Safety and Efficacy of ApTOLL in Patients With Ischemic Stroke Undergoing Endovascular Treatment: A Phase 1/2 Randomized Clinical Trial.

Importance: ApTOLL is a TLR4 antagonist with proven preclinical neuroprotective effect and a safe profile in healthy volunteers.

Objective: To assess the safety and efficacy of ApTOLL in combination with endovascular treatment (EVT) for patients with ischemic stroke.

Design, Setting, And Participants: This phase 1b/2a, double-blind, randomized, placebo-controlled study was conducted at 15 sites in Spain and France from 2020 to 2022.

APRIL: A double-blind, placebo-controlled, randomized, Phase Ib/IIa clinical study of ApTOLL for the treatment of acute ischemic stroke.

Unlabelled: In the reperfusion era, a new paradigm of treating patients with endovascular treatment (EVT) and neuroprotective drugs is emerging as a promising therapeutic option for patients with acute ischemic stroke (AIS). In this context, ApTOLL, a Toll-like receptor 4 (TLR4) antagonist with proven neuroprotective effect in preclinical models of stroke and a very good pharmacokinetic and safety profile in healthy volunteers, is a promising first-in-class aptamer with the potential to address this huge unmet need. This protocol establishes the clinical trial procedures to conduct a Phase Ib/IIa clinical study (APRIL) to assess ApTOLL tolerability, safety, pharmacokinetics, and biological effect in patients with AIS who are eligible for EVT.

Intravenous vortioxetine to accelerate onset of effect in major depressive disorder: a 7-day randomized, double-blind, placebo-controlled exploratory study.

This 7-day randomized, double-blind, placebo-controlled fixed-dose study (NCT03766867) explored the potential for accelerating the onset of antidepressant efficacy of single-dose intravenous (IV) vortioxetine at oral vortioxetine treatment initiation. Patients (ages 18-65 years) hospitalized per standard-of-care with major depressive disorder, who were currently treated with a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor for a major depressive episode [Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥ 30], received one dose of single-blind IV placebo (1-day placebo lead-in period) before being randomly switched to either single-dose IV vortioxetine 25 mg plus daily oral vortioxetine 10 mg (n = 39), or IV placebo plus daily oral placebo (n = 41). In the placebo lead-in period, patients improved slightly by 0.

Management of Depression in Adolescents in Japan.

In Japan, there are currently no approved antidepressant treatments for pediatric patients with depression. This study aimed to estimate the prevalence of depression among adolescents under medical care in Japan, the pharmacological treatments used, and the perceived unmet needs among the medical specialties treating depression in the pediatric population. The study was conducted in November 2014 as an internet survey among physicians in clinical practice.

Consistency checks to improve measurement with the Montgomery-Asberg Depression Rating Scale (MADRS).

International Society for CNS Clinical Trials and Methodology convened an expert Working Group that assembled consistency/inconsistency flags for the Montgomery-Asberg Depression Rating Scale (MADRS). Twenty-two flags were identified. Seven flags are believed to be strong flags that suggest that a thorough review of rating is warranted.

Renal lactate elimination is maintained during moderate exercise in humans.

Reduced hepatic lactate elimination initiates blood lactate accumulation during incremental exercise. In this study, we wished to determine whether renal lactate elimination contributes to the initiation of blood lactate accumulation. The renal arterial-to-venous (a-v) lactate difference was determined in nine men during sodium lactate infusion to enhance the evaluation (0.

The brain at work: a cerebral metabolic manifestation of central fatigue?

Central fatigue refers to circumstances in which strength appears to be limited by the ability of the central nervous system to recruit motoneurons. Central fatigue manifests when the effort to contract skeletal muscles is intense and, thus, is aggravated when exercise is performed under stress, whereas it becomes attenuated following training. Central fatigue has not been explained, but the cerebral metabolic response to intense exercise, as to other modalities of cerebral activation, is a reduction in its "metabolic ratio" (MR), i.

[The muscles work, but the brain gets tired].

