Global Drug Research Articles

The impact of COVID-19 on psychoactive products consumers

Introduction: The emergence of COVID-19 changed the lifestyle of individuals through the appearance of lockdown. This period seems to have potential effect on some health determinants related to behaviors such as drug addiction. Objectives: compare the prevalence and behavior of drug consumers before and during the lockdown. Methods: A cross-sectional study was carried out on 1001 Moroccan addict between April and July 2020, using the international questionnaire: The global drug survey “Special Edition on COVID-19”. Results: before lockdown, tobacco use (80.2%), alcohol (70.9%), cannabis (46.3%). During lockdown: tobacco consumption remains unchanged (80.7%), alcohol and cannabis consumption reduced significantly, respectively (39.6%) and (40.8%). Results show also the weaning of hallucinogens and solvents. The reasons behind these changes were: 39.8% worried about health issues, 26.6% have less opportunities to consume, 23.7% think that lifestyle make it difficult to use, 23.4% think they have less ability to obtain drugs. Conclusions: The lockdown seems to be an opportunity for addicts to reduce drugs consumption. However, setting up support services with targeted interventions is the best chance to decrease psychological stress and avoid the consequences of this reduction. Keywords: COVID-19, lockdown, drug consumption, online survey.

DOP88 Long-term real-world data of ustekinumab in Crohn’s Disease – the Stockholm ustekinumab study – STOCUSTE

Abstract Background Ustekinumab (UST), an anti-interleukin-12/23 antibody, has successfully been introduced in the treatment of IBD, mainly in patients failing anti-TNF-agents. The STOCUSTE study includes IBD patients treated with UST at four teaching hospitals in Stockholm to provide long-term follow-up data. Here, we report the outcome in Crohn’s disease over the first 12 months. Methods This retrospective study includes patients diagnosed with Crohn’s disease and treated with UST who were followed until withdrawal of treatment for any reason, or until end of study, July 31, 2021. Disease activity (Harvey-Bradshaw Index (HBI); Physician Global Assessment (PGA), laboratory parameters and drug persistence were assessed. The primary outcome was remission (HBI ≤4; PGA = 0) and response (decrease HBI ≥3; PGA ≥1 from baseline) at 3 and 12 months, respectively. Results 120 patients, 61 women (51%), with a median age of 27 (IQR 27) at start of UST were included. All patients had luminal disease and 19 (16%) also fistulizing disease. 109 (91%) had failed ≥1 and 59 (49%) ≥2 anti-TNF drugs. In addition, 50 patients (42%) failed vedolizumab. At inclusion, 106 (88%) had active disease; 40 (33%) were on corticosteroid treatment and 22 (18%) on thiopurines. The persistence on UST was high, 93% at 3 months and 56% at 12 months. Of patients on UST at 3 months, 38% were in remission, and, at 12 months, 53%. An additional 26% were in response at 12 months. Of the 40 patients initially on corticosteroids, 17 (43%) and 28 (70%) had stopped steroids at 3 and 12 months, respectively. The median faecal calprotectin level declined from 272 (90–1763) at baseline to 75 (49–99) µg/g at 3 months (p<0.01). There was a slight decrease in CRP over 12 months, from 3 (2–12) to 1 (1–2) mg/l, together with increases in haemoglobin and serum albumin (n.s). Withdrawal from treatment during the first 12 months was 44% (53/120), mainly due to persisting disease activity. Four patients were withdrawn due to adverse events, three needed bowel surgery, two had malignancy and one patient suffered from systemic infection. Conclusion In this group of difficult-to-treat patients with Crohn’s disease, UST was shown to be effective in the majority, with high drug persistence at 12 months in combination with a favorable safety profile.

Study of Antiviral Activity of Some Pyrimidine Ring Containing Compounds against COVID-19 Based on Molecular Docking and Quantum Chemical Calculations by DFT Method

The novel coronavirus, COVID-19, caused by SARS-CoV-2, is a global health pandemic and currently no specific drug is available to prevent or cure this novel coronavirus (SARS-CoV-2) disease. We have been put forth five pyrimidine ring containing compounds as potential antiviral candidatures for the treatment of COVID-19 diseases based on quantum chemical properties predicted by molecular docking study and DFT calculations at the level of B3LYP method with 6-311++G (d,p) basis set. Our findings were also compared to remdesivir, a control ligand. Blind docking with the main protease revealed that the ligands preferentially bind to the active site. Interestingly, all of the ligands exhibited low binding free energies i.e., strong inhibitory interactions with the active sites of the main protease. Ligand L1 was one of them, which revealed significantly low binding energies (-8.8 kcal/mol) with SARS-CoV-2 Mpro. These binding energies are even lower than those of remdesivir’s potent active metabolite. All of the drugs interact with the key active site residues, including His41 and Cys145. These findings are also strongly supported by quantum chemical investigations.

