Integrated Approach for Synthetic Cathinone Drug Prioritization and Risk Assessment: In Silico Approach and Sub-Chronic Studies in Daphnia magna and Tetrahymena thermophila.

Synthetic cathinones (SC) are drugs of abuse that have been reported in wastewaters and rivers raising concern about potential hazards to non-target organisms. In this work, 44 SC were selected for in silico studies, and a group of five emerging SC was prioritized for further in vivo ecotoxicity studies: buphedrone (BPD), 3,4-dimethylmethcathinone (3,4-DMMC), butylone (BTL), 3-methylmethcathinone (3-MMC), and 3,4-methylenedioxypyrovalerone (MDPV). In vivo short-term exposures were performed with the protozoan Tetrahymena thermophila (28 h growth inhibition assay) and the microcrustacean Daphnia magna by checking different indicators of toxicity across life stage (8 days sublethal assay at 10.00 µg L-1). The in silico approaches predicted a higher toxic potential of MDPV and lower toxicity of BTL to the model organisms (green algae, protozoan, daphnia, and fish), regarding the selected SC for the in vivo experiments. The in vivo assays showed protozoan growth inhibition with MDPV > BPD > 3,4-DMMC, whereas no effects were observed for BTL and stimulation of growth was observed for 3-MMC. For daphnia, the responses were dependent on the substance and life stage. Briefly, all five SC interfered with the morphophysiological parameters of juveniles and/or adults. Changes in swimming behavior were observed for BPD and 3,4-DMMC, and reproductive parameters were affected by MDPV. Oxidative stress and changes in enzymatic activities were noted except for 3-MMC. Overall, the in silico data agreed with the in vivo protozoan experiments except for 3-MMC, whereas daphnia in vivo experiments showed that at sublethal concentrations, all selected SC interfered with different endpoints. This study shows the importance to assess SC ecotoxicity as it can distress aquatic species and interfere with food web ecology and ecosystem balance.

New trends in synthetic drugs and natural products targeting 20S proteasomes in cancers.

Cancer is a global health challenge that remains to be a field of extensive research aiming to find new anticancer therapeutics. The 20S proteasome complex is one of the targets of anticancerdrugs, as it is correlated with several cancer types. Herein, we aim to discuss the 20S proteasome subunits and investigatethe currently studied proteasome inhibitors targeting the catalytically active proteasome subunits. In this review, we summarize the proteindegradation mechanism of the 20S proteasome complex and compareit with the 26S proteasome complex. Afterwards, the localization of the 20S proteasome is summarized as well as its use as a diagnosticandprognostic marker. The FDA-approved proteasome inhibitors (PIs) under clinical trials are summarized and their current limited use in solid tumors is also reviewed in addition to the expression of theß5 subunit in differentcell lines. The review discusses in-silico analysis of the active subunit of the 20S proteasome complex. For development of new proteasome inhibitor drugs, the natural products inhibiting the 20S proteasome are summarized, as well as novel methodologies and challenges for the natural product discovery and current information about the biosynthetic gene clusters encoding them. We herein briefly summarize some resistancemechanismsto the proteasomeinhibitors. Additionally, we focus on the three main classes of proteasome inhibitors: 1] boronic acid, 2] beta-lactone and 3] epoxide inhibitor classes, as well as other PI classes, and their IC50 values and their structure-activity relationship (SAR). Lastly,we summarize several future prospects of developing new proteasome inhibitors towards the treatment of tumors, especially solid tumors.

Bis(Benzofuran-1,3-N,N-heterocycle)s as Symmetric and Synthetic Drug Leads against Yellow Fever Virus.

