Isopropylphenidate: An Ester Homolog of Methylphenidate with Sustained and Selective Dopaminergic Activity and Reduced Drug Interaction Liability

Objective: The most widely utilized pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD) is the psychostimulant methylphenidate (MPH). Most MPH formulations consist of the racemic mixture of d-threo-(R, R)-MPH and l-threo-(S, S)-MPH isomers. MPH is characterized by its low bioavailability and short half-life (2?3 hours). Additionally, significant inter-individual variability in MPH pharmacokinetics has been consistently documented. Accordingly, efforts have been directed at developing alternatives to MPH as therapeutic agents. A wide range of MPH analogues (dl-α-[2-piperidyl]-phenylacetic acid esters) have been synthesized with the dopamine transporter (DAT) and norepinephrine transporter (NET) as principle neuropharmacological targets. The present study investigated the metabolic profiles and pharmacological activity of the isopropyl ester derivative of MPH, dl-isopropylphenidate (IPH), both in vitro and in vivo. Methods: The synthesis, monoaminergic transporter binding, cellular uptake profiles, and assessment of metabolic hydrolysis and transesterification in the presence of ethanol are described using MPH as a comparator. Additionally, an in vivo assessment of IPH stimulant effects (vs. saline) in rats was performed with locomotor activity as a pharmacodynamic outcome. Results: IPH displayed unique pharmacological characteristics including greater DAT than NET binding and cellular uptake activity, and greater resistance to hydrolysis and transesterification via carboxylesterase 1 relative to MPH. Further, sustained psychostimulant properties offer the prospect of an enhanced duration of action. Conclusions: Our findings are consistent with IPH exhibiting attributes distinguishing it from MPH and warranting further study and development of IPH as a novel psychotherapeutic agent.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140321/1/cap.2013.0074.pd

Donepezil Effects on Mood in Patients with Schizophrenia and Schizoaffective Disorder

Donepezil, 5 mg/d for 6 wk then 10 mg/d for 6 wk, and placebo daily for 12 wk in a double-blind cross-over paradigm, was added to the therapeutic regimen of 13 patients with schizophrenia or schizoaffective disorders, clinically stable on atypical antipsychotic medications. Patients had varying degrees of depressive symptoms, ranging from no depression to clinically significant depression. There was no worsening or induction of depression in individual patients or the group as a whole. In addition there was a statistically significant antidepressant effect in the group as a whole during the donepezil condition and a clinically significant antidepressant effect in the patients with clinically significant depressive symptoms, although there were not enough depressed patients in the group to conclude that donepezil may have antidepressant effects. Thus, in this study, donepezil did not induce or worsen depressive symptoms in schizophrenic and schizoaffective disorder patients

Tissue-specific patterns of gene expression in the epithelium and stroma of normal colon in healthy individuals in an aspirin intervention trial

AbstractRegular aspirin use reduces colon adenoma and carcinoma incidence. UDP-glucuronosyltransferases (UGT) are involved in aspirin metabolism and clearance, and variant alleles in UGT1A6 have been shown to alter salicylic acid metabolism and risk of colon neoplasia. In a randomized, cross-over, placebo-controlled trial of 44 healthy men and women, homozygous for UGT1A6*1 or UGT1A6*2, we explored differences between global epithelial and stromal expression, using Affymetrix U133+2.0 microarrays and tested effects of 60-day aspirin supplementation (325mg/d) on epithelial and stromal gene expression and colon prostaglandin E2 (PGE2) levels. We conducted a comprehensive study of differential gene expression between normal human colonic epithelium and stroma from healthy individuals. Although no statistically significant differences in gene expression were observed in response to aspirin or UGT1A6 genotype, we have identified the genes uniquely and reproducibly expressed in each tissue type and have analyzed the biologic processes they represent. Here we describe in detail how the data, deposited in the Gene Expression Omnibus (GEO) – accession number GSE71571 – was generated including the basic analysis as contained in the manuscript published in BMC Medical Genetics with the PMID 25927723 (Thomas et al., 2015 [9])