Global Drug Diffusion and Innovation with the Medicines Patent Pool

Global Drug Diffusion and Innovation with the Medicines Patent Pool

A review of manufacturing techniques for subcutaneous drug delivery implants

The global drug delivery implant market is growing at an unprecedented rate owing to the implant’s advantages over traditional drug delivery methods. While the scientific literature extensively covers the medical aspects of these devices, insufficient attention has been paid to their manufacture. In the present work, the issues surrounding their manufacture will be explored on the example of typical subcutaneous implant topologies. The various drug delivery implant products currently in use will be explored first along with a review of the materials used and of their manufacturing properties. An account of the manufacturing processes used for the implant’s components and their assembly follows.

Programme costs of longer and shorter tuberculosis drug regimens and drug import: a modelling study for Karakalpakstan, Uzbekistan.

BackgroundThe introduction of new and often shorter tuberculosis (TB) drug regimens affects the cost of TB programmes.MethodsWe modelled drug purchase and import costs for 20-month, 9-month and 4- to 6-month TB drug regimens based on 2016–2020 treatment numbers from a TB programme in Karakalpakstan, Uzbekistan, and 2021 Global Drug Facility prices.ResultsOn average, 2225±374 (±sd) people per year started TB treatment, 30±2.1% of whom were diagnosed with drug-resistant forms of TB. Transitioning from a 6-month to a 4-month drug-susceptible (DS)-TB drug regimen increased the TB programme's annual DS-TB drug cost from USD 65±10 K to USD 357±56 K (p<0.001) and its drug import cost from USD 6.4±1.0 K to USD 9.3±1.4 K (p=0.008). Transitioning from a 20-month all-oral multidrug-resistant (MDR)-TB drug regimen to a 9-month MDR-TB drug regimen with an injectable antibiotic decreased the TB programme's annual MDR-TB drug cost from USD 1336±265 K to USD 266±53 K (p<0.001) and had no significant effect on the drug import cost (USD 28±5.5 K versus USD 27±5.4 K; p=0.88). Purchasing (USD 577±114 K) and importing (USD 3.0±0.59 K) the 6-month all-oral MDR-TB drug regimen cost more than procuring the 9-month MDR-TB drug regimen but less than the 20-month all-oral MDR-TB drug regimen (both p<0.01).ConclusionIntroducing new and shorter TB drug regimens could increase the cost of TB programmes with low drug resistance rates and decrease the cost of TB programmes with high drug resistance rates.

Exploring Televend, an innovative combination of cryptomarket and messaging app technologies for trading prohibited drugs

BackgroundDigital technologies continue to facilitate drug trading. Televend was an innovative combination of multiple digital technologies, with its backend hosted on the darknet, while purchases were made through the messaging app Telegram. Here, we provide an initial characterisation of this nascent market. MethodsTelevend and White House Market (WHM) were scraped (Jun–Jul 2021) and a global cross-sectional web survey of 15,513 drug buyers (Global Drug Survey; GDS) was conducted (Dec 2020–Mar 2021). ResultsTelevend was 10% of the size of WHM, the largest drug cryptomarket (4515/44,830 listings per week). Both markets predominantly contained drug-related listings covering similar drug categories, with similar country of origin and destination. Very few GDS drug buyers reported use of Televend (0.73%). Most Televend buyers (68/114) reported buying cannabis, then cocaine (20), MDMA (17), and LSD (12). The Televend and darknet groups had similar demographic and drug use characteristics; whereas compared with app purchasers, older age increased the odds of Televend use (aRRR = 1.06, p < .001), identifying as a cisgender woman decreased the odds (aRRR=0.43, p = .004), while last-year use of a greater number of drug types (aRRR = 1.20, p < .001) and less frequent drug use (aRRR=0.998, p = .032) increased the odds of Televend purchase. ConclusionsWhile smaller, Televend was not noticeably different in its drug offerings to its largest cryptomarket competitor, and it attracted a cohort more similar to darknet than to app drug buyers. Future Televend-like markets may be attractive to people with less specialised technical knowledge who already routinely scroll through social media feeds.

