Exploring Nanotechnologies for the Effective Therapy of Malaria using Plant-Based Medicines

Malaria is a potentially lethal disease caused by species of the plasmodium parasite. Despite the advances in the interventions for its control and approaches to manage fatality, morbidity and mortality rates associated with malaria are still high. At present, artemisinin-based combination therapy is the first line of treatment. However, there is the need to explore newer approaches as reduced effectiveness and multi-drug resistance (even to artemisinin) has been reported in some regions and is expected to widen in scope. Phytomedicines have shown promise for the management of this debilitating disease and there are abundant resources in most of the areas where this disease is endemic. This report would systematically review the literature, emphasizing the challenges encountered in the control of malaria, active phytochemicals currently utilised in the management, drug delivery approaches as well as the nanotechnology-based systems that could be exploited in its treatment. These phytomedicines, either delivered conventionally or via the use of advanced delivery systems may suggest new strategies towards the better management of malaria

Potential P-Glycoprotein-Mediated Drug-Drug Interactions of Antimalarial Agents in Caco-2 cells

Antimalarials are widely used in African and Southeast Asian countries, where they are combined with other drugs for the treatment of concurrent ailments. The potential for P-glycoprotein (P-gp)-mediated drug-drug interactions (DDIs) between antimalarials and P-gp substrates was examined using a Caco-2 cell-based model. Selected antimalarials were initially screened for their interaction with P-gp based on the inhibition of rhodamine-123 (Rho-123) transport in Caco-2 cells. Verapamil (100 mM) and quinidine (1 mM) were used as positive inhibition controls. Lumefantrine, amodiaquin, and artesunate all showed blockade of Rho-123 transport. Subsequently, the inhibitory effect of these antimalarials on the bi-directional passage of digoxin (DIG) was examined. All of the drugs decreased basal-toapical (B-A) P-gp-mediated DIG transport at concentrations of 100 mM and 1 mM. These concentrations may reflect therapeutic doses for amodiaquin and artesunate. Therefore, clinically relevant DDIs may occur between certain antimalarials and P-gp substrates in general

Pharmacokinetic Herb-Drug Interactions: Insight into Mechanisms and Consequences

Herbal medicines are currently in high demand, and their popularity is steadily increasing. Because of their perceived effectiveness, fewer side effects and relatively low cost, they are being used for the management of numerous medical conditions. However, they are capable of affecting the pharmacokinetics and pharmacodynamics of coadministered conventional drugs. These interactions are particularly of clinically relevance when metabolizing enzymes and xenobiotic transporters, which are responsible for the fate of many drugs, are induced or inhibited, sometimes resulting in unexpected outcomes. This article discusses the general use of herbal medicines in the management of several ailments, their concurrent use with conventional therapy, mechanisms underlying herb-drug interactions (HDIs) as well as the drawbacks of herbal remedy use. The authors also suggest means of surveillance and safety monitoring of herbal medicines. Contrary to popular belief that "herbal medicines are totally safe," we are of the view that they are capable of causing significant toxic effects and altered pharmaceutical outcomes when coadministered with conventional medicines. Due to the paucity of information as well as sometimes conflicting reports on HDIs, much more research in this field is needed. The authors further suggest the need to standardize and better regulate herbal medicines in order to ensure their safety and efficacy when used alone or in combination with conventional drugs

Global prevalence of percutaneous injuries among healthcare workers: a systematic review and meta-analysis

