Cannabinoid Formulations and Delivery Systems: Current and Future Options to Treat Pain.

The field of Cannabis sativa L. research for medical purposes has been rapidly advancing in recent decades and a growing body of evidence suggests that phytocannabinoids are beneficial for a range of conditions. At the same time impressing development has been observed for formulations and delivery systems expanding the potential use of cannabinoids as an effective medical therapy. The objective of this review is to present the most recent results from pharmaceutical companies and research groups investigating methods to improve cannabinoid bioavailability and to clearly establish its therapeutic efficacy, dose ranges, safety and also improve the patient compliance. Particular focus is the application of cannabinoids in pain treatment, describing the principal cannabinoids employed, the most promising delivery systems for each administration routes and updating the clinical evaluations. To offer the reader a wider view, this review discusses the formulation starting from galenic preparation up to nanotechnology approaches, showing advantages, limits, requirements needed. Furthermore, the most recent clinical data and meta-analysis for cannabinoids used in different pain management are summarized, evaluating their real effectiveness, in order also to spare opioids and improve patients' quality of life. Promising evidence for pain treatments and for other important pathologies are also reviewed as likely future directions for cannabinoids formulations.

Superoxide Dismutase Administration: A Review of Proposed Human Uses.

Superoxide dismutases (SODs) are metalloenzymes that play a major role in antioxidant defense against oxidative stress in the body. SOD supplementation may therefore trigger the endogenous antioxidant machinery for the neutralization of free-radical excess and be used in a variety of pathological settings. This paper aimed to provide an extensive review of the possible uses of SODs in a range of pathological settings, as well as describe the current pitfalls and the delivery strategies that are in development to solve bioavailability issues. We carried out a PubMed query, using the keywords "SOD", "SOD mimetics", "SOD supplementation", which included papers published in the English language, between 2012 and 2020, on the potential therapeutic applications of SODs, including detoxification strategies. As highlighted in this paper, it can be argued that the generic antioxidant effects of SODs are beneficial under all tested conditions, from ocular and cardiovascular diseases to neurodegenerative disorders and metabolic diseases, including diabetes and its complications and obesity. However, it must be underlined that clinical evidence for its efficacy is limited and consequently, this efficacy is currently far from being demonstrated.

Strategies to expand the therapeutic potential of superoxide dismutase by exploiting delivery approaches.

The overproduction of free radicals can cause oxidative-stress damage to a range of biomolecules, and thus potentially contribute to several pathologies, from neurodegenerative disorders to cardiovascular diseases and metabolic disorders. Endogenous antioxidant enzymes, such as superoxide dismutase (SOD), play an important role in diminishing oxidative stress. SOD supplementation could therefore be an effective preventive strategy to reduce the risk of free-radical overproduction. However, the efficacy of SOD administration is hampered by its rapid clearance. Several different approaches to improve the bioavailability of SOD have been explored in recent decades. This review intends to describe the rationale that underlie the various approaches and chemical strategies that have led to the most recent advances in SOD delivery. This critical description includes SOD conjugates, SOD loaded into particulate carriers (micelles, liposomes, nanoparticles, microparticles) and the most promising and suitable formulations for oral delivery, with a particular emphasis on reports of preclinical/clinical results. Likely future directions are also considered and reported.

Ozonated Oils as Antimicrobial Systems in Topical Applications. Their Characterization, Current Applications, and Advances in Improved Delivery Techniques.

The search for a wide spectrum of antimicrobial agents that can avoid resistance while maintaining reasonable side effects has led to ozonated oils experiencing an increase in scientific interest and clinical applications. The treatment of vegetable oils with ozone leads to the creation of a reservoir of ozone that slowly releases into the skin thanks to the fact that ozone can be held as ozonides of unsaturated fatty acids. Interest in the use of ozonated oils has meant that several ozonated-vegetable-oil-containing products have been commercialized as cosmetic and pharmaceutical agents, and in innovative textile products with antibacterial activity. New approaches to the delivery of ozonated oils have very recently appeared in an attempt to improve their characteristics and reduce drawbacks, such as an unpleasant odor, high viscosity and undesired effects on skin, including irritation and rashes. The present review focuses on the current status of delivery agents that use ozonated oils as antimicrobial agents in topical (dermal, skin, and soft tissues) treatments. Challenges and future opportunities for these delivery systems will also be discussed.

Efficacy and safety of a new device for intravesical thermochemotherapy in non-grade 3 BCG recurrent NMIBC: a phase I-II study.

PURPOSE: We report for the first time the activity and safety of Unithermia(®) (Elmedical Ltd, Hod-Hasharon, Israel), a novel device for administration of MMC-C with hyperthermia (HT), that employs conductive heating, in a series of non-grade 3 non-muscle-invasive bladder cancer (NMIBC) that failed Bacillus Calmette-Guerin (BCG). METHODS: Patients with non-grade 3 NMIBC recurring after at least a full induction course of BCG were eligible for this phase I-II prospective single-arm study. Six weekly instillations with Unithermia(®) were scheduled following complete TUR. Primary end points were treatment safety and response rate (RR), and the latter defined as the absence of any unfavourable outcome at 12 months. Any grade 3 and/or muscle-invasive (T > 1) recurrence was considered disease progression. Kaplan-Meier estimation of the time to recurrence and progression, cancer-specific survival and overall survival was taken as secondary end points. RESULTS: Thirty-four eligible patients entered the study between January 2009 and April 2011. RR was documented in 20/34 (59%). Among the 14/34 (41%) non-responders, four developed G3 disease, one developed carcinoma in situ, and one progressed to muscle-invasive bladder cancer, with an overall 18% progression rate at 1 year. At a median follow-up of 41 months, recurrence and progression rates were 35.3 and 23.5%, respectively. Toxicity did not go beyond grade 2 except in five cases. CONCLUSIONS: Initial experience with MMC-HT with Unithermia(®) showed an interesting activity and safety profile in non-grade 3 NMIBC recurring after BCG, suggesting a role as second-line therapy in this selected subgroup of NMIBC.

EC-145, a folate-targeted Vinca alkaloid conjugate for the potential treatment of folate receptor-expressing cancers.

EC-145, under development by Endocyte, is a conjugate composed of desacetylvinblastine monohydrazide linked through a peptide spacer to the targeting moiety folic acid, for the potential intravenous treatment of folate receptor-overexpressing tumors, in particular ovarian and lung cancers. In vitro studies demonstrated that EC-145 selectively binds to cells that overexpress the folate receptor, causing dose-dependent cytotoxicity. Furthermore, coincubation of the KB human nasopharyngeal carcinoma cell line with EC-145 and doxorubicin resulted in synergistic antitumor activity. Experiments in mouse tumor xenograft models have confirmed the potency of EC-145 and the curative effects of the drug conjugate were demonstrated in an aggressive lymphoma xenograft model. In a phase I clinical trial in patients with advanced or metastatic solid tumors, adverse events were generally of moderate severity with the most frequent being fatigue, constipation and peripheral sensory neuropathy. Preliminary data from a phase II clinical trial in patients with advanced ovarian cancer demonstrated that third- or fourth-line treatment with EC-145 yielded better disease control than second- or third-line liposomal doxorubicin. Coadministration of EC-145 and liposomal doxorubicin produced a statistically significant increase in progression-free survival over standard therapy in patients with platinum-resistant ovarian cancer. Phase III clinical trials are expected to confirm these promising results.