Mesenchymal Stem Cell-Derived Exosome Therapy of Microbial Diseases: From Bench to Bed

Microbial diseases are a global health threat, leading to tremendous casualties and economic losses. The strategy to treat microbial diseases falls into two broad categories: pathogen-directed therapy (PDT) and host-directed therapy (HDT). As the typical PDT, antibiotics or antiviral drugs directly attack bacteria or viruses through discerning specific molecules. However, drug abuse could result in antimicrobial resistance and increase infectious disease morbidity. Recently, the exosome therapy, as a HDT, has attracted extensive attentions for its potential in limiting infectious complications and targeted drug delivery. Mesenchymal stem cell-derived exosomes (MSC-Exos) are the most broadly investigated. In this review, we mainly focus on the development and recent advances of the application of MSC-Exos on microbial diseases. The review starts with the difficulties and current strategies in antimicrobial treatments, followed by a comprehensive overview of exosomes in aspect of isolation, identification, contents, and applications. Then, the underlying mechanisms of the MSC-Exo therapy in microbial diseases are discussed in depth, mainly including immunomodulation, repression of excessive inflammation, and promotion of tissue regeneration. In addition, we highlight the latest progress in the clinical translation of the MSC-Exo therapy, by summarizing related clinical trials, routes of administration, and exosome modifications. This review will provide fundamental insights and future perspectives on MSC-Exo therapy in microbial diseases from bench to bedside.

The history, current state and perspectives of aerosol therapy

Nebulization is a very effective method of drug administration. This technique has been popular since ancient times when inhalation of plants rich in tropane alkaloids with spasmolytic and analgesic effects was widely used. Undoubtedly, the invention of anasthesia in the 19th century had an influence on the development of this technique. It resulted in the search for devices that facilitated anasthesia such as pulveriser or hydronium. From the second half of the 21st century, when the first DPI and MDI inhalers were launched, the constant development of aerosol therapy has been noticed. This is due to the fact that nebulization, compared with other means of medicinal substance application (such as oral and intravenous routes of administration), is safer and it exhibits a positive dose/efficacy ratio connected to the reduction of the dose. It enables drugs administration through the lung and possesses very fast onset action. Therefore, various drugs prescribed in respiratory diseases (such as corticosteroids, β-agonists, anticholinergics) are present on the market in a form of an aerosol.

N-Alkylmorpholines: Potent Dermal and Transdermal Skin Permeation Enhancers

Transdermal drug delivery is an attractive non-invasive method offering numerous advantages over the conventional routes of administration. The main obstacle to drug transport is, however, the powerful skin barrier that needs to be modulated, for example, by transdermal permeation enhancers. Unfortunately, there are still only a few enhancers showing optimum properties including low toxicity and reversibility of enhancing effects. For this reason, we investigated a series of new N-alkylmorpholines with various side chains as potential enhancers in an in vitro permeation study, using three model permeants (theophylline, indomethacin, diclofenac). Moreover, electrical impedance, transepidermal water loss, cellular toxicity and infrared spectroscopy measurements were applied to assess the effect of enhancers on skin integrity, reversibility, toxicity and enhancers’ mode of action, respectively. Our results showed a bell-shaped relationship between the enhancing activity and the hydrocarbon chain length of the N-alkylmorpholines, with the most efficient derivatives having 10–14 carbons for both transdermal and dermal delivery. These structures were even more potent than the unsaturated oleyl derivative. The best results were obtained for indomethacin, where particularly the C10-14 derivatives showed significantly stronger effects than the traditional enhancer Azone. Further experiments revealed reversibility in the enhancing effect, acceptable toxicity and a mode of action based predominantly on interactions with stratum corneum lipids.