The global impact of COVID-19 on drug purchases: A cross-sectional time series analysis

BackgroundThe drug supply chain is global and at risk of disruption and subsequent drug shortages, especially during unanticipated events. ObjectiveOur objective was to determine the impact of coronavirus disease 2019 (COVID-19) on drug purchases overall, by class, and for specific countries. MethodsA cross-sectional time series analysis of country-level drug purchase data from August 2014 to August 2020 from IQVIA MIDAS was conducted. Standardized units per 100 population and percentage increase in units purchased were assessed from 68 countries and jurisdictions in March 2020 (when the World Health Organization declared COVID-19 a pandemic). Analyses were compared by United Nations development status and drug class. Autoregressive integrated moving average models tested the significance of changes in purchasing trends. ResultsBefore COVID-19, standardized medication units per 100 population ranged from 3990 to 4760 monthly. In March 2020, there was a global 15% increase in units of drugs purchased to 5309.3 units per 100 population compared with the previous year; the increase was greater in developed countries (18.5%; P < 0.001) than in developing countries (12.8%; P < 0.0001). After the increase in March 2020, there was a correction in the global purchase rate decreasing by 4.7% (April to August 2020 rate, 21,334.6/100 population; P < 0.001). Globally, we observed high purchasing rates and large changes for respiratory medicines such as inhalers and systemic adrenergic drugs (March 2020 rate, 892.7/100 population; change from 2019, 28.5%; P < 0.001). Purchases for topical dermatologic products also increased substantially (42.2%), although at lower absolute rates (610.0/100 population in March 2020; P < 0.0001). Interestingly, purchases for systemic anti-infective agents (including antiviral drugs) increased in developing countries (11.3%; P < 0.001), but decreased in developed countries (1.0%; P = 0.06). ConclusionWe observed evidence of global drug stockpiling in the early months of the COVID-19 pandemic, especially among developed countries. Actions toward equitable distribution of medicines through a resilient drug supply chain should be taken to increase global response to future unanticipated events, such as pandemics.

Impacts of changes in alcohol consumption patterns during the first 2020 COVID-19 restrictions for people with and without mental health and neurodevelopmental conditions: A cross sectional study in 13 countries.

BackgroundThe initial period of COVID-19-related restrictions affected substance use in some population groups. We explored how changes in alcohol use at the beginning of the pandemic impacted the health and wellbeing of people with and without mental health and neurodevelopmental conditions (MHDCs).MethodsData came from the Global Drug Survey Special Edition on COVID-19 conducted in May-June 2020. Measured were; changes in drinking compared to February 2020 (pre-COVID-19 restrictions), reasons for changes, and impact on physical health, mental health, relationships, finances, work/study, and enjoyment. This study included 38,141 respondents (median age = 32 IQR 25-45; 51.9% cis man; 47.8% cis woman; 1.2% trans/non-binary; 30.2% with MHDCs e.g. depression 20.0%, anxiety 16.3%, ADHD 3.8%, PTSD 3.3%).ResultsA third (35.3%) of respondents with MHDCs and 17.8% without MHDCs indicated that increased drinking affected their mental health negatively (p<.001); 44.2% of respondents with MHDCS compared to 32.6% without MHDCs said it affected their physical health negatively (p<.001). Reduced drinking was associated with better mental health among a fifth (21.1%) of respondents with MHDCS and 14.4% without MHDCs (p<.001). Age, relationship status, living arrangements, employment, coping and distress were significant predictors of increases in drinking.ConclusionAmong people with MHDCS, reduced alcohol consumption was associated with better mental health, while the negative effects of increased drinking were more pronounced when compared to people without MHDCS. When supporting people in reducing alcohol consumption during uncertain times, people with MHDCS may need additional support, alongside those experiencing greater levels of distress.

Cost-effectiveness of bedaquiline, pretomanid and linezolid for treatment of extensively drug-resistant tuberculosis in South Africa, Georgia and the Philippines

ObjectivesPatients with highly resistant tuberculosis have few treatment options. Bedaquiline, pretomanid and linezolid regimen (BPaL) is a new regimen shown to have favourable outcomes after six months. We present an...

Reduced Zeb1 Expression in Prostate Cancer Cells Leads to an Aggressive Partial-EMT Phenotype Associated with Altered Global Methylation Patterns.

