Shifting North American drug markets and challenges for the system of care

Drug markets are dynamic systems which change based on demand, competition, legislation and revenue. Shifts that are not met with immediate and appropriate responses from the healthcare system can lead to public health crises with tragic levels of morbidity and mortality, as experienced Europe in the early 1990s and as is the case in North America currently. The major feature of the current drug market shift in North America is towards highly potent synthetic opioids such as fentanyl and fentanyl analogues. An additional spike in stimulant use further complicates this issue. Without understanding the ever-changing dynamics of drug markets and consequent patterns of drug use, the healthcare system will continue to be ineffective in its response, and morbidity and mortality will continue to increase. Economic perspectives are largely neglected in research and clinical contexts, but better treatment alternatives need to consider the large-scale macroeconomic conditions of drug markets as well as the behavioural economics of individual substance use. It is important for policy makers, health authorities, first responders and medical providers to be aware of the clinical implications of drug market changes in order to best serve people who use drugs. Only with significant clinical research, a comprehensive reorganization of the system of care across all sectors, and an evidence-driven governance, will we be successful in addressing the challenges brought on by the recent shifts in drug markets.

What is Matter in Aristotle's Hylomorphism?

Aristotle's notion of matter has been seen either as unintelligible, it being some mysterious potential entity that is nothing in its own right, or as simply the notion of an everyday object. The latter is the common assumption in contemporary approaches to hylomorphism, but as has been pointed out, especially by scholars with a background in ancient philosophy, if we conceive of matter as an object itself we cannot account for the unity of hylomorphic substances. Thus, they assume that a hylomorphic substance is an essential unity and matter not a constituent at all. This solution to the problem of unity, however, brings us back to the mysterious notion of matter. For these reasons, I will revisit Aristotle's conception of matter in this paper. I will argue that an understanding of form as a cause of being requires that matter be an independent constituent of the individual substance. However, I agree that the conception of matter as an individual object with an essence makes it impossible to solve the problem of unity. We therefore need to take seriously Aristotle's assertion that matter is nothing in its own right and not an individual. By denying that matter is an individual, Aristotle does not introduce a mysterious entity, nor does he deny that it can be identified independently of the whole; instead, matter for Aristotle is an irreducible plurality, and this explains why it is not an individual and has no essence. I will conclude with some observations on how this gives rise to two competing versions of hylomorphic constitution.

Pairwise genetic meta-analyses between schizophrenia and substance dependence phenotypes reveals novel association signals

Almost half of individuals diagnosed with schizophrenia also present with a substance use disorder, however, little is known about potential molecular mechanisms underlying this comorbidity. We used genetic analyses to enhance our understanding of the molecular overlap between these conditions. Our analyses revealed a positive genetic correlation between schizophrenia and the following dependence phenotypes: alcohol (rg = 0.3685, SE = 0.0768, P = 1.61 × 10−06), cannabis use disorder (rg = 0.309, SE = 0.0332, P = 1.19 × 10−20) and nicotine dependence (rg = 0.1177, SE = 0.0436, P = 7.0 × 10-03), as well as lifetime cannabis use (rg = 0.234, SE = 0.0298, P = 3.73 × 10−15) and drinks per week (rg = 0.0688, SE = 0.0217, P = 1.5 × 10−03). We further constructed latent causal variable (LCV) models to test for partial genetic causality and found evidence for a potential causal relationship between alcohol dependence and schizophrenia (GCP = 0.6, SE = 0.22, P = 1.6 × 10−03). This putative causal effect with schizophrenia was not seen using a continuous phenotype of drinks consumed per week, suggesting that distinct molecular mechanisms underlying dependence are involved in the relationship between alcohol and schizophrenia. To localise the specific genetic overlap between schizophrenia and substance use disorders, we conducted a gene-based and gene-set pairwise meta-analysis between schizophrenia and each of the four individual substance dependence phenotypes in up to 790,806 individuals. These bivariate meta-analyses identified 44 associations not observed in the individual GWAS, including five shared genes that play a key role in early central nervous system development. These genes may play an important role in substance dependence in schizophrenia, and, as a result, could represent important targets for future treatment or early intervention, as comorbid substance dependence is associated with poor treatment adherence, greater chronicity and increased mortality.