The yellow fever virus (YFV) is an emerging RNA virus and has caused large outbreaks in Africa and Central and South America. The virus is often transmitted through infected mosquitoes and spreads from area to area because of international travel. Being an acute viral hemorrhagic disease, yellow fever can be prevented by an effective, safe, and reliable vaccine, but not be eliminated. Currently, there is no antiviral drug available for its cure. Thus, two series of novel bis(benzofuran−1,3-imidazolidin-4-one)s and bis(benzofuran−1,3-benzimidazole)s were designed and synthesized for the development of anti-YFV lead candidates. Among 23 new bis-conjugated compounds, 4 of them inhibited YFV strain 17D (Stamaril) on Huh-7 cells in the cytopathic effect reduction assays. These conjugates exhibited the most compelling efficacy and selectivity with an EC50 of <3.54 µM and SI of >15.3. The results are valuable for the development of novel antiviral drug leads against emerging diseases.

Antiapoptotic and antioxidative efficacy of rhizomes of Curcuma amada on the management of diabetes-induced male infertility in albino rat: An effective fraction selection study.

Men with diabetes have negative effects on reproduction that causes sexual dysfunction. Medicinal plants are non-toxic and much safer than synthetic drugs because regular use of synthetic drugs shows long-term side effects. Curcuma amada (Roxb) is a medicinal plant used in Ayurveda and Unani medicinal systems in India. The goal of this study is to rummage the potential efficiency of the most potent solvent fraction of effective extract of hydro-methanol 60:40 of C. amada rhizome on male gonadal hypofunction in streptozotocin-induced diabetic rat. Diabetes-induced testicular hypofunction was evaluated by glycemic, spermiological, biochemical, genomic, flow cytometric, and histology of testicular tissue. The n-hexane, chloroform, ethyl-acetate, and n-butanol solvent fractions of the said extract were administrated for 4 weeks at 10 mg dose/100 g body weight/day. Among all the used fractions, the ethyl-acetate solvent fraction-treated group showed maximum recovery in serum insulin (177.42%), sperm count (92.84%), sperm motility (97.15%), and serum testosterone (164.33%). The diabetic rats treated with ethyl-acetate solvent fraction also exhibited the maximum resettlement in flow cytometric analysis of sperm viability (55.84%) and sperm mitochondrial integrity (149.79%), gene expression patterns of key markers for androgenesis (Δ5, 3ß-HSD 87.50%, and 17ß-HSD 74.66%) and apoptosis (Bax 44.63%, Bcl-2 54.03%, and Caspase-3 35.77%) along with testicular histology. The ethyl-acetate fraction contains alkaloids, flavonoids, and polyphenols where all of these components are not present in other fractions, may be the most effective cause for the recovery of diabetes-linked oxidative stress-mediated testicular hypofunctions. PRACTICAL APPLICATIONS: Nowadays worldwide, the use of synthetic drugs are reduced due to their toxic effect. At present, synthetic drugs are replaced by several herbal drugs, the natural source of medicine which has many therapeutic values. C. amada has strong antioxidant activity due to the presence of bio-active compound(s) that can able to manage streptozotocin-induced diabetes linked to oxidative damage of male gonadal organs. Therefore, these bio-active compound(s)-containing said medicinal plant may use as a good source of antioxidative food in the food industry as nutraceuticals and in pharmaceutical industries for the development of the herbal drug to manage diabetes-linked male gonadal hypofunctions. At present, WHO also gives emphasis for developing one drug-multi-disease therapy. From such a viewpoint, this active fraction-containing phytomolecules may have corrective efficacy against diabetes as well as oxidative stress-linked testicular complications.

Anti-Cancer Activity of Gedunin by Induction of Apoptosis in Human Gastric Cancer AGS Cells.

