Predicted effect size of lisdexamfetamine treatment of attention deficit/hyperactivity disorder (ADHD) in European adults: Estimates based on indirect analysis using a systematic review and meta-regression analysis.

BACKGROUND: There are few approved therapies for adults with attention-deficit/hyperactivity disorder (ADHD) in Europe. Lisdexamfetamine (LDX) is an effective treatment for ADHD; however, no clinical trials examining the efficacy of LDX specifically in European adults have been conducted. Therefore, to estimate the efficacy of LDX in European adults we performed a meta-regression of existing clinical data. METHODS: A systematic review identified US- and Europe-based randomized efficacy trials of LDX, atomoxetine (ATX), or osmotic-release oral system methylphenidate (OROS-MPH) in children/adolescents and adults. A meta-regression model was then fitted to the published/calculated effect sizes (Cohen's d) using medication, geographical location, and age group as predictors. The LDX effect size in European adults was extrapolated from the fitted model. Sensitivity analyses performed included using adult-only studies and adding studies with placebo designs other than a standard pill-placebo design. RESULTS: Twenty-two of 2832 identified articles met inclusion criteria. The model-estimated effect size of LDX for European adults was 1.070 (95% confidence interval: 0.738, 1.401), larger than the 0.8 threshold for large effect sizes. The overall model fit was adequate (80%) and stable in the sensitivity analyses. CONCLUSION: This model predicts that LDX may have a large treatment effect size in European adults with ADHD.

Some metabotropic glutamate receptor ligands reduce kynurenate synthesis in rats by intracellular inhibition of kynurenine aminotransferase II.

Some metabotropic glutamate receptor (mGluR) ligands, such as quisqualate, L-(+)-2-amino-4-phosphonobutyric acid (L-AP4), 4-carboxy-3-hydroxyphenylglycine (4C3HPG), and L-serine-O:-phosphate (L-SOP), reduced the formation of the endogenous excitatory amino acid receptor antagonist kynurenate in brain and liver slices. The use of novel, subtype-selective mGluR agonists and antagonists excluded a role for any known mGluR subtype in this effect. The reduction of kynurenate formation was no longer observed when slices were incubated with the active mGluR ligands in the absence of extracellular Na(+). trans-Pyrrolidine-2,4-dicarboxylate (trans-PDC), a broad-spectrum ligand of Na(+)-dependent glutamate transporters, was also able to reduce kynurenate formation. Quisqualate, 4C3HPG, L-AP4, and L-SOP did not further reduce kynurenate formation in the presence of trans-PDC, suggesting that the two classes of drugs may share the same mechanism of action. Hence, we hypothesized that the active mGluR ligands are transported inside the cell and act intracellularly to reduce kynurenate synthesis. We examined this possibility by assessing the direct effect of mGluR ligands on the activity of kynurenine aminotransferases (KATs) I and II, the enzymes that transaminate kynurenine to kynurenate. In brain tissue homogenates, KAT II (but not KAT I) activity was inhibited by quisqualate, 4C3HPG, L-AP4, L-SOP, and trans-PDC. Drugs that were unable to reduce kynurenate formation in tissue slices were inactive. We conclude that some mGluR ligands act intracellularly, inhibiting KAT II activity and therefore reducing kynurenate formation. This effect should be taken into consideration when novel mGluR ligands are developed for the treatment of neurological and psychiatric diseases.

Quantitative differences in the effects of de novo produced and exogenous kynurenic acid in rat brain slices.

Kynurenic acid (KYNA) is an antagonist of (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors and it blocks the glycine site of the NMDA receptor preferentially (IC50 = 7.9 microM). KYNA is produced endogenously by transamination of its precursor L-kynurenine (L-KYN). We tested the hypothesis that effects of endogenous, de novo produced KYNA, following bath-application of L-KYN to slices, would be different than effects of commercially-synthesized (exogenous) KYNA. The ability to block spontaneous epileptiform activity, induced by lowering extracellular magnesium, was examined in area CA3 of hippocampus and the entorhinal cortex. At a concentration of 200 microM L-KYN, which produced 0.89 +/- 0.20 microM KYNA, there were fewer slices with spontaneous epileptiform activity than slices exposed to 2 microM exogenous KYNA. The results indicate a more potent neuromodulatory action of endogenous KYNA than has been previously realized.

