Current issues around the pharmacotherapy of ADHD in children and adults

Background New drugs and new formulations enter the growing market for ADHD medication. The growing awareness of possible persistence of ADHD impairment beyond childhood and adolescence resulting in increased pharmacotherapy of ADHD in adults, is also a good reason for making an inventory of the what is generally known about pharmacotherapy in ADHD. Aim To discuss current issues in the possible pharmacotherapy treatment of ADHD in children, adolescents and adults with respect to the position of pharmacotherapy in ADHD treatment guidelines, the pharmacoepidemiological trends, and current concerns about the drugs used. Methods A search of the literature with an emphasis on the position of pharmacotherapy in ADHD treatment guidelines, the pharmacoepidemiological trends, and current concerns about the drugs used in pharmacotherapy. Results According to the guidelines, the treatment of ADHD in children consists of psychosocial interventions in combination with pharmacotherapy when needed. Stimulants are the first-choice drugs in the pharmacological treatment of ADHD in children despite a number of well known and frequently reported side effects like sleep disorders and loss of appetite. With regard to the treatment of adults, stimulant treatment was recommended as the first-choice pharmacotherapy in the single guideline available. Both in children and adults, there appears to be an additional though limited role for the nonadrenergic drug atomoxetine. The increase of ADHD medication use, in children, adolescents and in adults, can not only be interpreted as a sign of overdiagnosis of ADHD. Despite the frequent use of stimulants, there is still a lack of clarity on the effects of long-term use on growth and nutritional status of children. Cardiovascular effects of both stimulants and atomoxetine are rare but can be severe. The literature suggests that atomoxetine may be associated with suicidal ideation in children. Conclusion Although pharmacotherapy is increasing common in the treatment of ADHD in both children and adults, there are still a lot of questions about side effects and how best to counter them. This suggests an important role for close monitoring of children and adults treated with stimulants or atomoxetine

Brain-derived neurotrophic factor enhances calcium regulatory mechanisms in human airway smooth muscle.

Neurotrophins (NTs), which play an integral role in neuronal development and function, have been found in non-neuronal tissue (including lung), but their role is still under investigation. Recent reports show that NTs such as brain-derived neurotrophic factor (BDNF) as well as NT receptors are expressed in human airway smooth muscle (ASM). However, their function is still under investigation. We hypothesized that NTs regulate ASM intracellular Ca(2+) ([Ca(2+)](i)) by altered expression of Ca(2+) regulatory proteins. Human ASM cells isolated from lung samples incidental to patient surgery were incubated for 24 h (overnight) in medium (control) or 1 nM BDNF in the presence vs. absence of inhibitors of signaling cascades (MAP kinases; PI3/Akt; NFκB). Measurement of [Ca(2+)](i) responses to acetylcholine (ACh) and histamine using the Ca(2+) indicator fluo-4 showed significantly greater responses following BDNF exposure: effects that were blunted by pathway inhibitors. Western analysis of whole cell lysates showed significantly higher expression of CD38, Orai1, STIM1, IP(3) and RyR receptors, and SERCA following BDNF exposure, effects inhibited by inhibitors of the above cascades. The functional significance of BDNF effects were verified by siRNA or pharmacological inhibition of proteins that were altered by this NT. Overall, these data demonstrate that NTs activate signaling pathways in human ASM that lead to enhanced [Ca(2+)](i) responses via increased regulatory protein expression, thus enhancing airway contractility

Diverse Role of <i>bla</i>_CTX-M and Porins in Mediating Ertapenem Resistance among Carbapenem-Resistant Enterobacterales