The Arthrobacter Species FB24 Arth_1007 (DnaB) Intein Is a Pseudogene

An Arthrobacter species FB24 gene (locus tag Arth_1007) was previously annotated as a putative intein-containing DnaB helicase of phage origin (Arsp-FB24 DnaB intein). However, it is not a helicase gene because the sequence similarity is limited to inteins. In fact, the flanking exteins total only 66 amino acids. Therefore, the intein should be referred to as the Arsp-FB24 Arth_1007 intein. The Arsp-FB24 Arth_1007 intein failed to splice in its native precursor and in a model precursor. We previously noted that the Arsp-FB24 Arth_1007 intein is the only putative Class 3 intein that is missing the catalytically essential Cys at position 4 of intein Motif F, which is one of the three defining signature residues of this class. Additionally, a catalytically essential His in position 10 of intein Motif B is also absent; this His is the most conserved residue amongst all inteins. Splicing activity was not rescued when these two catalytically important positions were ‘reverted’ back to their consensus residues. This study restores the unity of the Class 3 intein signature sequence in active inteins by demonstrating that the Arsp-FB24 Arth_1007 intein is an inactive pseudogene

Identifying DNA methylation biomarkers for non-endoscopic detection of Barrett’s esophagus

We report a biomarker-based non-endoscopic method for detecting Barrett’s esophagus (BE), based on detecting methylated DNAs retrieved via a swallowable balloon-based esophageal sampling device. BE is the precursor of, and a major recognized risk factor for, developing esophageal adenocarcinoma (EAC). Endoscopy, the current standard for BE detection, is not cost-effective for population screening. We performed genome-wide screening to ascertain regions targeted for recurrent aberrant cytosine methylation in BE, identifying high-frequency methylation within the CCNA1 locus. We tested CCNA1 DNA methylation as a BE biomarker in cytology brushings of the distal esophagus from 173 individuals with or without BE. CCNA1 DNA methylation demonstrated an area under the curve (AUC)=0.95 for discriminating BE-related metaplasia and neoplasia cases versus normal individuals, performing identically to methylation of VIM DNA, an established BE biomarker. When combined, the resulting two biomarker panel was 95% sensitive and 91% specific. These results were replicated in an independent validation cohort of 149 individuals, who were assayed using the same cutoff values for test positivity established in the training population. To progress toward non-endoscopic esophageal screening, we engineered a well-tolerated, swallowable, encapsulated balloon device able to selectively sample the distal esophagus within 5 minutes. In balloon samples from 86 individuals, tests of CCNA1 plus VIM DNA methylation detected BE metaplasia with 90.3% sensitivity and 91.7% specificity. Combining the balloon sampling device with molecular assays of CCNA1 plus VIM DNA methylation enables an efficient, well-tolerated, sensitive, and specific method of screening at-risk populations for BE