Background Healthcare workers (HCWs) are at risk of occupational exposure to blood-borne pathogens through contact with human blood and other body fluids. This study was conducted to estimate the global and regional 1-year prevalence of percutaneous injuries (PCIs) among HCWs. Methods We systematically searched EMBASE, PubMed, CINAHL and PsychInfo databases for studies published from January 2008 to January 2018 that reported the prevalence of PCIs among HCWs. A random-effects meta-analysis was conducted to estimate pooled prevalence of PCIs among HCWs. Results Of the 5205 articles identified, 148 studies from 43 countries met the inclusion criteria. The pooled global 1-year prevalence estimate of PCIs was 36.4% [95% confidence interval (CI): 32.9–40.0]. There were substantial regional variations in the 1-year prevalence of PCIs, ranging from 7.7% (95% CI: 3.1–12.4) in South America to 43.2% (95% CI: 38.3–48.0) in Asia. The estimates for Africa and Europe were comparable with values of 34.5% (95% CI: 29.9–39.1) and 31.8% (95% CI: 25.0–38.5), respectively. The highest 1-year prevalence by job category was among surgeons, at 72.6% (95% CI: 58.0–87.2). The estimates for medical doctors (excluding surgeons), nurses (including midwives) and laboratory staff (including laboratory technicians) were 44.5% (95% CI: 37.5–51.5), 40.9% (95% CI: 35.2–46.7) and 32.4% (95% CI: 20.9–49.3), respectively. PCIs commonly occurred among HCWs working in hospital (41.8%, 95% CI: 37.6–46.0) than non-hospital (7.5%, 95% CI: 5.9–9.1) settings. Conclusions Our findings suggest high rates of PCIs among HCWs with direct patient care across many regions of the world. However, paucity of data from some countries was a major limitation

Global access to antibiotics without prescription in community pharmacies: a systematic review and meta-analysis

Objective: To estimate the proportion of over-the-counter antibiotic requests or consultations that resulted in non-prescription supply of antibiotics in community pharmacies globally. Methods: We systematically searched EMBASE, Medline and CINAHL databases for studies published from January 2000 to September 2017 reporting the frequency of non-prescription sale and supply of antibiotics in community pharmacies across the world. Additional articles were identified by checking reference lists and a Google Scholar search. A random effects meta-analysis was conducted to calculate pooled estimates of non-prescription supply of antibiotics. Results: Of the 3302 articles identified, 38 studies from 24 countries met the inclusion criteria and were included in the review. All the included countries with the exception of one, classified antibiotics as prescription-only medicines. The overall pooled proportion of non-prescription supply of antibiotics was 62% (95% CI 53 – 72). The pooled proportion of non-prescription supply of antibiotics following a patient request was 78% (95% CI 59 - 97) and based on community pharmacy staff recommendation was 58% (95% CI 48 – 68). The regional supply of non-prescription antibiotics was highest in South America, 78% (95% CI 72 - 84). Antibiotics were commonly supplied without a prescription to patients with symptoms of urinary tract infections (68%, 95% CI 42 – 93) and upper respiratory tract infections (67%, 95% CI 55 - 79). Fluoroquinolones and Penicillins respectively were the most commonly supplied antibiotic classes for these indications. Conclusion: Antibiotics are frequently supplied without prescription in many countries. This overuse of antibiotics could facilitate the development and spread of antibiotic resistance

‘Temporary Plasticiser’: A Novel Solution to Fabricate 3D Printed Patient-Centred Cardiovascular ‘Polypill’ Architectures

Hypertension and dyslipidaemia are modifiable risk factors associated with cardiovascular diseases (CVDs) and often require a complex therapeutic regimen. The administration of several medicines is commonly associated with poor levels of adherence among patients, to which World Health Organisation (WHO) proposed a fixed-dose combination unit (polypill) as a strategy to improve adherence. In this work, we demonstrate the fabrication of patient-specific polypills for the treatment of CVDs by fused deposition modelling (FDM) 3D printing and introduce a novel solution to meet critical quality attributes. The construction of poly(vinyl alcohol) (PVA)-based polypills containing four model drugs (lisinopril dihydrate, indapamide, rosuvastatin calcium and amlodipine besylate) was revealed for the first time. The impact of tablet architecture was explored using multi-layered and unimatrix structures. The novel approach of using distilled water as a ‘temporary co-plasticiser’ is reported and was found to significantly lower the extruding (90°C) and 3D printing (150°C) temperatures from 170°C and 210°C respectively, with consequent reduction in thermal stress to the chemicals. XRD indicated that lisinopril dihydrate and amlodipine besylate maintained their crystalline form while indapamide and rosuvastatin calcium were essentially amorphous in the PVA tablets. From the multilayer polypills, the release profile of each drug was dependent on its position in the multilayer. In addition to the multilayer architecture offering a higher flexibility in dose titration and a more adaptive solution to meet the expectations of patient-centred therapy, we identify that it also allows orchestrating the release of drugs of different physicochemical characteristics. Adopting such an approach opens up a pathway towards low-cost multidrug delivery systems such as tablets, stents or implants for wider range of globally approved actives