Central fatigue is the term used to describe when muscle contractions become limited by the ability of the central nervous system to recruit motor neurones. Central fatigue becomes manifest when the effort is intense and is associated not only with reduced strength but also with an inability to maintain the contraction. The contractions thereby resemble those developed during partial neuromuscular blockade that mainly affect slow twitch muscle fibres.

High glycogen levels in the hippocampus of patients with epilepsy.

During intense cerebral activation approximately half of the glucose plus lactate taken up by the human brain is not oxidized and could replenish glycogen deposits, but the human brain glycogen concentration is unknown. In patients with temporal lobe epilepsy, undergoing curative surgery, brain biopsies were obtained from pathologic hippocampus (n=19) and from apparently 'normal' cortical grey and white matter. We determined the in vivo brain glycogen level and the activity of glycogen phosphorylase and synthase.

Cerebrospinal fluid IL-6, HSP72, and TNF-alpha in exercising humans.

During exercise the concentration of interleukin (IL)-6 and of heat shock protein (HSP) 72 increases in plasma, especially in fasting subjects. Both IL-6 and HSP72 are involved in a variety of metabolic and immunological processes, including some within the central nervous system and, accordingly, they are present not only in plasma but also in the cerebrospinal fluid (CSF). To evaluate whether, the two pools equilibrate we determined the levels of IL-6 and HSP72 in CSF, at a time when their plasma levels were increased due to exercise.

Fuelling cerebral activity in exercising man.

The metabolic response to brain activation in exercise might be expressed as the cerebral metabolic ratio (MR; uptake O2/glucose + 1/2 lactate). At rest, brain energy is provided by a balanced oxidation of glucose as MR is close to 6, but activation provokes a 'surplus' uptake of glucose relative to that of O2. Whereas MR remains stable during light exercise, it is reduced by 30% to 40% when exercise becomes demanding.

Kidneys extract BNP and NT-proBNP in healthy young men.

Renal metabolism of the cardiac marker NH2-terminal-pro-brain natriuretic peptide (NT-proBNP) has been suggested. Therefore, we determined the renal extraction ratios of NT-proBNP and its bioactive coproduct brain natriuretic peptide (BNP) at rest and during exercise. In addition, the cerebral ratios were evaluated.

Limitations to systemic and locomotor limb muscle oxygen delivery and uptake during maximal exercise in humans.

Reductions in systemic and locomotor limb muscle blood flow and O2 delivery limit aerobic capacity in humans. To examine whether O2 delivery limits both aerobic power and capacity, we first measured systemic haemodynamics, O2 transport and O2 uptake during incremental and constant (372 +/- 11 W; 85% of peak power; mean +/- S.E.

Cerebral ammonia uptake and accumulation during prolonged exercise in humans.

We evaluated whether peripheral ammonia production during prolonged exercise enhances the uptake and subsequent accumulation of ammonia within the brain. Two studies determined the cerebral uptake of ammonia (arterial and jugular venous blood sampling combined with Kety-Schmidt-determined cerebral blood flow; n = 5) and the ammonia concentration in the cerebrospinal fluid (CSF; n = 8) at rest and immediately following prolonged exercise either with or without glucose supplementation. There was a net balance of ammonia across the brain at rest and at 30 min of exercise, whereas 3 h of exercise elicited an uptake of 3.

Dynamic cerebral autoregulation during exhaustive exercise in humans.

We investigated whether dynamic cerebral autoregulation is affected by exhaustive exercise using transfer-function gain and phase shift between oscillations in mean arterial pressure (MAP) and middle cerebral artery (MCA) mean blood flow velocity (V(mean)). Seven subjects were instrumented with a brachial artery catheter for measurement of MAP and determination of arterial Pco(2) (Pa(CO(2))) while jugular venous oxygen saturation (Sv(O(2))) was determined to assess changes in whole brain blood flow. After a 10-min resting period, the subjects performed dynamic leg-cycle ergometry at 168 +/- 5 W (mean +/- SE) that was continued to exhaustion with a group average time of 26.

