A Mechanistic and Pathophysiological Approach for Stroke Associated with Drugs of Abuse

Drugs of abuse are associated with stroke, especially in young individuals. The major classes of drugs linked to stroke are cocaine, amphetamines, heroin, morphine, cannabis, and new synthetic cannabinoids, along with androgenic anabolic steroids (AASs). Both ischemic and hemorrhagic stroke have been reported due to drug abuse. Several common mechanisms have been identified, such as arrhythmias and cardioembolism, hypoxia, vascular toxicity, vascular spasm and effects on the thrombotic mechanism, as causes for ischemic stroke. For hemorrhagic stroke, acute hypertension, aneurysm formation/rupture and angiitis-like changes have been implicated. In AAS abuse, the effect of blood pressure is rather substance specific, whereas increased erythropoiesis usually leads to thromboembolism. Transient vasospasm, caused by synthetic cannabinoids, could lead to ischemic stroke. Opiates often cause infective endocarditis, resulting in ischemic stroke and hypereosinophilia accompanied by pyogenic arthritis, provoking hemorrhagic stroke. Genetic variants are linked to increased risk for stroke in cocaine abuse. The fact that case reports on cannabis-induced stroke usually refer to the young population is very alarming

The blood-brain barrier and beyond: Nano-based neuropharmacology and the role of extracellular matrix

Restrained drug delivery due to the blood-brain barrier (BBB) considerably limits options for the treatment of brain pathologies. The utilization of nanoparticulate (NP) carriers has been proposed as a solution. The development strategies need to address the important hurdle of NP passage across the BBB as well as the altered cellular up-take due to the pathophysiological changes of the damaged or diseased tissue as well as immunological and toxicological aspects of nanomedicine penetration. This review therefore scopes to: 1) outline the state-of-the art knowledge on BBB passage, 2) address the significant influence of pathological conditions on nanoparticulate drug delivery, and, 3) highlight the largely neglected role of the extracellular matrix (ECM). Interactions of the nanosystem with biological barriers, cells and ECM in the milieu of brain pathologies are critically discussed in order to present a holistic overview of the advances and pits of nanomedicine applications in brain disease

Nanoaggregates of Biphilic Carboxyl-Containing Copolymers as Carriers for Ionically Bound Doxorubicin

Application of nanocarriers for drug delivery brings numerous advantages, allowing both minimization of side effects common in systemic drug delivery and improvement in targeting, which has made it the focal point of nanoscience for a number of years. While most of the studies are focused on encapsulation of hydrophobic drugs, delivery of hydrophilic compounds is typically performed via covalent attachment, which often requires chemical modification of the drug and limits the release kinetics. In this paper, we report synthesis of biphilic copolymers of various compositions capable of self-assembly in water with the formation of nanoparticles and suitable for ionic binding of the common anticancer drug doxorubicin. The copolymers are synthesized by radical copolymerization of N-vinyl-2-pyrrolidone and acrylic acid using n-octadecyl-mercaptan as a chain transfer agent. With an increase of the carboxyl group’s share in the chain, the role of the electrostatic stabilization factor of the nanoparticles increased as well as the ability of doxorubicin as an ion binder. A mathematical description of the kinetics of doxorubicin binding and release is given and thermodynamic functions for the equilibrium ionic binding of doxorubicin are calculated

Nanosized carriers based on amphiphilic poly-N-vinyl-2-pyrrolidone for intranuclear drug delivery

AIM: Ability to deliver drugs into the cell nuclei can significantly increase the efficacy of cancer therapies, in particular in the case of multidrug-resistant cancer Results: Polymer nanocarriers based on amphiphilic thiooctadecyl-terminated poly-N-vinyl-2-pyrrolidone were produced and loaded with a model hydrophobic drug, curcumin. Two commonly used loading approaches - emulsification and ultrasonic dispersion - were found to lead to two different size distributions with distinctively different biological effect. While nanocarriers produced via the emulsion method penetrated cells by dynamin-dependent endocytic mechanisms, sub-100 nm dispersion-produced nanocarriers were capable of crossing the membranes via biologically independent mechanisms.CONCLUSION: This finding opens an intriguing possibility of intranuclear delivery by merely tailoring the size of polymeric carriers, thus promising a new approach for cancer therapies.</p

Rethinking Subthreshold Effects in Regulatory Chemical Risk Assessments

A great number of dose–response studies indicate that hormesis is a common phenomenon, occurring in numerous organisms exposed to singular or combined environmental stressors, such as pharmaceuticals, heavy metals, micro/nanoplastics, organic flame retardants, pesticides, and rare earths. (1−6) While biological responses to low exposure levels are often beneficial, exposure to doses below the no-observed-adverse-effect-level (NOAEL; hereafter subthreshold doses) does not always translate to beneficial responses. (2,4) For example, subthreshold contaminant doses can enhance the virulence of phytopathogenic microbes and promote the resistance of crop pests with significant implications for crop production. (2,7,8) Subthreshold contaminant exposures can also stimulate infectious animal/human pathogens and promote their resistance to antibiotics and other drugs, threatening long-term sustainability. Importantly, the hormetic function of common pathways that regulate cancer progress indicate that current regulatory standards may not protect adequately against cancer risks. (9−11)We are grateful to Dr. Patrick H. Brown, Distinguished Professor of Plant Science at the University of California, Davis, U.S.A., and Dr. Adrian Covaci, Professor of Environmental Toxicology and Chemistry at the University of Antwerp, Belgium, for comments and suggestions on an early draft of the paper. This study did not receive a specific grant from funding agencies in the public, commercial, or not-for-profit sectors. E.A. acknowledges support from the National Natural Science Foundation of China (No. 4210070867), The Startup Foundation for Introducing Talent of Nanjing University of Information Science & Technology (NUIST), Nanjing, China (No. 003080), and the Jiangsu Distinguished Professor program of the People’s Government of Jiangsu Province. E.J.C. acknowledges longtime support from the U.S. Air Force (AFOSR FA9550-13-1-0047) and ExxonMobil Foundation (S18200000000256). The sponsors were not involved in the study design; the collection, analysis or interpretation of the data; the preparation of the manuscript or the decision where to submit the manuscript for publication. All authors hold senior editorial positions in various scientific journals. The views presented herein are those of the authors and do not represent views of journals’ editorial board as a unit, journals’ editorial office, journals themselves or their publishers, authors’ institutions, or scientific societies where authors hold senior positions.Peer reviewe