2-Oxoacids regulate kynurenic acid production in the rat brain: studies in vitro and in vivo.

This study was designed to examine the role of 2-oxoacids in the enzymatic transamination of L-kynurenine to the excitatory amino acid receptor antagonist, kynurenate, in the rat brain. In brain tissue slices incubated in Krebs-Ringer buffer with a physiological concentration of L-kynurenine, pyruvate, and several other straight- and branched-chain 2-oxoacids, substantially restored basal kynurenate production in a dose-dependent manner without increasing the intracellular concentration of L-kynurenine. All 2-oxoacids tested also reversed or attenuated the hypoglycemia-induced decrease in kynurenate synthesis, but only pyruvate and oxaloacetate also substantially restored intracellular L-kynurenine accumulation. Thus, 2-oxoacids increase kynurenate formation in the brain primarily by functioning as co-substrates of the transamination reaction. This was supported further by the fact that the nonspecific kynurenine aminotransferase inhibitors (aminooxy)acetic acid and dichlorovinylcysteine prevented the effect of pyruvate on kynurenate production in a dose-dependent manner. Moreover, all 2-oxoacids tested attenuated or prevented the effects of veratridine, quisqualate, or L-alpha-aminoadipate, which reduce the transamination of L-kynurenine to kynurenate. Finally, dose-dependent increases in extracellular kynurenate levels in response to an intracerebral perfusion with pyruvate or alpha-ketoisocaproate were demonstrated by in vivo microdialysis. Taken together, these data show that 2-oxoacids can directly augment the de novo production of kynurenate in several areas of the rat brain. 2-Oxoacids may therefore provide a novel pharmacological approach for the manipulation of excitatory amino acid receptor function and dysfunction.

Indole-3-propionate: a potent hydroxyl radical scavenger in rat brain.

The hydroxyl radical scavenging activity of indole-3-propionate was evaluated by kinetic competition studies with the hydroxyl radical trapping reagent 2,2'-azino-bis-(3-ethyl-benz-thiazoline-6-sulfonic acid) (ABTS) and by measuring hydroxyl radical-initiated lipid peroxidation in the rat striatum. Using ABTS, the indole was shown to act as a potent hydroxyl radical scavenger with a rate constant of 7.8x1010 mol l-1 s-1. Hydroxyl radical-initiated lipid peroxidation, determined by measuring tissue malondialdehyde formation, was inhibited dose-dependently both in vitro and in vivo. Indole-3-propionate reacts with hydroxyl radicals at a diffusion controlled rate and can thereby provide on-site protection against the oxidative damage of biomolecules induced by these highly reactive and toxic oxygen intermediates. While it remains to be established if endogenous brain tissue levels of indole-3-propionate are sufficiently high to have a significant impact on total antioxidative capacity, the compound itself or a structurally related agent may be useful as an antioxidant adjuvant to combat hydroxyl radical-mediated oxidative stress.

Modulation and function of kynurenic acid in the immature rat brain.

Using in vivo and in vitro paradigms, the regulation and function of the brain metabolite kynurenic acid (KYNA) was examined in rats on postnatal days (PND) 7 and 14. As shown previously in adult rats, glucose removal and d-amphetamine (d-Amph) administration caused decreases in KYNA formation, while exposure to pyruvate up-regulated KYNA synthesis. The effect of glucose deprivation was substantially blunted in immature animals. In PND 14 rats, d-Amph pre-treatment exacerbated the excitotoxic effects of an intrastriatal N-methyl-D-aspartate (NMDA) injection. This potentiation was prevented by m-nitrobenzoylalanine, a kynurenine 3-hydroxylase inhibitor that also antagonized the KYNA reduction caused by d-Amph. These and additional experiments with the competitive NMDA receptor antagonist CGP 40116 indicate the existence of a functionally significant, novel high-affinity receptor for KYNA in the brain.

Metabolic control of kynurenic acid formation in the rat brain.