Prostate cancer is the most common cancer in American men and the second leading cause of cancer-related death. Most of these deaths are associated with metastasis, a process involving the epithelial-to-mesenchymal (EMT) transition. Furthermore, growing evidence suggests that partial-EMT (p-EMT) may lead to more aggressive disease than complete EMT. In this study, the EMT-inducing transcription factor Zeb1 was knocked down in mesenchymal PC-3 prostate cancer cells (Zeb1KD) and resulting changes in cellular phenotype were assessed using protein and RNA analysis, invasion and migration assays, cell morphology assays, and DNA methylation chip analysis. Inducible knockdown of Zeb1 resulted in a p-EMT phenotype including co-expression of epithelial and mesenchymal markers, a mixed epithelial/mesenchymal morphology, increased invasion and migration, and enhanced expression of p-EMT markers relative to PC-3 mesenchymal controls (p ≤ 0.05). Treatment of Zeb1KD cells with the global de-methylating drug 5-azacytidine (5-aza) mitigated the observed aggressive p-EMT phenotype (p ≤ 0.05). DNA methylation chip analysis revealed 10 potential targets for identifying and/or targeting aggressive p-EMT prostate cancer in the future. These findings provide a framework to enhance prognostic and/or therapeutic options for aggressive prostate cancer in the future by identifying new p-EMT biomarkers to classify patients with aggressive disease who may benefit from 5-aza treatment.

Surveys/Research Exploring Japanese Phase I Studies in Global Drug Development: Are They Necessary Prior to Joining Global Clinical Trials?

Surveys/Research Exploring Japanese Phase I Studies in Global Drug Development: Are They Necessary Prior to Joining Global Clinical Trials?

Colombia, the Drug Wars and the Politics of Drug Policy Displacement – from La Violencia to UNGASS 2016

This article breaks new conceptual ground by questioning orthodox interpretations of nation state agency in the global drug wars. Specifically, it challenges the David vs. Goliath conception of Colombia as a passive, client state simply abiding to the United States’ hegemonic war on drugs. It provides the first published analysis of Colombia’s leadership during the UN General Assembly Special Session on Drugs (UNGASS) in 2016. It argues that the UN served as a useful forum for Colombia’s displacement of state building dilemmas, including drug control, and that Bogota utilised the UN as a proxy negotiating mechanism with the US and other international donors.

Global Biosimilar Drug Development: Any Chance for Consolidation after 15 Years of Positive Regulatory Experience?

Global Biosimilar Drug Development: Any Chance for Consolidation after 15 Years of Positive Regulatory Experience?

Nitrosamine impurities: from raw materials to final drug product.

Nitrosamine impurities: from raw materials to final drug product.

The Age of Intoxication: Origins of the Global Drug Trade by Benjamin Breen

<i>The Age of Intoxication: Origins of the Global Drug Trade</i> by Benjamin Breen

A simple and isocratic protein-based high performance liquid chromatography method for the enantioseparation of amphetamine derivatives

New amphetamine derivatives, a substance class belonging to the New Psychoactive Substances (NPS), have fundamentally changed the global drug market during the last years. Also known as “legal highs” they are sold under various names like "bath salts", "air fresheners" and so forth. Structures of well-known illicit drugs such as amphetamine, methamphetamine and 3,4-methylenedioxyamphetamine are slightly modified to circumvent law and samples are traded worldwide via various internet shops. Many of these new derivatives possess a chiral centre and the pharmacological differences of the two enantiomers are not yet investigated for many of them. This makes the continuous development of analytical methods for their chiral separation crucial.The aim of this study was to develop a simple, isocratic HPLC-UV method for enantioseparation and to test this method on a set of 26 amphetamine derivatives, including latest products on the drug market. A Daicel Chiralpak® CBH 150×3.0 mm column (5 µm particle size) served for chiral separation. The influence of the organic modifier and type, molarity and pH of the buffer on separation results was investigated. UV detection was performed at 210 and 254 nm. As final mobile phase, a mixture of 5 mM sodium dihydrogen phosphate buffer (pH = 6.9) / methanol (85 : 15 v/v) was chosen. Under these conditions, all 26 tested amphetamines were separated successfully into their enantiomers. Thus, the results showed that all analytes were traded as racemic mixtures.

