Antiparasitic Activity of Tea Tree Oil (TTO) and Its Components against Medically Important Ectoparasites: A Systematic Review.

Ectoparasites are pathogens that can infect the skin and cause immense pain, discomfort, and disease. They are typically managed with insecticides. However, the fast-emerging antimicrobial resistance and the slow rate of development of new bio-actives combined with environmental and health concerns over the continued use of neurotoxic insecticides warrant newer and alternative methods of control. Tea tree oil (TTO), as an alternative agent, has shown remarkable promise against ectoparasites in recent studies. To our knowledge, this is the first systematic review to assess preclinical and clinical studies exploring the antiparasitic activity of TTO and its components against clinically significant ectoparasites, such as Demodex mites, scabies mites, house dust mites, lice, fleas, chiggers, and bed bugs. We systematically searched databases, including PubMed, MEDLINE (EBSCOhost), Embase (Scopus), CENTRAL, Cochrane Library, CINAHL, ScienceDirect, Web of Science, SciELO, and LILACS in any language from inception to 4 April 2022. Studies exploring the therapeutic activity of TTO and its components against the ectoparasites were eligible. We used the ToxRTool (Toxicological data reliability assessment) tool, the Joanna Briggs Institute (JBI) critical appraisal tools, and the Jadad scale to assess the methodological qualities of preclinical (in vitro and in vivo) studies, non-randomised controlled trials (including cohort, case series, and case studies), and randomised controlled trials, respectively. Of 497 identified records, 71 studies were included in this systematic review, and most (66%) had high methodological quality. The findings of this review revealed the promising efficacy of TTO and its components against ectoparasites of medical importance. Most importantly, the compelling in vitro activity of TTO against ectoparasites noted in this review seems to have translated well into the clinical environment. The promising outcomes observed in clinical studies provide enough evidence to justify the use of TTO in the pharmacotherapy of ectoparasitic infections.

Therapeutic Potential of Tea Tree Oil for Tungiasis.

Tungiasis (sand flea disease) is a neglected tropical disease caused by penetration of female sand fleas, Tunga penetrans, into a person's skin usually in their feet. The disease inflicts immense pain and suffering on millions of people, particularly children. The condition is most prevalent in Latin America, the Caribbean, and sub-Saharan Africa. Currently, there is no standard drug treatment for tungiasis. The available treatment options are fairly limited and unrealistic to use in endemic areas; as a result, in desperation, the affected people do more harm to themselves by extracting the fleas with non-sterile instruments, further exposing themselves to secondary bacterial infections and/or transmission of diseases such as hepatitis B virus, hepatitis C virus, or HIV. This highlights the urgent need for simpler, safer, and effective treatment options for tungiasis. Tea tree oil (TTO) has long been used as an antiseptic with extensive safety and efficacy data. The evidence on parasiticidal properties of TTO against ectoparasites such as head lice, mites, and fleas is also compelling. The purpose of this review is to discuss the current tungiasis treatment challenges in endemic settings and highlight the potential role of TTO in the treatment of tungiasis.

Treatment of tungiasis using a tea tree oil-based gel formulation: protocol for a randomised controlled proof-of-principle trial.

