Marijuana-based drugs: innovative therapeutics or designer drugs of abuse?

The principal psychoactive component of marijuana, Δ(9)-tetrahydrocannabinol (THC), activates CB1 cannabinoid receptors (CB1Rs). Unfortunately, pharmacological research into the design of effective THC analogs has been hampered by psychiatric side effects. THC-based drug design of a less academic nature, however, has led to the marketing of "synthetic marijuana," labeled as K2 or "Spice," among other terms, which elicits psychotropic actions via CB1R activation. Because of structural dissimilarity to THC, the active ingredients of K2/Spice preparations are widely unregulated. The K2/Spice "phenomenon" provides a context for considering whether marijuana-based drugs will truly provide innovative therapeutics or merely perpetuate drug abuse.     

Novel antimalarial drugs from plants?

In all countries where malaria is endemic, plants are used in traditional medicine for treatment of the disease. Examples are numerous - the plant product data base napralert (Box I) lists 152 genera which are allegedly used for the treatment of malaria. But with the urgent need to develop new, safe and effective drugs against malaria, it is vital that such claims be fully investigated. In this article, David Phillipson and Melanie O'Neill discuss the potential of plant products for new antimoloriols, drawing attention particularly to the quassinoids - a diverse group of terpenoids from the family Simoroubaceoe.     

How statin drugs affect exosomes?

Statins reduce serum cholesterol and isoprenoids by the inhibition of cholesterol synthesis in the mevalonate pathway. Exosomes are extracellular vesicles (30–200 nm) released by all cells that regulate cell-to-cell communication in health and disease by transferring functional proteins, metabolites and nucleic acids to recipient cells. There are many reports that show an effect of statins on exosomes, from their production and release to their content and performance. In this review, we have summarized existing data on the impact of statins on the biosynthesis, secretion, content, uptake and function of exosomes.     

New drugs from fat bugs?

Signal transduction cascades, such as Hedgehog (Hh) signaling, are potentially important targets for new drugs. A new study in this issue of Cell Metabolism identifies hedgehog signaling in the formation of the Drosophila fly body and in mammalian adipogenesis.     

Will new antischistosomal drugs finally emerge?

It has been often observed that the chemotherapeutic armamentarium against an important disease such as schistosomiasis consists of just one drug, praziquantel. Thus, development of drug resistance is an impending danger, with serious implications for the health protection of many millions of people. This rational and legitimate concern might now begin to be relieved by the recent proposal of a new class of compounds that could represent a novel source of drugs against schistosomiasis.     

Can we rationally design promiscuous drugs?

Structure-based drug design is now used widely in modern medicinal chemistry. The application of structural biology to medicinal chemistry has heralded the "rational drug design" vision of discovering exquisitely selective ligands. However, recent advances in post-genomic biology are indicating that polypharmacology may be a necessary trait for the efficacy of many drugs, therefore questioning the "one drug, one target" assumption of current rational drug design. By combining advances in chemoinformatics and structural biology, it might be possible to rationally design the next generation of promiscuous drugs with polypharmacology.     

Understanding drugs and diseases by systems biology?

Systems biology aims to provide a holistic and in many cases dynamic picture of biological function and malfunction, in case of disease. Technology developments in the generation of genome-wide datasets and massive improvements in computer power now allow to obtain new insights into complex biological networks and to copy nature by computing these interactions and their kinetics and by generating in silico models of cells, tissues and organs. The expectations are high that systems biology will pave the way to the identification of novel disease genes, to the selection of successful drug candidates—that do not fail in clinical studies due to toxicity or lack of human efficacy—and finally to a more successful discovery of novel therapeutics. However, further research is necessary to fully unleash the potential of systems biology. Within this review we aim to highlight the most important and promising top-down and bottom-up systems biology applications in drug discovery.     

Are all "cytoprotective" drugs gastroprotective?

The effect of three--structurally different--groups of compounds was compared against gastric mucosal damages induced by ethanol or prostaglandin (PG) synthesis inhibitors, as well as against carrageenan-induced inflammation. All the compounds studied--SH-compounds (cysteamine, 2,3-dimercaptosuccinic acid, D,L-penicillamine), SH-blocking N-ethylmaleimide (NEM) and morphine-exerted dose-dependent inhibition on carrageenan edema test and against ethanol-induced gastric damage. Mucosal lesions induced by PG synthesis inhibitors (indomethacin 20 mg/kg, naproxen 75 mg/kg, piroxicam 60 mg/kg) were inhibited by drugs studied when the compounds were given before the damaging agents. However, when the drugs were injected 1 h after the inhibitors of PG synthesis opposite actions were observed; SH-compounds exerted protective, while NEM (2 mg/kg p.o.) and morphine (5 mg/kg p.o.) aggravating action. The results suggest that: 1. SH-compounds might have therapeutic importance in the treatment of gastric damage induced by prostaglandin synthesis inhibitors. 2. Reconsideration of the use of the term "cytoprotection" is necessary, since "cytoprotective" agents may aggravate mucosal damage in other ulcer model.     

RNA nanomedicines: the next generation drugs?

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Do antihypertensive drugs precipitate diabetes in predisposed men?

OBJECTIVE--To evaluate the influence of antihypertensive treatment and metabolic characteristics on the development of diabetes mellitus in middle aged men. DESIGN--Prospective study over an average of nine years. SETTING--Community based health survey of middle aged men carried out at the University of Uppsala. SUBJECTS--Seventy three hypertensive men aged 49-54 and 65 normotensive controls matched for body mass index, glucose disappearance rate (k value) at an intravenous glucose tolerance test, and serum triglyceride and cholesterol concentrations. INTERVENTIONS--Hypertensive group was treated with beta blockers, thiazides, hydralazine, or combinations of these drugs. Treatment was not randomised. MEASUREMENTS and MAIN RESULTS--Intravenous glucose tolerance, fasting blood glucose and serum lipid and insulin concentrations, body weight and height, three skinfold measurements, and blood pressure were recorded both during an initial health screening survey in 1970-3 and at a follow up survey in 1980-3. In the period between the two surveys 12 hypertensive men and two controls developed diabetes. Review of values obtained at the initial survey showed that the hypertensive men who developed diabetes or impaired glucose tolerance could be distinguished from those hypertensive men who did not by virtue of a higher fasting serum insulin concentration (26.1 v 15.2 mU/l (confidence interval of difference -15.2 to -6.2)), a lower peak serum insulin concentration (78.9 v 94.3 mU/l (confidence interval of difference -1.1 to 41.1)), and a lower k value (1.29 v 1.68 (confidence interval of difference -0.02 to 0.68)). The insulin index (peak insulin concentration divided by fasting insulin concentration), however, decreased significantly in the hypertensive men over time irrespective of whether they developed diabetes but did not change in the controls. Furthermore, the serum triglyceride concentration increased in the treated group and decreased in the controls. CONCLUSION--A severalfold difference in the incidence of diabetes between treated hypertensive and non-treated, normotensive men may be a consequence of the treatment, which may be particularly deleterious in men predisposed to diabetes.