Currently, gastric cancer is considered one of the major causes of high mortality and morbidity worldwide. Recent advances in therapeutics, clinical treatment, staging procedures, and imaging techniques are high, yet the prevalence of gastric cancer has not been reduced. Usage of the synthetic drug has many side effects that can lead to other ailments. Gedunin, a phytochemical derived from Azadirachta indica (neem tree), exhibits several pharmacological activities including antitumor, anti-inflammatory, antiulcer, antipyretics, antibacterial, antifungal, anti-diabetic, and antimalarial properties. In the current investigation, the effect of gedunin on the cell viability; reactive oxygen species (ROS) generation by DCFH-DA staining; mitochondrial membrane potential (MMP) by Rh-123 staining; apoptosis by AO/EtBr staining; cell migration and wound healing ability by wound scratch assay; and Bcl-2, Bax, caspase-3, and caspase-9 by ELISA techniques were analyzed in the AGS cells. The treatment with gedunin effectively inhibited the cell viability with IC50 = 20µM, increased the ROS generation, and triggered the apoptosis in AGS cells. The gedunin-treated AGS cells also demonstrated a decreased MMP status. The increment in the ROS generation leads to oxidative stress which in turn induce the apoptosis. The activity of Bax gene was upregulated and the activity of Bcl-2 gene was down-regulated in the AGS cells after the treatment with gedunin. In the AGS cells treated with gedunin, the caspase-3 and caspase-9 activities were increased. In overall, these findings suggested that gedunin can be used as a potent chemotherapeutic agent in the future to treat gastric cancer.

Synthetic Zeolite Supplementation as a Potential Candidate for the Therapy of Diabetic Syndrome.

<b>Background and Objective:</b> Natural and Synthetic Zeolite (SZ) is potentially useful for biopharmaceuticals and bio tools due to its unique and outstanding physical and chemical properties. Thus, the present study aimed to evaluate the possible effect of synthetic zeolite in (STZ)-induced diabetic rats. <b>Materials and Methods:</b> About 4 groups of rats were used, (I) normal control, (II) SZ group, (300 mg/kg/day), (III) STZ group, diabetic rats acted as positive control and (IV) STZ+SZ group, included diabetic rats treated with synthetic zeolite (300 mg/kg/day), statistical analysis comparisons between means were carried out using one-way analysis of variance (ANOVA) followed by a post hock (Tukey) multiple comparisons test at p<u>></u>0.05. <b>Results:</b> After six weeks, treatment of diabetic animals with synthetic zeolite markedly exhibited a significant reduction in glucose, lipids, DNA fragmentation, Alanine Aminotransferase (ALAT), Aspartate Aminotransferase (ASAT), urea, creatinine, Malondialdehyde (MDA) and Nitric Oxide (NO) levels concomitant with a significant rise in insulin, Glutathione (GSH), Superoxide Dismutase (SOD) and Catalase (CAT) values close to the corresponding values of healthy ones. <b>Conclusion:</b> In conclusion, synthetic zeolite exhibits multi-health benefits with promising potentials against STZ-induced diabetes, this behaviour may be attributed to its antioxidant and free radical scavenging mechanisms.

Emerging synthetic drugs for the treatment of liver cirrhosis.

Introduction: The number of deaths and prevalent cases of cirrhosis are increasing worldwide, but there are no licensed antifibrotic or pro-regenerative medicines and liver transplantation is a limited resource. Cirrhosis is characterized by extreme liver fibrosis, organ dysfunction, and complications related to portal hypertension. Advances in our understanding of liver fibrosis progression and regression following successful etiological therapy betray vulnerabilities in common and disease-specific mechanisms that could be targeted pharmacologically.Area covered: This review summarizes the cellular and molecular pathogenesis of cirrhosis as a preface to discussion of the current drug development landscape. The dominant indication for global pharma R&D pipelines is cirrhosis related to nonalcoholic steatohepatitis (NASH). We searched Clinicaltrials.gov, GlobalData, Pharmaprojects and PubMed for pertinent information on emerging synthetic drugs for cirrhosis, with a focus on compounds listed in phase 2 and phase 3 trials.Expert opinion: Although cirrhosis can regress following successful etiological treatment, there are no specific antifibrotic or pro-regenerative drugs approved for this condition. Obstacles to drug development in cirrhosis include intrinsic biological factors, a heterogeneous patient population, and lack of acceptable surrogate endpoints. Nevertheless, several synthetic drugs are being evaluated in clinical trials and the NASH field is rapidly embracing a drug combination approach.