INTRODUCTION: Tungiasis (sand flea disease or jigger infestation) is a neglected tropical disease caused by penetration of female sand fleas, Tunga penetrans, in the skin. The disease inflicts immense pain and suffering on millions of people, particularly children, in Latin America, the Caribbean and sub-Saharan Africa. Currently, there is no standard treatment for tungiasis, and a simple, safe and effective tungiasis treatment option is required. Tea tree oil (TTO) has long been used as a parasiticidal agent against ectoparasites such as headlice, mites and fleas with proven safety and efficacy data. However, current data are insufficient to warrant a recommendation for its use in tungiasis. This trial aims to generate these data by comparing the safety and efficacy of a 5% (v/w) TTO proprietary gel formulation with 0.05% (w/v) potassium permanganate (KMnO4) solution for tungiasis treatment. METHODS AND ANALYSIS: This trial is a randomised controlled trial (RCT) in primary schools (n=8) in South-Western Kenya. The study will include school children (n=88) aged 6-15 years with a confirmed diagnosis of tungiasis. The participants will be randomised in a 1:1 ratio to receive a 3-day two times a day treatment of either 5% TTO gel or 0.05% KMnO4 solution. Two viable embedded sandflea lesions per participant will be targeted and the viability of these lesions will be followed throughout the study using a digital handheld microscope. The primary outcome is the proportion of observed viable embedded sand fleas that have lost viability (non-viable lesions) by day 10 (9 days after first treatment). Secondary outcomes include improvement in acute tungiasis morbidities assessed using a validated severity score for tungiasis, safety assessed through adverse events and product acceptability assessed by interviewing the participants to rate the treatment in terms of effectiveness, side effects, convenience, suitability and overall satisfaction. ETHICS AND DISSEMINATION: The trial protocol has been reviewed and approved by the University of Canberra Human Research Ethics Committee (HREC-2019-2114). The findings of the study will be presented at scientific conferences and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: Australian New Zealand Clinical Trials Registry (ACTRN12619001610123); PACTR202003651095100 and U1111-1243-2294.

Medication non-adherence in chronic kidney disease: a mixed-methods review and synthesis using the theoretical domains framework and the behavioural change wheel.

OBJECTIVE: Medication non-adherence is a well-recognised issue in chronic diseases but data in patients with chronic kidney disease (CKD) not receiving kidney replacement therapy (KRT) remains limited. This review summarised the prevalence of medication non-adherence and assessed determinants and outcomes associated with it in adults with CKD, not on KRT. METHOD: We searched PubMed, Embase, PsychInfo, Web of Science, and Cochrane (CENTRAL) for studies published until January 2020. Pooled prevalence of medication non-adherence was reported. Determinants of adherence-identified from quantitative and qualitative studies-were mapped into the theoretical domains framework and interventions proposed using the behavioural change wheel. RESULTS: Twenty-seven studies (22 quantitative and 5 qualitative) were included. The pooled prevalence of medication non-adherence was 39% (95% CI 30-48%). Nine studies reported association between non-adherence and outcomes, including blood pressure, disease progression, adverse events, and mortality. Modifiable determinants of non-adherence were mapped into 11 of the 14 Theoretical Domains Framework-of which, six appeared most relevant. Non-adherence decisions were usually due to lack of knowledge on CKD, comorbidities, and medications; polypharmacy and occurrence of medication side effects; changes in established routines such as frequent medication changes; higher medication cost, poor accessibility to medications, services and facilities; inadequate patient-healthcare professional communication; and forgetfulness. Using the behavioural change wheel, we identified several areas where interventions can be directed to improve medication adherence. CONCLUSION: Medication non-adherence is common in adults with CKD, not on KRT and may lead to poor outcomes. Evidence synthesis using mixed study designs was crucial in identifying determinants of non-adherence, drawing on a parsimonious approach from behaviour science. PROSPERO REGISTRATION: CRD42020149983.

Quality-by-Design Approach for the Development of Nano-Sized Tea Tree Oil Formulation-Impregnated Biocompatible Gel with Antimicrobial Properties.

Despite the promising properties of tea tree oil (TTO) as potential therapeutics for several superficial skin conditions, certain limitations such as physical instability and skin irritation have restricted its widespread use. This study focuses on developing a rationally designed lipid-based nanoformulation (TTO-LNF) in accordance with the US Food and Drug Administration standard using a well-recognized quality-by-design (QbD) approach. Using a mixture experimental design, TTO-LNF has been optimized with 5% TTO, 10% surfactant, 5% co-surfactant, and 80% water, which showed a 14.4 ± 4.4 nm droplet size and 0.03 ± 0.01 polydispersity index (PDI). To ease the topical administration, the TTO-LNF gel formulation was further developed using xanthan gum to achieve the desired viscosity and form a gel. The in vitro antibacterial tests of TTO-LNF showed promising inhibitory effects toward both Gram-negative and Gram-positive bacteria. In fact, a complete growth inhibition of S. epidermidis was observed when exposed to TTO-LNF and TTO-LNF gel for 24 h, showing better activity than antibiotic kanamycin (25 µg/mL). Additionally, the in vitro release study showed a sustained release profile with a 50% release in 24 h, which could be beneficial to reduce the toxicity and thereby improve the therapeutic efficacy for long-acting applications. Furthermore, the formulations were remarkably stable at 40 °C/75% Relative humidity (RH) for at least 4 weeks. Therefore, this study presents a promising strategy to develop a biocompatible and stable formulation that can be used for the topical treatment of skin infections.