Tobacco/Nicotine Use Among Individuals Using Cannabis for Therapeutic Purposes

OBJECTIVE: While the relationship between recreational cannabis and nicotine use is well established, little is known about nicotine use among users of cannabis for therapeutic purposes (CTP). METHOD: Patients attending a medical marijuana dispensary (N = 697; 75.3% White; 60.0% male) completed a survey examining nicotine use, routes of administration of nicotine and cannabis, and CTP qualifying conditions. RESULTS: More than one-third (39.3%) of participants reported current nicotine use. Compared to exclusive cigarette smokers, non-users of nicotine, and e-cigarette users were approximately four times more likely to vape, rather than to smoke, cannabis. Almost a third of those reporting e-cigarette use (30.6%) and more than half (56.7%) of those reporting smoking cigarettes reported stopping for one day or longer in the past year because they were trying to quit. Furthermore, 46.8% of cigarette smokers reported plans to quit smoking in the next six months (but not in the next month) and an additional 31.6% planned to quit in the next month. Having a psychiatric condition was associated with nicotine use and higher motivation to quit smoking. CONCLUSIONS: Users of CTP are more likely to use nicotine products than the general population. Importantly, the route of administration of nicotine products is related to the route of administration of CTP. If aerosolized (vaped) CTP is a less harmful route of administration than smoked CTP, dispensary staff should be aware of this relationship and take this into account when recommending a non-combustible route.

Clinical Trials of Oncolytic Viruses in Breast Cancer

Breast cancer is the second most common kind of cancer worldwide and oncolytic viruses may offer a new treatment approach. There are three different types of oncolytic viruses used in clinical trials; (i) oncolytic viruses with natural anti-neoplastic properties; (ii) oncolytic viruses designed for tumor-selective replication; (iii) oncolytic viruses modified to activate the immune system. Currently, fourteen different oncolytic viruses have been investigated in eighteen published clinical trials. These trials demonstrate that oncolytic viruses are well tolerated and safe for use in patients and display clinical activity. However, these trials mainly studied a small number of patients with different advanced tumors including some with breast cancer. Future trials should focus on breast cancer and investigate optimal routes of administration, occurrence of neutralizing antibodies, viral gene expression, combinations with other antineoplastic therapies, and identify subtypes that are particularly suitable for oncolytic virotherapy.

Exploring Pharmacological Mechanisms of Essential Oils on the Central Nervous System

Essential oils (EOs) have been traditionally used as ancient remedies to treat many health disorders due to their enormous biological activities. As mainstream allopathic medication currently used for CNS disorders is associated with adverse effects, the search to obtain safer alternatives as compared to the currently marketed therapies is of tremendous significance. Research conducted suggests that concurrent utilization of allopathic medicines and EOs is synergistically beneficial. Due to their inability to show untoward effects, various scientists have tried to elucidate the pharmacological mechanisms by which these oils exert beneficial effects on the CNS. In this regard, our review aims to improve the understanding of EOs’ biological activity on the CNS and to highlight the significance of the utilization of EOs in neuronal disorders, thereby improving patient acceptability of EOs as therapeutic agents. Through data compilation from library searches and electronic databases such as PubMed, Google Scholar, etc., recent preclinical and clinical data, routes of administration, and the required or maximal dosage for the observation of beneficial effects are addressed. We have also highlighted the challenges that require attention for further improving patient compliance, research gaps, and the development of EO-based nanomedicine for targeted therapy and pharmacotherapy.

Use of long term aprepitant as a treatment for refractory nausea following oesophageal stent insertion – a case report

Background: Aprepitant, a substance P neurokinin-1 receptor antagonist, is licenced for the prevention of acute and delayed nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy. Case: A 33 year-old male with metastatic gastro-oesophageal cancer had multiple admissions for refractory nausea and vomiting following insertion of an oesophageal stent. Action: Mechanical issues with the stent, stent removal and central causes were excluded. Multiple anti-emetic agents were trialled in combination and with varying routes of administration without significant symptomatic improvement. Formulation: A trial of aprepitant was proposed as an off-licence therapy. Outcome: One hundred sixty-five milligrammes of aprepitant was given orally every 3 days and then up titrated to once daily with significant symptomatic improvement enabling the patient to tolerate an oral diet. The patient remained stable at 12 weeks and has been accepted into two clinical trials for potential further cancer treatment. Lessons: Aprepitant can be effective in refractory nausea and vomiting outside of emetogenic chemotherapy and safely used as a chronic treatment. The prevalence of refractory nausea and vomiting as a rare adverse outcome post-oesophageal stent insertion should be studied. What now? Further research of neurokinin-1 inhibitors for indications other than chemotherapy-induced nausea and vomiting is indicated.