Novel synthetic drugs for the treatment of non-Hodgkin lymphoma.

Introduction: Over the past two decades, deeper understanding of B-cell signaling pathways and other mechanisms of lymphomagenesis have yielded promising targets for novel drugs in the treatment of non-Hodgkin lymphoma.Areas covered: This article provides a comprehensive review of approved synthetic drugs targeting the BTK, PI3K, immunomodulation, proteasome, HDAC, EZH2, and nuclear export pathways in non-Hodgkin lymphoma. The review includes coverage of the pharmacology, efficacy, toxicity, and active areas of research for each drug. The authors also provide their expert perspectives on the field and their opinions for the future.Expert opinion: Although novel synthetic drugs have generally not impacted clinical practice to the same extent as immune and cellular therapies, there remains an important role for targeted drugs in the treatment of non-Hodgkin lymphoma, particularly in the relapsed setting and for patients ineligible for more intensive therapies. Clinical outcomes and tolerability may improve further with the development of newer generations of synthetic drugs and emerging combination regimens with other targeted and immune therapies.

Discriminative stimulus effects of 3,4-methylenedioxypyrovalerone (MDPV) and structurally related synthetic cathinones.

The 3,4-methylenedioxypyrovalerone (MDPV), and other structurally related synthetic cathinones, are popular alternatives to prototypical illicit psychostimulants, such as cocaine and methamphetamine. These drugs are often referred to as 'bath salts' and function either as cocaine-like inhibitors of monoamine uptake, or amphetamine-like substrates for dopamine, norepinephrine and serotonin transporters. These studies used male Sprague-Dawley rats trained to discriminate MDPV from saline to evaluate the substitution profiles of structurally related synthetic cathinones, cocaine, and other direct-acting dopamine and noradrenergic receptor agonists in order to characterize the relative contributions of dopamine, norepinephrine and serotonin to the discriminative stimulus effects of MDPV. As expected, each of the cathinones and cocaine dose-dependently increased MDPV-appropriate responding, with a rank-order potency that was positively correlated with their potency to inhibit dopamine and norepinephrine, but not serotonin, a relationship that is consistent with the rank order to maintain self-administration. The dopamine D2/3 receptor-preferring agonist quinpirole produced a modest increase in MDPV-appropriate responding, whereas the dopamine D1/5 receptor agonist, SKF 82958, nonselective dopamine receptor agonist, apomorphine, as well as the α-1, and α-2 adrenergic receptor agonists, phenylephrine and clonidine, respectively, failed to increase MDPV-appropriate responding at doses smaller than those that suppressed responding altogether. Although these studies do not support a role for serotonergic or adrenergic systems in mediating/modulating the discriminative stimulus effects of MDPV, convergent evidence is provided to suggest that the discriminative stimulus effects of MDPV are primarily mediated by its capacity to inhibit dopamine uptake, and the subsequent activation of dopamine D2 or D3 receptors.

Inhibition of Virulence Factors and Biofilm Formation of Acinetobacter Baumannii by Naturally-derived and Synthetic Drugs.

Acinetobacter baumannii is a gram-negative, aerobic, non-motile, and pleomorphic bacillus. A. baumannii is also a highly-infectious pathogen causing high mortality and morbidity rates in intensive care units. The discovery of novel agents against A. baumannii infections is urgently needed due to the emergence of drug-resistant A. baumannii strains and the limited number of efficacious antibiotics available for treatment. In addition to the production of several virulence factors, A. baumannii forms biofilms on the host cell surface as well. Formation of biofilms occurs through initial surface attachment, microcolony formation, biofilm maturation, and detachment stages, and is one of the major drug resistance mechanisms employed by A. baumannii. Several studies have previously reported the efficacy of naturally-derived and synthetic compounds as anti- biofilm and anti-virulence agents against A. baumannii. Here, inhibition of biofilm formation and virulence factors of A. baumannii using naturally-derived and synthetic compounds are reviewed.