Manuka Oil-A Review of Antimicrobial and Other Medicinal Properties.

Manuka oil is an essential oil derived from Leptospermum scoparium, a plant that has been used by the indigenous populations of New Zealand and Australia for centuries. Both the extracted oil and its individual components have been associated with various medicinal properties. Given the rise in resistance to conventional antibiotics, natural products have been targeted for the development of antimicrobials with novel mechanism of action. This review aimed to collate available evidence on the antimicrobial, anti-parasitic and anti-inflammatory activities of manuka oil and its components. A comprehensive literature search of was conducted using PubMed and Embase (via Scopus) targeting articles from database inception until June 2020. Chemical structures and IUPAC names were sourced from PubChem. Unpublished information from grey literature databases, Google search, targeted websites and Google Patents were also included. The present review found extensive in vitro data supporting the antimicrobial effects of manuka oil warrants further clinical studies to establish its therapeutic potential. Clinical evidence on its efficacy, safety and dosing guidelines are necessary for its implementation for medical purposes. Further work on regulation, standardization and characterization of the medicinal properties of manuka oil is required for establishing consistent efficacy of the product.

Evaluation of dietary and lifestyle changes as modifiers of S100ß levels in Alzheimer's disease.

There is a significant body of research undertaken in order to elucidate the mechanisms underlying the pathology of Alzheimer's disease (AD), as well as to discover early detection biomarkers and potential therapeutic strategies. One such proposed biomarker is the calcium binding protein S100ß, which, depending on its local concentration, is known to exhibit both neurotrophic and neuroinflammatory properties in the central nervous system. At present, relatively little is known regarding the effect of chronic S100ß disruption in AD. Dietary intake has been identified as a modifiable risk factor for AD. Preliminary in vitro and animal studies have demonstrated an association between S100ß expression and dietary intake which links to AD pathophysiology. This review describes the association of S100ß to fatty acids, ketone bodies, insulin, and botanicals as well as the potential impact of physical activity as a lifestyle factor. We also discuss the prospective implications of these findings, including support of the use of a Mediterranean dietary pattern and/or the ketogenic diet as an approach to modify AD risk.

Chemotherapy in Pancreatic Cancer: A Systematic Review.

BACKGROUND AND AIM: Pancreatic cancer is one of the most fatal cancers. Cytotoxic chemotherapy remains the mainstream treatment for unresectable pancreatic cancer. This systematic review evaluated and compared the overall survival (OS) and progression-free survival (PFS) outcomes obtained from recent phase 2 and 3 clinical trials of pancreatic cancer chemotherapy. MATERIALS AND METHODS: Thirty-two studies were included and compared based on chemotherapy agents or combinations used. Additionally, outcomes of first-line versus second-line chemotherapy in pancreatic cancer were compared. RESULTS: In studies that investigated the treatments in adjuvant settings, the highest OS reported was for S-1 in patients, who received prior surgical resection (46.5 months). In neoadjuvant settings, the combination of gemcitabine, docetaxel, and capecitabine prior to the surgical resection had promising outcomes (OS of 32.5 months). In non-adjuvant settings, the highest OS reported was for the combination of temsirolimus plus bevacizumab (34.0 months). Amongst studies that investigated second-line treatment, the highest OS reported was for the combination of gemcitabine plus cisplatin (35.5 months), then temsirolimus plus bevacizumab (34.0 months). CONCLUSIONS: There is a need to develop further strategies besides chemotherapy to improve the outcomes in pancreatic cancer treatment. Future studies should consider surgical interventions, combination chemotherapy, and individualized second-line treatment based on the prior chemotherapy.

