SciCombinator

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Concept: Drug

314

Illegal drug use continues to be a major threat to community health and safety. We used international drug surveillance databases to assess the relationship between multiple long-term estimates of illegal drug price and purity.

Concepts: Drug, Drug addiction, Heroin, Occupational safety and health, MDMA, Illegal drug trade, Single Convention on Narcotic Drugs

279

In March and October 2015, the Drug Enforcement Administration (DEA) and CDC, respectively, issued nationwide alerts identifying illicitly manufactured fentanyl (IMF) as a threat to public health and safety (1,2). IMF is unlawfully produced fentanyl, obtained through illicit drug markets, includes fentanyl analogs, and is commonly mixed with or sold as heroin (1,3,4). Starting in 2013, the production and distribution of IMF increased to unprecedented levels, fueled by increases in the global supply, processing, and distribution of fentanyl and fentanyl-precursor chemicals by criminal organizations (3). Fentanyl is a synthetic opioid 50-100 times more potent than morphine (2).* Multiple states have reported increases in fentanyl-involved overdose (poisoning) deaths (fentanyl deaths) (2). This report examined the number of drug products obtained by law enforcement that tested positive for fentanyl (fentanyl submissions) and synthetic opioid-involved deaths other than methadone (synthetic opioid deaths), which include fentanyl deaths and deaths involving other synthetic opioids (e.g., tramadol). Fentanyl deaths are not reported separately in national data. Analyses also were conducted on data from 27 states(†) with consistent death certificate reporting of the drugs involved in overdoses. Nationally, the number of fentanyl submissions and synthetic opioid deaths increased by 426% and 79%, respectively, during 2013-2014; among the 27 analyzed states, fentanyl submission increases were strongly correlated with increases in synthetic opioid deaths. Changes in fentanyl submissions and synthetic opioid deaths were not correlated with changes in fentanyl prescribing rates, and increases in fentanyl submissions and synthetic opioid deaths were primarily concentrated in eight states (high-burden states). Reports from six of the eight high-burden states indicated that fentanyl-involved overdose deaths were primarily driving increases in synthetic opioid deaths. Increases in synthetic opioid deaths among high-burden states disproportionately involved persons aged 15-44 years and males, a pattern consistent with previously documented IMF-involved deaths (5). These findings, combined with the approximate doubling in fentanyl submissions during 2014-2015 (from 5,343 to 13,882) (6), underscore the urgent need for a collaborative public health and law enforcement response.

Concepts: Drug, Opioid, Morphine, Drug addiction, Heroin, Naloxone, Opioids, Drug Enforcement Administration

259

The US Food and Drug Administration Amendments Act requires results from clinical trials of Food and Drug Administration-approved drugs to be posted at ClinicalTrials.gov within 1 y after trial completion. We compared the timing and completeness of results of drug trials posted at ClinicalTrials.gov and published in journals.

Concepts: Pharmacology, Clinical trial, Drug, ClinicalTrials.gov, Drugs, Food and Drug Administration

234

To describe the incidence of recorded mental illness and challenging behaviour in people with intellectual disability in UK primary care and to explore the prescription of psychotropic drugs in this group.

Concepts: Epidemiology, Drug, Opioid, Psychoactive drug, Ketamine, Recreational drug use

199

Food and Drug Administration (FDA) rules are often forged in crisis. After the 1937 sulfanilamide disaster that killed more than 100 people, Congress passed the Food, Drug, and Cosmetic Act (FDCA), requiring drugs to be safe and properly labeled. In 1962, a requirement was introduced for proof of drug efficacy through “adequate and well-controlled investigations,” partly in response to the thalidomide tragedy. Rules protecting human-research subjects owe a debt to Tuskegee and Nuremberg. Sometimes it takes a disaster to spur the adoption of appropriate regulation. Today, compounding pharmacies are at the center of a controversy after a rare outbreak of . . .

Concepts: Pharmacology, Drug, Pharmaceutical drug, Food and Drug Administration, Pure Food and Drug Act, Federal Food, Drug, and Cosmetic Act, Compounding, Drug Efficacy Study Implementation

188

Open source drug discovery offers potential for developing new and inexpensive drugs to combat diseases that disproportionally affect the poor. The concept borrows two principle aspects from open source computing (i.e., collaboration and open access) and applies them to pharmaceutical innovation. By opening a project to external contributors, its research capacity may increase significantly. To date there are only a handful of open source R&D projects focusing on neglected diseases. We wanted to learn from these first movers, their successes and failures, in order to generate a better understanding of how a much-discussed theoretical concept works in practice and may be implemented.

