Since the cloning of the histamine H(3) receptor cDNA in 1999 by Lovenberg and co-workers, this histamine receptor has gained the interest of many pharmaceutical companies as a potential drug target ...for the treatment of various important disorders, including obesity, attention-deficit hyperactivity disorder, Alzheimer's disease, schizophrenia, as well as for myocardial ischaemia, migraine and inflammatory diseases. Here, we discuss relevant information on this target protein and describe the development of various H(3) receptor agonists and antagonists, and their effects in preclinical animal models.
Biomarkers enable the characterization of patient populations and quantitation of the extent to which new drugs reach intended targets, alter proposed pathophysiological mechanisms and achieve ...clinical outcomes. In genomics, the biomarker challenge is to identify unique molecular signatures in complex biological mixtures that can be unambiguously correlated to biological events in order to validate novel drug targets and predict drug response. Biomarkers can stratify patient populations or quantify drug benefit in primary prevention or disease-modification studies in poorly served areas such as neurodegeneration and cancer. Clinically useful biomarkers are required to inform regulatory and therapeutic decision making regarding candidate drugs and their indications in order to help bring new medicines to the right patients faster than they are today.
Using US panel data on young workers, we demonstrate that those who receive performance pay are more likely to consume alcohol and illicit drugs. Recognizing that this likely reflects worker sorting, ...we first control for risk, ability, and personality proxies. We further mitigate sorting concerns by introducing worker fixed effects, worker-employer match fixed effects, and worker-employer-occupation match fixed effects. Finally, we present fixed effect IV estimates. All of these estimates continue to indicate a greater likelihood of substance use when a worker receives performance pay. The results support conjectures that stress and effort increase with performance pay and that alcohol and drug use is a coping mechanism for workers.
The poetry of Anelisa Thengimfene, through scholarly critique, certifies that applicatory subjects may be enacted in isiXhosa modern literature. Such applicatory subjects breathe pertinence to social ...issues that predominantly affect the South African youth and other organs of social anatomy. Using Anelisa Thengimfene's two selected isiXhosa poems (Imfundo andIziyobisi) , issues concerning education and drug abuse are critiqued in terms of content or subject matter in order to unmask their interfacing meanings. Textual analysis alongside qualitative research methodology is appointed to operate in a synergetic relationship. The principal objective of this article is to exhibit that education and drug addiction are social problems that continue to sabotage the lives of many young men and women in South Africa and elsewhere. The findings and discussions underscore that isiXhosa modern literature should be employed for the fact that it contests contemporary issues that are valuable and worth theoretical and practical debates. As a direct consequence of that, the closing remarks recommend a maintained scrutinisation of isiXhosa modern poetry. The contribution of this intellectual discourse can be pinned on the fact that Anelisa Thengimfene is an emerging isiXhosa literary writer, and therefore, new insights can be enacted from her literary art.
Twenty‐one U.S. states have passed recreational cannabis laws as of November 2022. Cannabis may be a substitute for prescription opioids in the treatment of chronic pain. Previous studies have ...assessed recreational cannabis laws' effects on opioid prescriptions financed by specific private or public payers or dispensed to a unique endpoint. Our study adds to the literature in three important ways: by (1) examining these laws' impacts on prescription opioid dispensing across all payers and endpoints, (2) adjusting for important opioid‐related policies such as opioid prescribing limits, and (3) modeling opioids separately by type. We implement two‐way fixed‐effects regressions and leverage variation from eleven U.S. states that adopted a recreational cannabis law (RCL) between 2010 and 2019. We find that RCLs lead to a reduction in codeine dispensed at retail pharmacies. Among prescription opioids, codeine is particularly likely to be used non‐medically. Thus, the finding that RCLs appear to reduce codeine dispensing is potentially promising from a public health perspective.
High-throughput and virtual screening are widely used to discover novel leads for drug design. On examination, many screening hits appear non-drug-like: they act noncompetitively, show little ...relationship between structure and activity, and have poor selectivity. Attempts to develop these peculiar molecules into viable leads are often futile, and much time can be wasted on the characterization of these “phony” hits. Despite their common occurrence, the mechanism of action of these promiscuous molecules remains unknown. To investigate this problem, 45 diverse screening hits were studied. Fifteen of these were previously reported as inhibitors of various receptors, including β-lactamase, malarial protease, dihydrofolate reductase, HIV Tar RNA, thymidylate synthase, kinesin, insulin receptor, tyrosine kinases, farnesyltransferase, gyrase, prions, triosephosphate isomerase, nitric oxide synthase, phosphoinositide 3-kinase, and integrase; 30 were from an in-house screening library of a major pharmaceutical company. In addition to their original targets, 35 of these 45 compounds were shown to inhibit several unrelated model enzymes. These 35 screening hits included compounds, such as fullerenes, dyes, and quercetin, that have repeatedly shown activity against diverse targets. When tested against the model enzymes, the compounds showed time-dependent but reversible inhibition that was dramatically attenuated by albumin, guanidinium, or urea. Surprisingly, increasing the concentration of the model enzymes 10-fold largely eliminated inhibition, despite a 1000-fold excess of inhibitor; a well-behaved competitive inhibitor did not show this behavior. One model to explain these observations was that the active form of the promiscuous inhibitors was an aggregate of many individual molecules. To test this hypothesis, light scattering and electron microscopy experiments were performed. The nonspecific inhibitors were observed to form particles of 30−400 nm diameter by both techniques. In control experiments, a well-behaved competitive inhibitor and an inactive dye-like molecule were not observed to form aggregates. Consistent with the hypothesis that the aggregates are the inhibitory species, the particle size and IC50 values of the promiscuous inhibitors varied monotonically with ionic strength; a competitive inhibitor was unaffected by changes in ionic strength. Unexpectedly, aggregate formation appears to explain the activity of many nonspecific inhibitors and may account for the activity of many promiscuous screening hits. Molecules acting via this mechanism may be widespread in drug discovery screening databases. Recognition of these compounds may improve screening results in many areas of pharmaceutical interest.
This paper examines the causal effect of earning a GED or vocational degree on future illicit drug use, employing random assignment into the United States' most comprehensive education and vocational ...training program for at-risk youth - Job Corps - as a source of exogenous variability in degree attainment. Nonparametric bounds under relatively weak monotonicity assumptions are constructed to allow the random assignment to violate the exclusion restriction when used as an instrument. We also use a fixed effect model and propensity score weighting to supplement the results. The results from different methods suggest that degree attainment may have the most significant effect in reducing the illicit drug use of blacks, while the results for whites and Hispanics are less conclusive.
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