Ex Vivo and In Vivo Investigations of the Effects of Extracts of Vernonia amygdalina, Carica papaya and Tapinanthus sessilifolius on Digoxin Transport and Pharmacokinetics: Assessing the Significance on Rat Intestinal P-glycoprotein Efflux

Vernonia amygdalina (VA), Carica papaya (CP), and Tapinanthus sessilifolius (ML) are widely used in some countries as medicinal herbs to treat ailments including malaria, cancer, and diabetes. We previously reported the inhibitory effects of these herbs on permeability glycoprotein (P-gp) in Caco-2 cell monolayers. This study used ex vivo and in vivo models to investigate the likelihood of P-gp-mediated herb-drug interactions occurring. The study utilized excised rat intestinal tissues mounted in Ussing chambers to predict changes in drug absorption and an in vivo study in rats using digoxin as the P-gp substrate. Apparent permeability values and pharmacokinetic parameters of digoxin were compared to determine if co-administration of digoxin with ML, CP, or VA modulated the activity of P-gp. When VA was co-administered, the total area under the plasma concentration-time curve was significantly higher (2.1-fold) than when digoxin was administered alone. Co-administration of ML, VA, and CP significantly increased the mean digoxin apparent permeability in the mucosal-to-serosal direction by 7.8, 43.3, and 54.5%, respectively, in comparison to when digoxin was administered alone. These findings suggest that VA increases intestinal absorption of digoxin in vivo by inhibiting P-gp and may also modulate the pharmacokinetic disposition of other p-gp substrate drugs

P-glycoprotein mediated efflux in Caco-2 cell monolayers: The influence of herbals on digoxin transport

ETHNOPHARMACOLOGICAL RELEVANCE: Several herbal medicines are concomitantly used with conventional medicines with a resultant increase in the recognition of herb-drug interactions. The phytomedicines Vernonia amygdalina Delile (VA), family Asteraceae; Azadiractha indica A. Juss (NL), family Meliaceae; Morinda lucida Benth (MLB), family Rubiaceae; Cymbopogon citratus Stapf (LG), family Poaceae; Curcuma longa L. (CUR), family Zingiberaceae; Carica papaya L. (CP), family Caricaceae and Tapinanthus sessilifolius Blume (ML), family Loranthaceae are used in African traditional medicine for the treatment of malaria. They are also used in several regions world over in managing other ailments like cancer and diabetes. This study investigated their interaction with digoxin (DIG) with a view to predict the potential of P-glycoprotein (p-gp) mediated drug-herb interactions occurring with p-gp substrate drugs. MATERIALS AND METHODS: To assess p-gp mediated transport and inhibition, bidirectional transport studies were carried out on Caco-2 cell monolayers using digoxin (DIG) as a model p-gp substrate. Cell functionality was demonstrated using the determinations of transepithelial electric resistance (TEER), cell cytotoxicity testing utilizing the MTT assay as well as the inclusion of inhibition controls. RESULTS: Under the conditions of this study, extracts of ML, VA and CP showed significant inhibition to (3)H-Digoxin basolateral-to-apical (B-A) transport at 0.02-20mg/mL; the concentrations examined. Their apical-to-basolateral (A-B) transport was further investigated. Increases in the mean A-B transport and significant decreases in the B-A transport and efflux ratio values were observed. The apparent permeability coefficient and efflux ratio were computed providing an estimate of drug absorption. CONCLUSION: The findings show that extracts of ML, VA and CP significantly inhibit p-gp in vitro and interactions with conventional p-gp substrate drugs are likely to occur on co-administration which may result in altered therapeutic outcomes