Concepts: Scientific method, Pharmacology, Drug, Pharmaceutical drug, Knowledge, Open source, Open content, Concepts

176

Preliminary estimates of U.S. drug overdose deaths exceeded 60,000 in 2016 and were partially driven by a fivefold increase in overdose deaths involving synthetic opioids (excluding methadone), from 3,105 in 2013 to approximately 20,000 in 2016 (1,2). Illicitly manufactured fentanyl, a synthetic opioid 50-100 times more potent than morphine, is primarily responsible for this rapid increase (3,4). In addition, fentanyl analogs such as acetylfentanyl, furanylfentanyl, and carfentanil are being detected increasingly in overdose deaths (5,6) and the illicit opioid drug supply (7). Carfentanil is estimated to be 10,000 times more potent than morphine (8). Estimates of the potency of acetylfentanyl and furanylfentanyl vary but suggest that they are less potent than fentanyl (9). Estimates of relative potency have some uncertainty because illicit fentanyl analog potency has not been evaluated in humans. This report describes opioid overdose deaths during July-December 2016 that tested positive for fentanyl, fentanyl analogs, or U-47700, an illicit synthetic opioid, in 10 states participating in CDC’s Enhanced State Opioid Overdose Surveillance (ESOOS) program.* Fentanyl analogs are similar in chemical structure to fentanyl but not routinely detected because specialized toxicology testing is required. Fentanyl was detected in at least half of opioid overdose deaths in seven of 10 states, and 57% of fentanyl-involved deaths also tested positive for other illicit drugs, such as heroin. Fentanyl analogs were present in >10% of opioid overdose deaths in four states, with carfentanil, furanylfentanyl, and acetylfentanyl identified most frequently. Expanded surveillance for opioid overdoses, including testing for fentanyl and fentanyl analogs, assists in tracking the rapidly changing illicit opioid market and informing innovative interventions designed to reduce opioid overdose deaths.

Concepts: Drug, Opioid, Morphine, Drug addiction, Heroin, Naloxone, Opioids, Drug overdose

173

The currently used anthelmintic drugs, in single oral application, have low efficacy against Trichuris trichiura infection, and hence novel anthelmintic drugs are needed. Nitazoxanide has been suggested as potential drug candidate.

Concepts: Pharmacology, Randomized controlled trial, Drug, Pharmaceutical industry, Clinical research, Whipworm, Anthelmintics, Anthelmintic

168

Angioedema is the end result of deep dermal, subcutaneous and/or mucosal swelling, and is potentially a life-threatening condition in cases where the pharynx or larynx is involved. Drug-induced angioedema has been reported to occur in response to a wide range of drugs and vaccines. Drug-induced angioedema, like other cutaneous drug reactions, has been reported to be most frequently elicited by beta-lactam antibiotics and non-steroidal anti-inflammatory drugs, although reliable data from epidemiologic studies are scarce. Recent reports suggested an increasing role of angiotensin-converting enzyme inhibitors (ACEIs) in the causation of life-threatening angioedema. ACEI-related angioedema is never accompanied by urticaria and occurs via a kinin-dependent mechanism. ACEI-related angioedema not only can start years after beginning the treatment, but it can then recur irregularly while under that treatment. Furthermore, allergy tests are unreliable for the diagnosis of ACEI-related angioedema, and so the relationship between angioedema and ACEIs is often missed and consequently quite underestimated. Accordingly, better understanding of the kinin-dependent mechanism, which is particular to angioedema, is necessary for the appropriate management of drug-induced angioedema.

Concepts: Pharmacology, Drug, Non-steroidal anti-inflammatory drug, Anti-inflammatory, Drug addiction, Penicillin, Angioedema, ACE inhibitor

161

Phosphatidylinositol 4-kinase type IIIα (PI4KA) is a host factor essential for Hepatitis C virus (HCV) replication and hence is a target for drug development. PI4KA has also been linked to ER-exit sites and generation of plasma membrane phosphoinositides. Here we developed highly specific and potent inhibitors of PI4KA and conditional knockout mice to study the importance of this enzyme in vitro and in vivo. Our studies showed that PI4KA is essential for the maintenance of plasma membrane PtdIns(4,5)P2 pools but only during strong stimulation of receptors coupled to PLC activation. Pharmacological blockade of PI4KA in adult animals leads to sudden death closely correlating with the drugs ability to induce PtdIns(4,5)P2 depletion after agonist stimulation. Genetic inactivation of PI4KA also leads to death, however, the cause in this case is due to severe intestinal necrosis. These studies highlight the risks of targeting PI4KA as an anti HCV strategy and also point to important distinctions between genetic and pharmacological studies when selecting host factors as putative therapeutic targets.

Concepts: Protein, Pharmacology, Drug, In vivo, In vitro, Hepatitis C, Hepatitis C virus, Target Corporation