The European Union in the World — A Community of Values

These are momentous times in Europe. The Euro has been successfully introduced, the enlargement negotiations are approaching their climax, and the European Convention (“Convention”) is moving towards the drafting of a constitution for a new, continent-wide political entity. At the same time, unrest is manifest, particularly in two areas. On the one hand, many of our citizens, and not just the political elites, are dissatisfied with Europe\u27s performance on the world stage and are concerned about the maintenance of peace and security within the Union. In these areas they would like to see a strengthened, more effective entity-- “more Europe.” On the other hand, their disenchantment with the long reach of European Union (“EU” or “Union”) regulation in the first pillar area of economic policy is growing. The feeling of loss of local control over their destiny and a vague feeling of potential loss of identity within an ever more centralized polity is palpable. Here, they want “less Europe.” In the outside world, change is also the order of the day. The ice-sheet of bipolarity, which overlaid and hid the complexity of international relations during the Cold War, is breaking up at an ever-increasing speed and revealing a world in which two paradigms are competing to become the underlying ordering principles for the new century. The traditional paradigm of interacting Nation States, each pursuing its own separate interests, with alliances allowing the small to compete with the large, is alive and well, and its proponents like Machiavelli or Churchill continue to be in vogue in the literature of international relations and the rhetoric of world leaders. At the same time, there is a school of thought which points to the growing economic and ecological interdependence of our societies and the necessity for new forms of global governance to complement national action. It is also becoming abundantly clear that the concept of a “Nation State” is often a fiction, positing as it does an identity between the citizens of a State and the members of a culturally homogenous society. For both reasons, the concept of the Nation State as the principal actor on the world stage, is called into question. The experience of the Union with the sharing of State sovereignty is clearly related to the second paradigm and also to the EU\u27s firm support for the development of the United Nations (“U.N.”) as well as other elements of multilateral governance. It would hardly be wise to suggest that any foreign policy, and certainly not that of the EU, should be based only on this paradigm. Given the recurrent threats to security, which seem to be part of the human condition expressed by some as the “inevitability of war”--the defense of territorial integrity; action against threats of aggression; and resistance to crimes against humanity such as genocide--the ability to conduct a security policy based much more on the old paradigm of interacting interests will continue to be required. That the EU needs to develop such a capability will be taken here as a given. Such a crisis-management capability will be essential to the Union, but will be distinguished here from the more long-term elements of foreign policy, which can be thought of as being designed to reduce the need for crisis management in the context of a security policy to a minimum. The crisis-management area of policy will not be treated further here. The thesis of this Essay is that the same set of political concepts can serve as a guide to the future internal development of the EU and as the basis of such a long-term foreign policy. Furthermore, it suggests that neither should be seen in terms of the balancing of interests but rather, as the expression of a small list of fundamental values. The list is as follows: (1) the rule of law as the basis for relations between members of society; (2) the interaction between the democratic process and entrenched human rights in political decision-making; (3) the operation of competition within a market economy as the source of increasing prosperity; (4) the anchoring of the principle of solidarity among all members of society alongside that of the liberty of the individual; (5) the adoption of the principle of sustainability of all economic development; and (6) the preservation of separate identities and the maintenance of cultural diversity within society. These values can be seen as the answer to the question posed both, by citizens of the Union and by our fellow citizens of the world: “What does the EU stand for?” In exploring these values we should, however, remember that in the real world there will be occasions on which Realpolitik will intrude and the interest-based paradigm will prevail

Measurement of the Target-Normal Single-Spin Asymmetry in Quasi-Elastic Scattering from the Reaction 3^3He↑(e,e′)^\uparrow(e,e^\prime)

We report the first measurement of the target single-spin asymmetry, $A_y$, in quasi-elastic scattering from the inclusive reaction $^3$He$^{\uparrow}(e,e^\prime)$ on a $^3$He gas target polarized normal to the lepton scattering plane. Assuming time-reversal invariance, this asymmetry is strictly zero for one-photon exchange. A non-zero $A_y$ can arise from the interference between the one- and two-photon exchange processes which is sensitive to the details of the sub-structure of the nucleon. An experiment recently completed at Jefferson Lab yielded asymmetries with high statistical precision at $Q^{2}=$ 0.13, 0.46 and 0.97 GeV$^{2}$. These measurements demonstrate, for the first time, that the $^3$He asymmetry is clearly non-zero and negative with a statistical significance of (8-10)$\sigma$. Using measured proton-to-$^{3}$He cross-section ratios and the effective polarization approximation, neutron asymmetries of $-$(1-3)% were obtained. The neutron asymmetry at high $Q^2$ is related to moments of the Generalized Parton Distributions (GPDs). Our measured neutron asymmetry at $Q^2=0.97$ GeV$^2$ agrees well with a prediction based on two-photon exchange using a GPD model and thus provides a new, independent constraint on these distributions