Synthetic Conjugates of Ursodeoxycholic Acid Inhibit Cystogenesis in Experimental Models of Polycystic Liver Disease.

BACKGROUND AND AIMS: Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of symptomatic biliary cysts. Current surgical and pharmacological approaches are ineffective, and liver transplantation represents the only curative option. Ursodeoxycholic acid (UDCA) and histone deacetylase 6 inhibitors (HDAC6is) have arisen as promising therapeutic strategies, but with partial benefits. APPROACH AND RESULTS: Here, we tested an approach based on the design, synthesis, and validation of a family of UDCA synthetic conjugates with selective HDAC6i capacity (UDCA-HDAC6i). Four UDCA-HDAC6i conjugates presented selective HDAC6i activity, UDCA-HDAC6i #1 being the most promising candidate. UDCA orientation within the UDCA-HDAC6i structure was determinant for HDAC6i activity and selectivity. Treatment of polycystic rats with UDCA-HDAC6i #1 reduced their hepatomegaly and cystogenesis, increased UDCA concentration, and inhibited HDAC6 activity in liver. In cystic cholangiocytes UDCA-HDAC6i #1 restored primary cilium length and exhibited potent antiproliferative activity. UDCA-HDAC6i #1 was actively transported into cells through BA and organic cation transporters. CONCLUSIONS: These UDCA-HDAC6i conjugates open a therapeutic avenue for PLDs.

Behavioral effects of four novel synthetic cathinone analogs in rodents.

A new generation of novel cathinone compounds has been developed as stimulant substitutes to avoid drug control laws and detection of use by blood tests. Dipentylone, N-ethylhexedrone, 4-chloroethcathinone (4-CEC), and 4'-methyl-α-pyrrolidinohexiophenone (MPHP) were tested for in vivo psychostimulant-like effects to assess their abuse liability. Locomotor activity was assessed in an open-field assay using Swiss-Webster mice to screen for locomotor stimulant effects and to identify behaviorally-active dose ranges, times of peak effect, and durations of action. Discriminative stimulus effects were assessed in separate groups of Sprague-Dawley rats trained to discriminate cocaine or methamphetamine from vehicle. Dipentylone, N-ethylhexedrone, 4-CEC, and MPHP dose-dependently increased locomotor activity. Dipentylone, N-ethylhexedrone, and MPHP produced maximal stimulant effects similar to cocaine and methamphetamine. 4-CEC was less efficacious, producing peak stimulant effects of about 74% of that of methamphetamine. The compounds were less potent than methamphetamine and approximately equipotent with cocaine. The doses of cocaine, methamphetamine, dipentylone, and 4-CEC that produced peak effects lasted 2 to 3 h, the peak dose of N-ethylhexedrone lasted 4 h, and the peak dose of MPHP lasted 6 h. All four compounds fully substituted for the discriminative stimulus effects of methamphetamine and cocaine, although full substitution by 4-CEC occurred at doses that substantially decreased response rate. Only 4-CEC fully substituted for MDMA. These data provide evidence that the novel cathinone compounds dipentylone, N-ethylhexedrone, 4-CEC, and MPHP demonstrate potential for abuse as psychostimulants, given their ability to stimulate locomotor activity and their substitution for the discriminative stimulus effects of methamphetamine and cocaine.

Anti-tumor effect of synthetic baicalin-rare earth metal complex drugs on SMMC-7721 cells.