Oral, topical, and inhalation of Calcarea carbonica derivative complex (M8) to treat inflammatory mammary carcinoma in dogs

Background: Inflammatory mammary carcinoma (IMC) is locally aggressive, fast growing, highly malignant tumor that affects humans and dogs. Affected dogs usually are presented with generalized edema, pain, erythema, and skin ulceration in mammary glands. Surgery is not recommended and an effective treatment has not been established [1]. Calcarea carbonica derivative complex (M8) has demonstrated anticancer properties in a murine model, by improving innate immune response against tumor cells [2]. M8 is a complex high diluted medication comprised of Calcarea carbonica 16x, Aconitum napellus 20x, Arsenicum album 18x, Asa foetida 20x, Conium maculatum 17x, Ipecacuanha 13x, Phosphorus 20x, Rhus toxicodendron 17x, Silicea 20x, Sulphur 24x, and Thuya occidentalis 19x, dilution procedures have followed standard methodology described at the Brazilian Homeopathic Pharmacopoeia. Aims: To describe different routes of M8 administration associated with oral pyroxican (non-steroidal anti-inflammatory drug) to treat dogs with IMC. Methodology: Three female dogs with 10 years old median age were presented to the Veterinary Teaching Hospital at Federal University of Parana, Curitiba (HV-UFPR) with cytological and clinical diagnosis of IMC. Patients were treated with oral (0.5 mL,q12h), topical (q12h) and inhalatory (2 mL, q24h, through an ultrasonic inhalation device) M8, and oral pyroxican (0.3mg/kg, q24h).Thoracic radiographs showed pulmonary metastasis in all dogs. Results: 7 days after initiating treatment all patients had clinical improvement. It was observed reduction on mammary glands inflammation and decreased pain sensitivity. One patient had 8 month of complete remission. The other two patients died 1 and 2 month after initial treatment. However none of the patients had pulmonary progressive disease, showed by radiographic examinations. Owners revealed treatment satisfaction in regards to quality of life improvement, easy M8 administration, good M8 palatability for dogs, and inflammation reduction. Conclusion: The present report suggests that M8 influenced positively the anti -inflammatory treatment. Keywords: Calcarea carbonica complex; inflammatory mammary carcinoma; routes of administration References [1] Sorenmo K. Canine mammary gland tumors. Veterinary Clinics of North America: Small Animal Practice. 2003 33(3):573-96. [2] Oliveira CC, Abud APR, Oliveira SM, Guimarães FSF, Andrade LF, Di Bernardi RP, Coletto ELO, Kuczera D, Da Lozzo EJ, Gonçalves JP, Trindade ES, Buchi DF. Developments on drug discovery and on new therapeutics: highly diluted tinctures act as biological response modifiers. BMC Complementary and Alternative Medicine 2011, 11(101): 2-11.

DO PROBIOTICS HAVE A FUTURE IN NEONATOLOGY? (ANALYSIS OF THE LATEST DATA. PART 3)

The issue of feasibility and effectiveness of probiotics use in newborns is still discussable. A position letter of the Committee on nutrition of the European Society for Pediatric NutritionGastroenterology, Hepatology, and(ESPGHAN) and the Working group of the ESPGHAN on probiotics and prebiotics issues was published in May 2020 in “Pediatric Gastroenterology and Nutrition” magazine as for the use of probiotics in premature newborns. The third part of the literature continues with the position paper and the results of many randomized controlled clinical trials of probiotics. The article considers the answers to 6 clinical questions posed by the working group of the Committee to assess the feasibility of use, routes of administration, dosage and duration of use, as well as the effectiveness and quality of probiotic drugs. It was proved that probiotics, in general, could decrease the level of necrotising enterocolitis, sepsis, and mortality. On the other hand, an increasing number of commercial products containing probiotics of non optimal quality are available. In addition, a large number of departments in the world regularly suggest probiotic supplements as a treatment standard despite the absence of any solid evidence. Moreover, the emphasis was placed on issues of safety of probiotic supplements for premature newborns. Guarantee of quality of probiotic product is deliverance of probiotic strains by transfer genes of resistance to antibiotics, the ability to regularly detect sepsis while using probiotics.