Excitotoxic neuronal loss can be precipitated by defects in cerebral energy metabolism. Antagonists of excitatory amino acid receptors, such as the endogenous metabolite kynurenic acid, can effectively block excitotoxic lesions. Using brain tissue slices, the present study was designed to examine a potential link between metabolic status and cerebral kynurenic acid formation in adult rats. The results demonstrate that fluctuations in cerebral energy metabolism are closely associated with changes in kynurenic acid synthesis. Taken together, the data are compatible with the idea that the production of kynurenic acid in the brain is critically affected by the availability of pyruvate or other 2-oxoacids (i.e. co-substrates for the enzymatic transamination of the bioprecursor of kynurenic acid, L-kynurenine). Such metabolic control of kynurenic acid function may play a role in excitotoxic brain diseases

Interference with cellular energy metabolism reduces kynurenic acid formation in rat brain slices: reversal by lactate and pyruvate.

This study was designed to investigate the role of cellular energy metabolism in the de novo formation of the endogenous excitatory amino acid receptor antagonist, kynurenic acid. Using rat cortical tissue slices, the roles of glucose transport, glycolysis, tricarboxylic acid cycle intermediates and oxidative phosphorylation were studied. Inhibition of glucose utilization resulted in quantitatively similar decreases in kynurenine uptake, kynurenic acid production and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction, a marker of mitochondrial activity. The end product of glycolysis, pyruvate, as well as lactate, attenuated all three deficits. Pyruvate also significantly increased kynurenic acid formation in normal brain slices without affecting kynurenine uptake. Oxaloacetate and alpha-ketoglutarate (tricarboxylic acid cycle intermediates) were the only compounds tested which were capable of duplicating the effects of pyruvate, indicating that 2-oxoacids can stimulate kynurenic acid synthesis by acting as aminoacceptors in the enzymatic transamination of kynurenine. When the mitochondrial electron transport chain was blocked by specific inhibitors, coincubation with succinate restored the rate of MTT formazan formation to normal (except in the case of 3-nitropropionic acid), yet failed to prevent the resulting reduction in kynurenic acid synthesis. Conversely, pyruvate increased kynurenic acid production in the presence of all inhibitors (except cyanide), but did not attenuate the reduction in kynurenine uptake and MTT formazan formation. Taken together, these results demonstrate that interference with cellular energy metabolism causes mechanistically diverse, pronounced reductions in the cerebral neosynthesis of kynurenic acid, and that 2-oxoacids and lactate can effectively reverse most of these detrimental effects.

Regulation of kynurenic acid levels in the developing rat brain.

Several brain-specific mechanisms control the formation of the endogenous excitatory amino acid receptor antagonist kynurenic acid (KYNA) in the adult rat brain. Two of these, dopaminergic neurotransmission and cellular energy metabolism, were examined in the brain of immature (postnatal day 7) rats. The results indicate that during the early postnatal period cerebral KYNA synthesis is exceptionally amenable to modulation by dopaminergic mechanisms but rather insensitive to fluctuations in cellular energy status. These findings may be of relevance for the role of KYNA in the function and dysfunction of the developing brain.

Brain-specific modulation of kynurenic acid synthesis in the rat.

This study was designed to investigate modulatory mechanisms that control the synthesis of the neuroprotective endogenous excitatory amino acid receptor antagonist kynurenate. De novo kynurenate formation was examined in vitro using tissue slices from rat brain, liver, and kidney. In slices from adult cerebral cortex, veratridine, quisqualate, and L-alpha-aminoadipate decreased kynurenate synthesis substantially. Glucose removal or changes in the ionic milieu, too, influenced kynurenate formation significantly, suggesting that demands on cellular energy interfere with kynurenate production in the adult rat brain. The effects of quisqualate and L-alpha-aminoadipate were also observed in the immature brain, in the quinolinate-lesioned adult striatum, and, to a lesser extent, in peripheral organs. In contrast, the effect of veratridine was not seen in the lesioned brain or in kidney and liver tissue, indicating its dependency on intact neuron-glia interactions. Compared with the normal adult brain, ionic manipulations yielded qualitatively distinct results in the developing brain and in the periphery, but their effects remained unchanged in the lesioned striatum. Glucose deprivation was less consequential in the immature than in the adult brain and was entirely ineffective in the lesioned striatum and in the periphery. These results further link cellular, especially astrocytic, energy metabolism to kynurenate formation in the brain. More generally, the existence of brain-specific mechanisms for the regulation of kynurenate production is suggestive of a modulatory role of this metabolite in excitatory amino acid receptor function and dysfunction.