Baicalin (BC)-rare earth metal complexes [BMCs (BC-Ce, BC-La, and BC-Y)] were synthesized by a complexation coordination method. A mouse tumor model with SMMC-7721 cells was used to examine BMCs for their anti-tumor activities in vivo. The results show that the three new BMCs, Na3Ce (C21H16O11)3·10H2O, Na2La (C21H16O11)2·8H2O, and Na2Y (C21H16O11)2·6H2O significantly inhibited SMMC-7721 cell proliferation, since the BMCs may induce the tumor apoptosis in a dose-dependent manner through decreasing cell membrane fluidity and mitochondrial membrane potential depolarization, blocking of the cell cycle at the G2/M phase, and increasing the expression of Bax and reducing the expression of Bcl-2. The effectiveness order of these three BCMs was as follows: BC-Ce > BC-La > BC-Y > BC. It is concluded that BC-Ce, BC-La, and BC-Y possess potent anti-tumor effects and may be a novel group of anti-tumor drugs. The novel baicalin-rare earth metal complexes (BMC) were synthesized, the anti-tumor effects of the BMC on SMMC-7721 cell analyzed comprehensively.

Psychotic disorder and cannabis use: Canadian hospitalization trends, 2006-2015. / Troubles psychotiques et consommation de cannabis : évolution des hospitalisations au Canada, 2006-2015.

INTRODUCTION: Given the recent and impending changes to the legal status of nonmedical cannabis use in Canada, understanding the effects of cannabis use on the health care system is important for evaluating the impact of policy change. The aim of this study was to examine pre-legalization trends in hospitalizations for mental and behavioural disorders due to the use of cannabis, according to demographics factors and clinical conditions. METHODS: We assessed the total number of inpatient hospitalizations for psychiatric conditions with a primary diagnosis of a mental or behavioural disorder due to cannabis use (ICD-10-CA code F12) from the Hospital Mental Health Database for ten years spanning 2006 to 2015, inclusive. We included hospitalizations from all provinces and territories except Quebec. Rates (per 100 000 persons) and relative proportions of hospitalizations by clinical condition, age group, sex and year are reported. RESULTS: Between 2006 and 2015, the rate of cannabis-related hospitalizations in Canada doubled. Of special note, however, is that hospitalizations during this time period for those with the clinical condition code "mental and behavioural disorders due to use of cannabinoids, psychotic disorder" (F12.5) tripled, accounting for almost half (48%) of all cannabis-related hospitalizations in 2015. CONCLUSION: Further research is required to investigate the reasons for the increase in hospitalizations for cannabis-related psychotic disorder. The introduction of high-potency cannabinoid products and synthetic cannabinoids into the illicit market are considered as possible factors.

JMV5656, a short synthetic derivative of TLQP-21, alleviates acid-induced lung injury and fibrosis in mice.

TLQP-21, a peptide encoded by the prohormone VGF, is expressed in neuroendocrine cells and can modulate inflammatory processes. Since TLQP-21 can bind the complement 3a receptor 1 on macrophages, interest has risen in this peptide as a potential drug for the treatment of Acute Respiratory Distress Syndrome (ARDS), whose hospital mortality can reach 35-46%. Since no effective pharmacologic therapies are available, our aim was to exploit the potential of a short analog of TLQP-21(JMV5656) in order to modulate the inflammatory process in ARDS and the progression to pulmonary fibrosis in an experimental model of unilateral acid aspiration in mice. Mice were divided in 2 treatment groups. In the acute protocol, mice received intra-peritoneal injection of either vehicle or 0.6 mg/kg JMV5656 on experimental days 1 and 2, and ARDS was induced on day 3 under deep anesthesia by instillation of HCl (1.5 ml/kg of 0.1 M HCl in 0.9% NaCl) into the right lung; all measurements were performed 24 h later. In the subacute protocol, mice were treated as previously, but treatment with vehicle or JMV5656 was repeated also on day 4 and measurements were made 2 weeks later. Twenty-four hours after acid instillation, the total number of immune cell in the BAL rose sharply due primarily to an increase in the PMN population which increased from 1% up to 58% of total cell numbers. JMV5656 significantly reduced PMN recruitment into the alveolar space, but had no effects on cytokine levels in BAL. Two weeks after acid injury, static compliance of the right lung was significantly higher in the JMV5656-treated group compared to vehicle-treated group. Treatment with JMV5656 also blunted the acid-induced collagen deposition in the right lung. These results suggest that JMV5656 can ameliorate mechanical compliance, and reduce collagen deposition in acid-injured lungs in mice. This effect was likely due to the ability of JMV5656 to inhibit PMN recruitment in the injured lung.