Structure–Activity Relationship of Novel Second-Generation Synthetic Cathinones: Mechanism of Action, Locomotion, Reward, and Immediate-Early Genes

Several new synthetic cathinones, which mimic the effect of classical psychostimulants such as cocaine or MDMA, have appeared in the global illicit drug market in the last decades. In fact, the illicit drug market is continually evolving by constantly adding small modifications to the common chemical structure of synthetic cathinones. Thus, the aim of this study was to investigate the in vitro and in vivo structure–activity relationship (SAR) of six novel synthetic cathinones currently popular as recreational drugs, pentedrone, pentylone, N-ethyl-pentedrone (NEPD), N-ethyl-pentylone (NEP), 4-methyl-pentedrone (4-MPD), and 4-methyl-ethylaminopentedrone (4-MeAP), which structurally differ in the absence or presence of different aromatic substituents and in their amino terminal group. Human embryonic kidney (HEK293) cells expressing the human isoforms of SERT and DAT were used for the uptake inhibition and release assays. Moreover, Swiss CD-1 mice were used to investigate the psychostimulant effect, rewarding properties (3, 10, and 30 mg/kg, i.p.), and the induction of immediate-early genes (IEGs), such as Arc and c-fos in the dorsal striatum (DS) and ventral striatum (VS) as well as bdnf in the medial prefrontal cortex (mPFC), of the test compounds. Our results demonstrated that all tested synthetic cathinones are potent dopamine (DA) uptake inhibitors, especially the N-ethyl analogs, while the ring-substituted cathinones tested showed higher potency as SERT inhibitors than their no ring-substituted analogs. Moreover, unlike NEP, the remaining test compounds showed clear “hybrid” properties, acting as DAT blockers but SERT substrates. Regarding the locomotion, NEP and NEPD were more efficacious (10 mg/kg) than their N-methyl analogs, which correlates with their higher potency inhibiting the DAT and an overexpression of Arc levels in the DS and VS. Furthermore, all compounds tested induced an increase in c-fos expression in the DS, except for 4-MPD, the least effective compound in inducing hyperlocomotion. Moreover, NEP induced an up-regulation of bdnf in the mPFC that correlates with its 5-HTergic properties. Finally, the present study demonstrated for the first time that NEP, 4-MPD, and 4-MeAP induce reward in mice. Altogether, this study provides valuable information about the mechanism of action and psychostimulant and rewarding properties as well as changes in the expression of IEGs related to addiction induced by novel second-generation synthetic cathinones.

Conditions for maintenance of hepatocyte differentiation and function in 3D cultures

SummarySpheroid cultures of primary human hepatocytes (PHH) are used in studies of hepatic drug metabolism and toxicity. The cultures are maintained under different conditions, with possible confounding results. We performed an in-depth analysis of the influence of various culture conditions to find the optimal conditions for the maintenance of an in vivo like phenotype. The formation, protein expression, and function of PHH spheroids were followed for three weeks in a high-throughput 384-well format. Medium composition affected spheroid histology, global proteome profile, drug metabolism and drug-induced toxicity. No epithelial-mesenchymal transition was observed. Media with fasting glucose and insulin levels gave spheroids with phenotypes closest to normal PHH. The most expensive medium resulted in PHH features most divergent from that of native PHH. Our results provide a protocol for culture of healthy PHH with maintained function - a prerequisite for studies of hepatocyte homeostasis and more reproducible hepatocyte research.

To get vaccinated or not? An investigation of the relationship of linguistic assignment of agency and the intention to obtain the COVID-19 vaccine

ABSTRACT Just nine months after the World Health Organization declared the outbreak of SARS-CoV-2 a global pandemic, the Food and Drug Administration granted emergency use authorization (EUA) for the Pfizer-BioNtech and Moderna vaccines in December 2020, followed by EUA for the Johnson & Johnson vaccine in February 2021. Although achieving herd immunity through vaccinations is the greatest hope for ending the pandemic, the COVID-19 vaccination effort has been plagued by misinformation and mistrust. Given the urgency to vaccinate the population, public health officials must construct messages that encourage individuals to obtain the COVID-19 vaccine. The current study examines the impact of linguistic assignment of agency on an individual’s desire to get vaccinated. Guided by the EPPM, participants (N= 296) were randomly assigned to receive either a virus agentic message or a human agentic message. The researchers discovered that the virus agentic message resulted in a greater intention to obtain the vaccine. Further, participants who received the virus agentic message reported a stronger sense of perceived self-efficacy and perceived susceptibility. Additionally, participants who perceived the societal reaction to the pandemic to be appropriate, as well as those who knew at least one person who had died from the virus, were more likely to express an intention to get vaccinated.