Inhibitors of the PI3K/Akt/mTOR Pathway in Prostate Cancer Chemoprevention and Intervention

The phosphatidylinositol 3-kinase (PI3K)/serine-threonine kinase (Akt)/mammalian target of the rapamycin (mTOR)-signaling pathway has been suggested to have connections with the malignant transformation, growth, proliferation, and metastasis of various cancers and solid tumors. Relevant connections between the PI3K/Akt/mTOR pathway, cell survival, and prostate cancer (PC) provide a great therapeutic target for PC prevention or treatment. Recent studies have focused on small-molecule mTOR inhibitors or their usage in coordination with other therapeutics for PC treatment that are currently undergoing clinical testing. In this study, the function of the PI3K/Akt/mTOR pathway, the consequence of its dysregulation, and the development of mTOR inhibitors, either as an individual substance or in combination with other agents, and their clinical implications are discussed. The rationale for targeting the PI3K/Akt/mTOR pathway, and specifically the application and potential utility of natural agents involved in PC treatment is described. In addition to the small-molecule mTOR inhibitors, there are evidence that several natural agents are able to target the PI3K/Akt/mTOR pathway in prostatic neoplasms. These natural mTOR inhibitors can interfere with the PI3K/Akt/mTOR pathway through multiple mechanisms; however, inhibition of Akt and suppression of mTOR 1 activity are two major therapeutic approaches. Combination therapy improves the efficacy of these inhibitors to either suppress the PC progression or circumvent the resistance by cancer cells.

Identifying Patterns of Association and Transition in the Use of Addictive Substances over Five Decades in the United States

Objectives. To conduct weighted itemset analysis to identify patterns of polysubstance use from National Survey on Drug Use and Health (NSDUH) data. Methods. We computed weighted support for every combination of one or more substances, termed as a drugset, used by individuals in the nationally representative NSDUH data over 5 decades (1965-2014). A computational framework for efficient representation and search of patterns of association between drugsets and demographics of user groups over time was developed. A new method for mining rules of transition between pairs of substances used within a time-interval was given. Results. We identified the frequent drugsets from individual substance use data, and determined their representation among different demographic groups at different intervals. An interesting pattern of use of pain relievers and tranquilizers was detected for the age-group of 26-34 years. Transition rules for heroin use in the last decade (2004-2015) of data were mined. Conclusions. Computation of weighted supports over time for every possible drugset in the data and their association with specific user groups produced a framework for generation and testing new and interesting hypotheses. The framework is useful to explore different combinations of substances used among diverse demographic groups including those that have received less attention in this problem.

Standardization of Dry Extract of Pumpkin Pulp Juice, Which Has a Hypolipidemic Effect on the Content of Β-Carotene

The objective is to standardize the content of β-carotene – one of the principal active substances with sufficient hypolipidemic activity in the resultant original product. Search for natural biologically active substances having a hypolipidemic effect is one of the topical questions in modern pharmacy. Most of the research is carried out by means of isolating individual substances from the plant object. We propose to study a native phytocomplex obtained from pumpkin pulp – a dry extract of pumpkin pulp juice. The following materials and methods were used: laboratory-obtained dry extract of pumpkin pulp juice and methods used to determine the qualitative and quantitative content of β-carotene in an individual substance. It was possible to adapt the methods applied to the analysis of an individual substance in relation to the resulting phytocomplex containing both lipophilic and hydrophilic fractions. The rapid method of quantitative determination of β-carotene described in the scientific literature was corrected. An effective alternative method for spectrophotometric determination of β-carotene in the phytocomplex has been developed. Phytocomplexes standardized for the main active substances can be used to obtain effective drugs and biologically active additives with minimal side effects. In addition, the expansion of the search for alternative natural objects containing complexes haaving a hypolipidemic effect is currently relevant. Based on the literature data, in the future it is planned to conduct a pharmacological study to establish the anti-inflammatory effect of the resulting complex on the state of the vascular wall.