Assessment of structure-activity relationships and biased agonism at the Mu opioid receptor of novel synthetic opioids using a novel, stable bio-assay platform.

Fentanyl and morphine are agonists of the Mu opioid receptor (MOR), which is a member of the GPCR family. Their analgesic effects are associated with unwanted side effects. On a signaling level downstream from MOR, it has been hypothesized that analgesia may be mediated through the G protein pathway, whereas the undesirable effects of opioids have been linked to the ß-arrestin (ßarr) pathway. Despite being an increasingly debated subject, little is known about a potential 'bias' (i.e. the preferential activation of one pathway over the other) of the novel synthetic opioids (NSO) - including fentanyl analogs - that have emerged on the illegal drug market. We have therefore developed and applied a novel, robust bio-assay platform to study the activity of 21 NSO, to evaluate to what extent these MOR agonists show biased agonism and to investigate the potential correlation with their structure. In addition, we evaluated the functional selectivity of TRV130, a purported G protein-biased agonist. We applied newly established stable bio-assays in HEK293T cells, based on the principle of functional complementation of a split nanoluciferase, to assess MOR activation via recruitment of a mini-Gi protein (GTPase domain of Gαi subunit) or ßarr2. All but two of the tested NSO demonstrated a concentration-dependent response at MOR in both bio-assays. The developed bio-assays allow to gain insight into the ßarr2 or G protein recruitment potential of NSO, which may eventually help to better understand why certain opioids are associated with higher toxicity. Adding to the recent discussion about the relevance of the biased agonism concept for opioids, we did not observe a significant bias for any of the evaluated compounds, including TRV130.

Synthetic cathinones - From natural plant stimulant to new drug of abuse.

As recreational substances, synthetic cathinones started to be used at the beginning of the 21st century. There is still limited data on these compounds, introduced to the illicit drug market for the most part after 2009. Considering that synthetic cathinones are currently the second largest group of new psychoactive and dangerous substances among over 670 new psychoactive substances identified in Europe and monitored by the EMCDDA, research on them should be regarded as extremely important. This review focuses on the availability of synthetic cathinones on the illicit drug market, presentation of current trends in the use of these substances, and their mechanisms of action and toxicity. The authors discuss cases of intoxication with synthetic cathinones and post-mortem diagnostics as well as the problem of combined used of synthetic cathinones with other psychoactive substances. Literature as well as clinical and forensic data indicate the need for further research on the metabolism, toxicokinetics, toxicodynamics, clinical effects, and addictive potential of synthetic cathinones, especially in the context of potential threats caused by increased consumption of this group of drugs in future.

Synthetic psychoactive cathinones: hypothermia and reduced lethality compared to methamphetamine and methylenedioxymethamphetamine.

