Vincent Forster

Liposome-supported peritoneal dialysis for detoxification of drugs and endogenous metabolites

Liposomes with transmembrane pH gradient can be used for peritoneal dialysis to extract harmful ionizable compounds, such as overdosed drugs. Detoxing with Nanoparticles Drug overdose can be life-threatening. Charcoal represents a broad antidote for drug intoxication, but has many limitations, including a narrow window of application. There has been a dearth of new, broad-spectrum treatments for drug overdose, with other antidotes being specific for certain drugs and poisons. Forster et al. developed a liposome-based peritoneal dialysis (PD) medium that sequesters ionizable compounds for removal from the body. The nanoparticles were filled with either a basic or acidic solution, thus creating a pH gradient across the membrane; acidic or basic small-molecule compounds would then concentrate in the respective particles’ cores. The authors demonstrated that liposomal PD rescued rats that had overdosed on verapamil, a heart drug that is frequently overdosed in patients, yet has no antidote. Other acidic and basic drugs associated with intoxication as well as endogenous metabolites associated with rare metabolic disorders were removed from rats via liposomes, demonstrating broad applicability in detoxification. Liposomal PD could therefore be a viable and simple alternative to intravenous toxin removal in emergency medicine. Peritoneal dialysis confers therapeutic advantages in patients with renal insufficiency and has proven beneficial in other indications, such as removal of excess metabolites or overdosed drugs. However, it is used in only about 10% of the dialyzed population worldwide, partly owing to the lower clearance rate compared with hemodialysis. We have developed a dialysis medium based on liposomes with a transmembrane pH gradient (basic or acidic aqueous core) that could improve the efficacy of peritoneal dialysis, specifically for the removal of excess metabolites or overdosed drugs. These scavenging vesicles are able to extract ionizable drugs and toxic metabolites into the peritoneal space and can be easily withdrawn from the body at the end of dialysis. This approach was used to successfully remove ammonia from rats with a greater extraction efficiency than traditional peritoneal dialysis, and may therefore prove useful in the treatment of severe hyperammonemia. Liposomal dialysis was also used to concentrate exogenous compounds in the rat peritoneal cavity, allowing for sequestration of several drugs that are frequently involved in overdose in people. In particular, liposomal dialysis counteracted the hypotensive action of the cardiovascular drug verapamil more efficiently than did control dialysis in a rat model of drug overdose. These findings highlight the versatility and advantage of this liposome-based approach for emergency dialysis.

Treatment of calcium channel blocker-induced cardiovascular toxicity with drug scavenging liposomes

Calcium channel blocker (CCB) overdose is potentially lethal. Verapamil and diltiazem are particularly prone to acute toxicity due to their dual effect on cardiac and vascular tissues. Unfortunately, conventional decontamination measures are ineffective in accelerating blood clearance and, to date, few efforts have been made to develop antidotes. To address the issue, injectable long-circulating liposomes bearing a transmembrane pH-gradient are proposed as efficient detoxifying agents of CCB poisoning. By scavenging the drug in situ, these circulating nanocarriers can restrict its distribution in tissues and hinder its pharmacological effect. In vitro, we showed that liposomes stability in serum and their ability to sequester CCBs could be finely-tuned by modulating their internal pH, surface charge, and lipid bilayer structure. Subsequently, we verified their efficacy in reversing the cardiovascular effects of verapamil in rats implanted with telemetric pressure/biopotential transmitters. In animals orally intoxicated to verapamil, an intravenous injection of the liposomal antidote rapidly attenuated the reduction in blood pressure. Areas under diastolic, systolic, and mean pressures curves were significantly reduced by up to 60% and the time to hemodynamic recovery was shortened from 19 to only 11 h. These findings confirm the protective effect of pH-gradient liposomes against cardiovascular failure after CBB intoxication, and endorse their potential as efficient, versatile antidotes.

3D strain map of axially loaded mouse tibia: a numerical analysis validated by experimental measurements

A combined experimental/numerical study was performed to calculate the 3D octahedral shear strain map in a mouse tibia loaded axially. This study is motivated by the fact that the bone remodelling analysis, in this in vivo mouse model should be performed at the zone of highest mechanical stimulus to maximise the measured effects. Accordingly, it is proposed that quantification of bone remodelling should be performed at the tibial crest and at the distal diaphysis. The numerical model could also be used to furnish a more subtle analysis as a precise correlation between local strain and local biological response can be obtained with the experimentally validated numerical model.

Nano-antidotes for drug overdose and poisoning

Nanotechnologies for detoxification—nano-antidotes—are rising to the challenge of the growing overdose epidemic. The number of intoxications from xenobiotics—natural or synthetic foreign chemicals, or substances given in higher doses than typically present in humans—has risen tremendously in the last decade, placing poisoning as the leading external cause of death in the United States. This epidemic has fostered the development of antidotal nanomedicines, which we call “nano-antidotes,” capable of efficiently neutralizing offending compounds in situ. Although prototype nano-antidotes have shown efficacy in proof-of-concept studies, the gap to clinical translation can only be filled if issues such as the clinical relevance of intoxication models and the safety profile of nano-antidotes are properly addressed. As the unmet medical needs in resuscitative care call for better treatments, this Perspective critically reviews the recent progress in antidotal medicine and emerging nanotechnologies.

Liposome-supported peritoneal dialysis in the treatment of severe hyperammonemia: An investigation on potential interactions

ABSTRACT Peritoneal dialysis (PD) performed with transmembrane pH‐gradient liposomes was reported to efficiently remove ammonia from the body, representing a promising alternative to current standard‐of‐care for patients with severe hepatic encephalopathy. In this study, we further characterized the properties of liposome‐supported peritoneal dialysis (LSPD) by 1) assessing its in‐use stability in the presence of ascitic fluids from liver‐disease patients; 2) investigating its interactions with drugs that are commonly administered to acute‐on‐chronic liver failure patients; and 3) analyzing the in vivo extraction profile of LSPD. We found that LSPD fluid maintained its in vitro ammonia uptake capability when combined with ascitic fluids. The co‐incubation of selected drugs (e.g., beta‐blockers, antibiotics, diuretics) with LSPD fluids and ammonia resulted in limited interaction effects for most compounds except for two fluoroquinolones and propranolol. However, considering the experimental set‐up, these results should be interpreted with caution and confirmatory drug‐drug interaction studies in a clinical setting will be required. Finally, metabolite‐mapping analysis on dialysates of LSPD‐treated rats revealed that the liposomes did not remove important metabolites more than a conventional PD fluid. Overall, these findings confirm that LSPD is a potentially safe and effective approach for treating hyperammonemic crises in the context of acute‐on‐chronic liver failure.