Investigating Non-Therapeutic Pharmaceutical Substances for Improving In-Vitro Efficacy of Clindamycin Phosphate Against MRSA and Staphylococcus Epidermidis

The aim of present study was to investigate the effect of pharmaceutical excipients and other active substances on antimicrobial efficacy of standard antibiotic against resistant and susceptible microorganisms. Pharmaceutical excipients (sodium lauryl sulfate [SLS], Tween-80, citric acid, NaOH, NaCl) and active substances (fusidic acid, sorbic acid) were investigated to check in-vitro efficacy and their effect on the efficacy of standard antibiotic. Clindamycin was selected as standard antibiotic. Clindamycin was found to be ineffective against methicillin-resistant Staphylococcus aureus (MRSA). Fusidic acid and SLS showed concentration dependent effect against MRSA. Other tested substances were also ineffective against MRSA, and also failed to improve the susceptibility of MRSA towards clindamycin. The clindamycin + fusidic acid (0.05 µg, 0.1 µg), and clindamycin + SLS (0.5 mg, 1 mg) showed concentration dependent effect on Staphylococcus epidermidis (S. epidermidis). Clindamycin combinations with fusidic acid or SLS showed better inhibition of S. epidermidis, than individual substance. At lower concentration of clindamycin (2 µg), the sorbic acid (25 µg) improves its effectiveness. SLS (0.5 mg, 1 mg) and clindamycin (4 µg, 10 µg) showed almost equal zone of inhibition against S. epidermidis, respectively. Present findings showed that certain pharmaceutical excipients (e.g. SLS) are effective against resistant and susceptible microbes, and suggested that more excipients should be screened for their antimicrobial potential and their ability to improve the efficacy of standard antibiotics.

Creating an ethical culture to support recovery from substance use disorders

There is a long-standing failure to create an ethical culture around substance use disorders (SUDs) or dependence that actively supports people’s recovery efforts. Issues which impede the development of prorecovery environments are complex, but include the far-reaching effects of the social stigma that surrounds SUDs; and the failure to harness relational and social support that allows debates to transcend blaming individual substance users. As part of efforts to create prorecovery environments, it is important to acknowledge that bioethics debate on SUDs is narrow in scope, prioritising topics related to its traditional interests in individual autonomy and novel technologies. As a result, it has not played a significant role in helping to transform the ethical cultures in which substance use recovery takes place. For example, it largely neglects the ethical challenges of developing an empathic, person-centred approach to substance use problems that listens and responds to the voices of clients. It has also participated little in efforts to develop a positive response to reducing the toxic effects of stigma. Indeed, some contributions from the field fan stigma, rather than alleviate it. The aim of this paper is to seed broader ethical debate, in academic literature and lay/professional communities, on how societies should respond to SUDs: steering a course between the critical, but narrow approach of bioethics and the empowerment discourse of evidence-based treatments.

Perceived problems with adolescent online gaming: National differences and correlations with substance use

BackgroundNot much is known about the correlation between gaming problems and substance use across different countries. This paper presents cross-national analyses of different gaming indicators and their relationship to substance use.MethodsBased on data from the 2015 ESPAD study, differences in the relationship between gaming and substance use across 35 countries were analysed using multi-level logistic regression, using substance use as an individual level predictor, economic wealth as a country-level predictor and a combined problem gaming indicator as the outcome.ResultsMulti-level logistic regressions revealed significant correlations between individual substance use and gaming problems, which varied across countries and were moderated by economic wealth. Students who used alcohol, tobacco or cannabis and who lived in high-income countries had a smaller risk of scoring positively on a combined problem gaming indicator than students who used alcohol, tobacco or cannabis and who lived in less prosperous countries.DiscussionDifferent gaming indicators varied substantially across countries, with self-perceived gaming problems being more common in countries with a low prevalence of gaming. Significant cross-level effects demonstrate the need to take the societal context into account when the relationship between problem gaming and substance use is analysed. Prevention measures need to take the fact into account that patterns of substance use among problem gamers vary across countries.