RATIONALE: Synthetic psychoactive cathinones (SPCs) are drugs with psychostimulant and entactogenic properties like methamphetamine (MA) and 3,4-methylenedioxymethamphetamine (MDMA). Despite clinical reports of human overdose, it remains to be determined if SPCs have greater propensity for adverse effects than MA or MDMA. OBJECTIVES: To determine whether the SPCs cathinone (CAT), methcathinone (MCAT), mephedrone (MMC), and methylenedioxypyrovalerone (MDPV) have lower LD50 values than MA or MDMA. METHODS: Male and female C57Bl/6J mice received single injections of one of 6 doses of a test drug (0-160 mg/kg IP). Temperature and behavioral observations were taken every 20 min for 2 h followed by euthanasia of surviving mice. Organs were weighed and evaluated for histopathological changes. RESULTS: LD50 values for MA and MDMA, 84.5 and 100.9 mg/kg respectively, were similar to previous observations. The LD50 for MMC was 118.8 mg/kg, but limited lethality was observed for other SPCs (CAT, MCAT, MDPV), so LD50 values could not be calculated. For all drugs, death was associated with seizure, when it was observed. Rather than hyperthermia, dose-dependent hypothermia was observed for MMC, MDPV, CAT, and MCAT. Contrary to initial expectations, none of the SPCs studied here had LD50 values lower than MA or MDMA. CONCLUSIONS: These data indicate that, under the conditions studied here: (1) SPCs exhibit less lethality than MA and MDMA; (2) SPCs impair thermoregulation; (3) effects of SPCs on temperature appear to be independent of effects on lethality.

Challenges and Opportunities in Preclinical Research of Synthetic Cannabinoids for Pain Therapy.

Cannabis has been used in pain management since 2900 BC. In the 20th century, synthetic cannabinoids began to emerge, thus opening the way for improved efficacy. The search for new forms of synthetic cannabinoids continues and, as such, the aim of this review is to provide a comprehensive tool for the research and development of this promising class of drugs. Methods for the in vitro assessment of cytotoxic, mutagenic or developmental effects are presented, followed by the main in vivo pain models used in cannabis research and the results yielded by different types of administration (systemic versus intrathecal versus inhalation). Animal models designed for assessing side-effects and long-term uses are also discussed. In the second part of this review, pharmacokinetic and pharmacodynamic studies of synthetic cannabinoid biodistribution, together with liquid chromatography-mass spectrometric identification of synthetic cannabinoids in biological fluids from rodents to humans are presented. Last, but not least, different strategies for improving the solubility and physicochemical stability of synthetic cannabinoids and their potential impact on pain management are discussed. In conclusion, synthetic cannabinoids are one of the most promising classes of drugs in pain medicine, and preclinical research should focus on identifying new and improved alternatives for a better clinical and preclinical outcome.

A synthetic lethal drug combination mimics glucose deprivation-induced cancer cell death in the presence of glucose.

Metabolic reprogramming in cancer cells can increase their dependence on metabolic substrates such as glucose. As such, the vulnerability of cancer cells to glucose deprivation creates an attractive opportunity for therapeutic intervention. Because it is not possible to starve tumors of glucose in vivo, here we sought to identify the mechanisms in glucose deprivation-induced cancer cell death and then designed inhibitor combinations to mimic glucose deprivation-induced cell death. Using metabolomic profiling, we found that cells undergoing glucose deprivation-induced cell death exhibited dramatic accumulation of intracellular l-cysteine and its oxidized dimer, l-cystine, and depletion of the antioxidant GSH. Building on this observation, we show that glucose deprivation-induced cell death is driven not by the lack of glucose, but rather by l-cystine import. Following glucose deprivation, the import of l-cystine and its subsequent reduction to l-cysteine depleted both NADPH and GSH pools, thereby allowing toxic accumulation of reactive oxygen species. Consistent with this model, we found that the glutamate/cystine antiporter (xCT) is required for increased sensitivity to glucose deprivation. We searched for glycolytic enzymes whose expression is essential for the survival of cancer cells with high xCT expression and identified glucose transporter type 1 (GLUT1). Testing a drug combination that co-targeted GLUT1 and GSH synthesis, we found that this combination induces synthetic lethal cell death in high xCT-expressing cell lines susceptible to glucose deprivation. These results indicate that co-targeting GLUT1 and GSH synthesis may offer a potential therapeutic approach for targeting tumors dependent on glucose for survival.