Cerebral metabolism during upper and lower body exercise.

When continuation of exercise calls for a "will," the cerebral metabolic ratio of O2 to (glucose + lactate) decreases, with the largest reduction (30-50%) at exhaustion. Because a larger effort is required to exercise with the arms than with the legs, we tested the hypothesis that the reduction in the cerebral metabolic ratio would become more pronounced during arm cranking than during leg exercise. The cerebral arterial-venous differences for blood-gas variables, glucose, and lactate were evaluated in two groups of eight subjects during exhaustive arm cranking and leg exercise.

Cerebral carbohydrate cost of physical exertion in humans.

Above a certain level of cerebral activation the brain increases its uptake of glucose more than that of O(2), i.e., the cerebral metabolic ratio of O(2)/(glucose + 12 lactate) decreases.

The CSF and arterial to internal jugular venous hormonal differences during exercise in humans.

Strenuous exercise increases the cerebral uptake of carbohydrate out of proportion to that of oxygen, but it is unknown whether such enhanced carbohydrate uptake is influenced by the marked endocrine response to exercise. During exhaustive exercise this study evaluated the a-v differences across the brain (a-v diff) of hormones that could influence its carbohydrate uptake (n= 9). In addition, neuroendocrine activity and a potential uptake of hormones via the cerebrospinal fluid (CSF) were assessed by lumbar puncture postexercise and at rest (n= 6).

Brain and central haemodynamics and oxygenation during maximal exercise in humans.

During maximal exercise in humans, fatigue is preceded by reductions in systemic and skeletal muscle blood flow, O(2) delivery and uptake. Here, we examined whether the uptake of O(2) and substrates by the human brain is compromised and whether the fall in stroke volume of the heart underlying the decline in systemic O(2) delivery is related to declining venous return. We measured brain and central haemodynamics and oxygenation in healthy males (n= 13 in 2 studies) performing intense cycling exercise (360 +/- 10 W; mean +/-s.

A reduced cerebral metabolic ratio in exercise reflects metabolism and not accumulation of lactate within the human brain.

During maximal exercise lactate taken up by the human brain contributes to reduce the cerebral metabolic ratio, O(2)/(glucose + 1/2 lactate), but it is not known whether the lactate is metabolized or if it accumulates in a distribution volume. In one experiment the cerebral arterio-venous differences (AV) for O(2), glucose (glc) and lactate (lac) were evaluated in nine healthy subjects at rest and during and after exercise to exhaustion. The cerebrospinal fluid (CSF) was drained through a lumbar puncture immediately after exercise, while control values were obtained from six other healthy young subjects.

Cerebral metabolism is influenced by muscle ischaemia during exercise in humans.

Maximal exercise reduces the cerebral metabolic ratio (O2/(glucose + 1/2 lactate)) to < 4 from a resting value close to 6, and only part of this decrease is explained by the 'intent' to exercise. This study evaluated whether sensory stimulation of brain by muscle ischaemia would reduce the cerebral metabolic ratio. In 10 healthy human subjects the cerebral arterial-venous differences (a-v differences) for O2, glucose and lactate were assessed before, during and after three bouts of 10 min cycling with equal workload: (1) control exercise at light intensity, (2) exercise that elicited a high rating of perceived exertion due to a 100 mmHg thigh cuff, and (3) exercise followed by 5 min of post-exercise muscle ischaemia that increased blood pressure by approximately 20 %.

The intent to exercise influences the cerebral O(2)/carbohydrate uptake ratio in humans.

During and after maximal exercise there is a 15-30 % decrease in the metabolic uptake ratio (O(2)/[glucose + 1/2 lactate]) and a net lactate uptake by the human brain. This study evaluated if this cerebral metabolic uptake ratio is influenced by the intent to exercise, and whether a change could be explained by substrates other than glucose and lactate. The arterial-internal jugular venous differences (a-v difference) for O(2), glucose and lactate as well as for glutamate, glutamine, alanine, glycerol and free fatty acids were evaluated in 10 healthy human subjects in response to cycling.