Among carbapenem-resistant Enterobacterales (CRE) are diverse mechanisms, including those that are resistant to meropenem but susceptible to ertapenem, adding further complexity to the clinical landscape. This study investigates the emergence of ertapenem-resistant, meropenem-susceptible (ErMs) Escherichia coli and Klebsiella pneumoniae CRE across five hospitals in San Antonio, Texas, USA, from 2012 to 2018. The majority of the CRE isolates were non-carbapenemase producers (NCP; 54%; 41/76); 56% of all NCP isolates had an ErMs phenotype. Among ErMs strains, E. coli comprised the majority (72%). ErMs strains carrying blaCTX-M had, on average, 9-fold higher copies of blaCTX-M than CP-ErMs strains as well as approximately 4-fold more copies than blaCTX-M-positive but ertapenem- and meropenem-susceptible (EsMs) strains (3.7 vs. 0.9, p blaCTX-M with and without a carbapenemase(s). ErMs also carried more mobile genetic elements, particularly IS26 composite transposons, than EsMs (37 vs. 0.2, p Vsa5 was uniquely more abundant in ErMs than either EsMs or ErMr strains, with over 30 more average ISVsa5 counts than both phenotype groups (p E. coli, with 92% of strains lacking full contig coverage of ompC. Overall, our findings characterize both collaborative and independent efforts between blaCTX-M and OmpC in ErMs strains, indicating the need to reappraise the term “non-carbapenemase (NCP)”, particularly for strains highly expressing blaCTX-M. To improve outcomes for CRE-infected patients, future efforts should focus on mechanisms underlying the emerging ErMs subphenotype of CRE strains to develop technologies for its rapid detection and provide targeted therapeutic strategies

Effect of prolonged BDNF exposure on expression of membrane-associated Ca²⁺ regulatory proteins in human ASM cells.

<p>Western blot analysis demonstrated increased expression of the ectoenzyme CD38, and the Ca²⁺ influx regulatory components Orai1 and STIM1, but not TRPC3 (A, B). Inhibition of MAP kinases with PD98059, PI3/Akt with Wortmannin, or NFκB with SN50 had differential blunting effects on BDNF enhancement of CD38 vs. STIM1 vs. Orai1 (A, B; see text for detailed description). Consistent with these results, inhibition of signaling intermediates (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044343#s2" target="_blank">Methods</a> for details) such as ERK, Raf, RSK and IKK blunted the effects of BDNF on CD38, while effects on STIM1 were more affected by IKK inhibition (C, D). In contrast, inhibition of Akt was generally less effective. Protein expression was normalized to GAPDH. *Significant difference from control; #Significant effect of inhibitor. Values are means ± SE (n = 4 patients).</p

Effect of prolonged BDNF exposure on store-operated Ca²⁺ entry (SOCE) in human ASM cells.

<p>SOCE was evaluated by depleting sarcoplasmic reticulum stores in the absence of extracellular Ca²⁺, and then rapidly re-introducing extracellular Ca²⁺ in the continued presence of CPA <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044343#pone.0044343-Ay1" target="_blank">[26]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044343#pone.0044343-White1" target="_blank">[28]</a> (A). Compared to vehicle controls, SOCE was significantly greater in cells exposed overnight to BDNF or to 7,8-Dihydroxyflavone. However, TAT-pep5 had no significant effect on either BDNF or 7,8-Dihydroxyflavone enhancement of SOCE (B). Values are means ± SE (n = 4 patients). *Significant difference from control (p<0.05).</p

Functional consequence of BDNF-induced changes in Ca²⁺ regulatory protein expression.

<p>Small interference RNA (siRNA) inhibition of CD38, Orai1 or STIM1 expression substantially reduced peak [Ca²⁺]_i responses to histamine not only in cells exposed to vehicle only (i.e. no BDNF), but also in those exposed for 24 h to BDNF (A). Transfection agent (Lipofectamine) or nonsense siRNA had no effect on [Ca²⁺]_i responses in either group (not shown). In contrast, siRNA inhibition of TRPC3 had substantially less effect on BDNF enhancement of peak [Ca²⁺]_I, suggesting that the other mechanisms were functionally linked to BDNF effects, and consistent with no change in TRPC3 expression. Similarly, in ASM cells exposed to BDNF for 24 h, inhibition of RyR channels (high concentration ryanodine) or IP₃ channels (Xestospongin C, XeC) or of SERCA (with cyclopiazonic acid; CPA) significantly blunted BDNF enhancement of peak [Ca²⁺]_i responses to histamine (B). *Significant difference from control; #Significant effect of inhibitor. Values are means ± SE (n = 4 patients).</p