment. Increasing doses of enalapril gave step-wise increments in serum MK-422. Plasma converting enzyme activity remained low for at least 24 h after each dose of enalapril (5, 10 and 20 mg). Compared to placebo patients (n = 8), those receiving enalapril (n = 8) tended to improve their exercise performance and clinical status, and showed a fall in right heart pressures after 12 weeks of treatment.

Enalapril maleate is a prodrug which when administered orally is hydrolysed to release the active converting enzyme inhibitor enalaprilat. Enalapril maleate is 60% absorbed and 40% bioavailable as enalaprilat. Both compounds undergo renal excretion without further metabolism. The functional half-life for accumulation of enalaprilat is 11 h, and this is increased in the presence of a reduction in renal function. Inhibition of converting enzyme inhibition is associated with reductions in plasma angiotensin II and plasma aldosterone, and with increases in plasma renin activity and plasma angiotensin I. Acute and chronic effects have been reviewed. When given with hydrochlorothiazide, enalapril attenuates the secondary aldosteronism and ameliorates the hypokalaemia from diuretics. Both acutely and chronically in patients with essential hypertension, enalapril reduced blood pressure with a rather flat dose-response curve. No evidence of a triphasic response such as seen with captopril has been demonstrated with enalapril, and blood pressure returns smoothly to pretreatment levels when the drug is abruptly discontinued. Once- or twice-daily dosing gives similar results. The antihypertensive effects of enalapril are potentiated by hydrochlorothiazide. Haemodynamically, blood pressure reduction is associated with a reduced peripheral vascular resistance and an increase in cardiac output and stroke volume with little change in heart rate. Renal vascular resistance decreases, and renal blood flow may increase without an increase in glomerular filtration in patients with normal renal function. In patients with essential hypertension and glomerular filtration rates below 80 ml/min/m2, both renal blood flow and glomerular filtration rates may increase.

1 Two single doses of 10 mg each of the converting enzyme inhibitor enalapril maleate or MK-421 and of its lysine analogue (MK-521) were administered p.o. to twelve male volunteers. 2 The active diacid metabolite of MK-421 and the lysine analogue were determined by radioimmunoassay and MK-421 by the active metabolite method following in vitro hydrolysis. 3 Peak serum levels of MK-421, active metabolite and lysine analogue were reached within 1, 3 to 4, and 6 h respectively. Practically all MK-421 had disappeared from serum within 4 h. 4 A close correlation between percent inhibition of plasma converting enzyme activity and the serum concentration of active metabolite was observed ( r = 0.98, n = 171, P less than 0.001). Similarly, converting enzyme blockade as expressed by the ratio plasma angiotensin II/angiotensin I was closely correlated with serum active metabolite levels (r = 0.93, n = 15, P less than 0.001).

The acute and chronic effects of enalapril (MK421) were assessed in a double-blind randomized trial in subjects with essential hypertension. In acute studies, twelve subjects received enalapril (10 mg p.o.), following which there was a fall in blood pressure, maximal at 6 h and lasting for 24 h. Serum MK422 (enalaprilic acid, the bioactive form of enalapril) and serum angiotensin converting enzyme (ACE) inhibition had a similar time course with good correlation between drug levels and ACE inhibition (P less than 0.001, r = 0.98, n = 16) and between ACE inhibition and the hypotensive effect (P less than 0.001, r = 0.84, n = 16). In chronic studies enalapril was titrated from 5 mg to 20 mg twice a day in eleven hypertensive patients to achieve a diastolic blood pressure less than 90 mmHg. Treatment continued for 3-12 months. Increasing serum MK422 was correlated with reducing serum ACE activity (P less than 0.001, r = 0.8, n = 104). The fall in blood pressure correlated both with serum MK422 level (P less than 0.05, r = 0.37, n = 39) as well as ACE inhibition (P less than 0.01, r = 0.45, n = 42). The drug level:ACE inhibition curve was shifted to the right during chronic enalapril treatment. ID50 for serum ACE was 32 ng MK422/ml following the single 10 mg dose of MK421 and 70 ng MK422/ml during chronic treatment. Blood pressure falls during acute and chronic treatment were similar over the range of serum MK422 levels achieved. The shift in the drug level:ACE inhibition curve suggests induction of ACE during chronic treatment with enalapril in man.