Gallium-transferrin binding in treated and untreated Parkinson's disease.

The binding of gallium (Ga) to transferrin (Tf) was studied in plasma from control patients, in patients with untreated Parkinson's disease (PD) and in patients with PD treated either with levodopa (L-dopa) alone or in combination with selegiline. Mean percentage Ga-Tf binding was significantly reduced in untreated and treated PD compared with controls. Binding, however, was significantly greater in treated than in untreated patients. There was no difference in binding between patients treated with L-dopa alone and those treated with L-dopa and selegiline. The data support the hypothesis that oxidation reactions may be of pathogenic significance in PD.

The severity of alpha-particle-induced DNA damage is revealed by exposure to cell-free extracts.

The rejoining of single-strand breaks induced by alpha-particle and gamma irradiation in plasmid DNA under two scavenging conditions has been compared. At the two scavenger capacities used of 1.5 x 10(7) and 3 x 10(6) s-1 using Tris-HCl as the scavenger, the ratio of single- to double-strand breaks for alpha particles is fivefold less than the corresponding ratios for gamma irradiation. The repair of such radiation-induced single-strand breaks has been examined using a cell-free system derived from human whole-cell extracts. We show that the rejoining of single-strand breaks for both alpha-particle- and gamma-irradiated plasmid is dependent upon the scavenging capacity and that the efficiency of rejoining of alpha-particle-induced single-strand breaks is significantly less than that observed for gamma-ray-induced breaks. In addition, for DNA that had been irradiated under conditions that mimic the cellular environment with respect to the radical scavenging capacity, 50% of alpha-particle-induced single-strand breaks are converted to double-strand breaks, in contrast with only approximately 12% conversion of gamma-ray-induced single-strand breaks, indicating that the initial damage caused by alpha particles is more severe. These studies provide experimental evidence for increased clustering of damage which may have important implications for the induction of cancer by low-level alpha-particle sources such as domestic radon.

Rejoining of gamma-radiation-induced single-strand breaks in plasmid DNA by human cell extracts: dependence on the concentration of the hydroxyl radical scavenger, Tris.

The rejoining of single-strand breaks induced by gamma irradiation in plasmid DNA under different scavenging conditions is described using human cell extracts. As the scavenging capacity of the irradiated solution increases from 1.5 x 10(7) to 3 x 10(8) s-1 using Tris-HCl as a scavenger, the ratio of single- to double-strand breaks is reduced from approximately 70:1 to 40:1. After irradiation, a proportion of DNA molecules have no initial strand breaks but contain damage that is converted to strand breaks when incubated either at 37 degrees C or in the presence of cellular extract. Repair of damage by the extracts is dependent upon the scavenging capacity of the irradiated solution. Optimal rejoining is observed when the scavenging capacity is < 1.5 x 10(7) s-1, and results in the repair of some initial strand breaks. As the scavenging capacity increases to 3 x 10(8) s-1 the proportion of breaks repaired is significantly reduced. The relative increase in the yield of double-strand breaks and reduced repairability of single-strand breaks at a scavenging capacity of 3 x 10(8) s-1 is consistent with the concept that the severity of damage increases upon increasing the scavenger concentration.

Reduced transferrin binding in Down syndrome: a route to senile plaque formation and dementia.

Plasma transferrin binding in Down syndrome and Alzheimer's disease is significantly reduced compared with age matched controls and it was thought this may help elucidate a pathological time sequence for the onset of dementia in Down syndrome. In Down syndrome, there was a reduction in gallium and aluminium transferrin binding both with age and the onset of dementia. Non-transferrin bound gallium species were identified as non-transportable phosphate or silicate. Thus, the route of entry of metals into the brain must be via a transferrin mediated complex only. A clear sequence of pathological events has been demonstrated in Down syndrome which shows the pathway to development of plaques and dementia and this is believed to have an immunological origin.