Monoclonal antibody therapy in cancer: When two is better (and considerably more expensive) than one.

WHAT IS KNOWN AND OBJECTIVE: It is 20 years since the US Food and Drug Administration approved the first successful monoclonal anticancer antibody, trastuzumab. The therapeutic utility of monoclonal antibodies in cancer is often limited by partial clinical responses and the development of tumour resistance. An expanding strategy, to be reviewed here, to overcome the limited response and resistance to monotherapy utilizes concurrent treatment with two synergistic monoclonal antibodies. COMMENT: Key examples include two monoclonal antibodies, each engaging a distinct site of human epidermal growth factor receptor 2 (HER2), in the treatment of breast cancer and a combination of antibodies to two distinct T-cell antigens for the treatment of melanoma. Here, we provide an overview of the rationale and evidence for using selected monoclonal antibodies in combination for treating some cancers, along with potential hazards, especially autoimmune-related toxicities. WHAT IS NEW AND CONCLUSION: Thorough research, the development of panels of biomarkers and individualization of therapy will be necessary to optimize the use of these combinations and minimize the substantial risk of overstimulating the immune system.

Treatment of scabies using a tea tree oil-based gel formulation in Australian Aboriginal children: protocol for a randomised controlled trial.

INTRODUCTION: In remote Aboriginal communities in Australia, scabies affects 7 out of 10 children before their first birthday. This is more than six times the rate seen in the rest of the developed world. Scabies infestation is frequently complicated by bacterial infection, leading to the development of skin sores and other more serious consequences, such as septicaemia and chronic heart and kidney diseases. Tea tree oil (TTO) has been used as an antimicrobial agent for several decades with proven clinical efficacy. Preclinical investigations have demonstrated superior scabicidal properties of TTO compared with widely used scabicidal agents, such as permethrin 5% cream and ivermectin. However, current data are insufficient to warrant a broad recommendation for its use for the management of scabies because previous studies were small or limited to in vitro observations. METHODS AND ANALYSIS: A pragmatic first trial will examine the clinical efficacy of a simple and low-cost TTO treatment against paediatric scabies and the prevention of associated secondary bacterial infections, with 1:1 randomisation of 200 participants (Aboriginal children, aged 5-16 years and living in remote Australia) into active control (permethrin 5% cream) and treatment (5% TTO gel) groups. The primary outcome for the study is clinical cure (complete resolution). Secondary outcome measures will include relief of symptoms, recurrence rate, adverse effects, adherence to treatment regimen and patient acceptability. ETHICS AND DISSEMINATION: The project has received approvals from the University of Canberra Human Research Ethics Committee (HREC 16-133), Wurli-Wurlinjang Health Service Indigenous subcommittee and the Aboriginal Medical Services Alliance Northern Territory reference group. The results of this study will be published in core scientific publications, with extensive knowledge exchange activities with non-academic audiences throughout the duration of the project. TRIAL REGISTRATION: ACTRN12617000902392; Pre-results.

Lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer: A systematic review
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OBJECTIVE: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer, which accounts for 20 - 25% of cases of breast cancers, is highly aggressive. Due to cardiotoxicity and increasing resistance associated with trastuzumab, the first-line treatment, there is a need for effective second-line therapies in treating HER2-positive breast cancer. In this context, there has been increasing interest in the combination of lapatinib plus capecitabine. The aim of this systematic review was to assess the efficacy of lapatinib plus capecitabine for HER2-positive breast cancer after progression with trastuzumab therapy, in comparison with capecitabine monotherapy and other agents such as vinorelbine and trastuzumab emtansine. MATERIALS AND METHODS: We performed a keyword search in five electronic databases (OVID MEDLINE, the Cochrane Library, Web of Science, SCOPUS, and CINAHL; January 2010 to April 2017) for trials in patients with HER2-positive breast cancer that has progressed on trastuzumab. After screening, the relevant studies were assessed for their methodological quality (including selection bias, randomization, control for confounders, and blinding) by two reviewers independently. RESULTS AND DISCUSSION: A total of 50 studies were identified; only 6 of those met the inclusion criteria and were analyzed. Five received a weak rating on the quality assessment tool, and none could be considered as being of high scientific quality after taking the risk of bias and other confounding variables into account. The studies demonstrated that lapatinib plus capecitabine is effective in extending median overall (OS) and progression-free survival (PFS) outcomes, achieving OS of 37.6 - 108.7 weeks and PFS of 21.1 - 30 weeks across studies. However, median OS and PFS for trastuzumab emtansine therapy were found to be considerably better (133.9 weeks and 41.6 weeks, respectively) than for lapatinib plus capecitabine. CONCLUSION: The results suggest that the combination of lapatinib plus capecitabine can improve PFS and OS in patients with HER2-positive breast cancer that has progressed on trastuzumab. However, it appears that trastuzumab emtansine provides better treatment outcomes in this context.
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The Effects of Resveratrol Supplementation in Overweight and Obese Humans: A Systematic Review of Randomized Trials.

BACKGROUND: Obesity and metabolic syndrome are significant global health issues, with current public health messages predominately focused on altering dietary and physical activity behaviors. Resveratrol is a polyphenol (stilbenoid) commonly found in grapes, and human trials to date have shown conflicting and limited beneficial effects with respect to health. The aim of this study was to determine the effect of resveratrol supplementation on reducing body weight and modifying associated inflammatory markers. METHODS: A systematic review was undertaken following the PRISMA guidelines and using five indexed databases (OVID MEDLINE, Cochrane Library, Web of Science, SCOPUS, and CINAHL). A search strategy was formulated to select randomized, double-blind, placebo-controlled human trials investigating the effects of resveratrol supplementation on obesity or overweight, including body weight, metabolic and inflammatory markers. RESULTS: Five thousand five hundred sixty-nine studies published from 1990 to November 2015 were identified, with only nine papers meeting the inclusion criteria. The studies involved 208 participants (aged 49.2 ± 8.3 years) and utilized a substantial range of resveratrol doses (75-3000 mg/day). Study durations were a minimum of 2 weeks (14-90 days). Seven studies indicated no significant change in body mass index or body weight (P > 0.05), and three studies showed no improvements in fat mass, fat volume, or abdominal fat distribution (P > 0.05). Four studies included measurements of inflammatory markers, with three of these finding resveratrol supplementation to have a significant positive effect (P > 0.05). CONCLUSION: Based on the included studies, there is currently insufficient evidence to support the recommendation of resveratrol supplements in management of obesity. However, there were significant but not entirely consistent anti-inflammatory effects after resveratrol supplementation in overweight and obese individuals.

Therapeutic Potential of Tea Tree Oil for Scabies.

Globally, scabies affects more than 130 million people at any time. In the developed world, outbreaks in health institutions and vulnerable communities result in a significant economic burden. A review of the literature demonstrates the emergence of resistance toward classical scabicidal treatments and the lack of effectiveness of currently available scabicides in reducing the inflammatory skin reactions and pyodermal progression that occurs in predisposed patient cohorts. Tea tree oil (TTO) has demonstrated promising acaricidal effects against scabies mites in vitro and has also been successfully used as an adjuvant topical medication for the treatment of crusted scabies, including cases that did not respond to standard treatments. Emerging acaricide resistance threatens the future usefulness of currently used gold standard treatments (oral ivermectin and topical permethrin) for scabies. The imminent development of new chemical entities is doubtful. The cumulative acaricidal, antibacterial, antipruritic, anti-inflammatory, and wound healing effects of TTO may have the potential to successfully reduce the burden of scabies infection and the associated bacterial complications. This review summarizes current knowledge on the use of TTO for the treatment of scabies. On the strength of existing data for TTO, larger scale, randomized controlled clinical trials are warranted.