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Females have long been underrepresented in preclinical research and clinical drug trials. Directives by the U.S. National Institutes of Health have increased female participation in research protocols, although analysis of outcomes by sex remains infrequent. The long-held view that traits of female rats and mice are more variable than those of males is discredited, supporting equal representation of both sexes in most studies. Drug pharmacokinetic analysis reveals that, among subjects administered a standard drug dose, women are exposed to higher blood drug concentrations and longer drug elimination times. This contributes to increased adverse drug reactions in women and suggests that women are routinely overmedicated and should be administered lower drug doses than men. The past decade has seen progress in female inclusion, but key subsequent steps such as sex-based analysis and sex-specific drug dosing remain to be implemented.

The uncontrolled release of drugs in conventional drug delivery systems has led to the introduction of new nanotechnology-based drug delivery systems and the use of targeted nanocarriers for cancer treatment. These targeted nanocarriers, which consist of intelligent nanoparticles modified with targeting ligands, can deliver drugs to specified locations at the right time and reduce drug doses to prevent side effects. Folate is a suitable targeting ligand for folate receptors overexpressed on cancer cells and has shown promising results in the diagnosis and treatment of cancer. In this review, we highlight the latest developments on the use of folate-conjugated nanoparticles in cancer diagnosis and treatment. Moreover, the toxicity, biocompatibility and efficacy of these nanocarriers are discussed.

Background: The clinical application of glabridin in treating skin diseases has been constrained by the limitations of its poor chemical stability and low skin permeability. Objective: Here, we describe Tip-loading Dissolving Microneedles (TDMNs) encapsulating drugs only in the tips of needles for glabridin delivery with improved stability and skin permeability. Methods: The TDMNs fabricated by solvent casting technique had sufficient mechanical strength to penetrate through the excised rat's skin without fracture. Drug delivery efficiency and drug residual in the skin of TDMNs were 63.16% and 49.28%, respectively. Glabridin encapsulated in the tips of TDMNs was effectively delivered into the abdominal skin of rat, and the in vivo delivery efficiency was inversely proportional to the drug doses. Results: Transepidermal Water Loss (TEWL) significantly increased to 34.80 g/m2·h after the application of TDMNs and returned to normal levels (11.31 g/m2·h) after 8 h, indicating that the TDMNs were well tolerated. The stability of glabridin at room temperature was appreciably improved when loaded in TDMNs. Conclusion: These results suggest that intradermal delivery of glabridin by TDMNs is a safe and efficient alternative to currently available routes of administration.

We recently introduced voxel-level images of drug occupancy from PET via our “Lassen plot filter.” Occupancy images revealed clear dependence of 11C-flumazenil displacement on dose of GABAa inhibitor, CVL-865, but with different scales in different brain regions. We hypothesized that regions requiring higher drug concentrations to achieve desired occupancy would have higher EC50 values. We introduce an “EC50 image” from human data to evaluate this hypothesis. Five healthy subjects were scanned with the nonselective GABAa tracer, 11C-flumazenil, before and (twice) after administration of CVL-865. We created ten occupancy images and applied an Emax model locally to create one EC50 image. We also performed simulations to confirm our observations of regional variation in EC50 and to identify the main source of variability in EC50. As expected, the EC50 image revealed spatial variation in apparent drug affinity. High EC50 was found in areas of low occupancy for a given drug dose. Simulations demonstrated that sampling from an inadequate range of plasma drug concentrations could impair precision. Our results argue for (a) confidence in the ability of the EC50 images to identify regional differences and (b) a need to tailor the range of drug doses in an occupancy study to regularize the precision of the EC50 throughout the brain. The EC50 image could add value to early-phase drug development by identifying regional variation in affinity that might impact therapy or safety and by guiding dose selection for later-phase trials.

The barrier properties of the topmost layer of the skin, stratum corneum have significant limitations for successful systemic delivery of a wide range of therapeutic molecules, especially macromolecules and genetic material. One solution is to utilize microneedles (MNs), which are capable of painlessly traversing through the stratum corneum and directly translocating protein drugs into the systematic circulation. This strategy involves the use of micron sized needles fabricated from different materials and using different geometries to create transient aqueous conduits across the skin. Microneedles in isolation, or in combination with other enhancing strategies, have been shown to dramatically enhance the skin permeability of numerous therapeutic molecules including biopharmaceuticals either in vitro, ex vivo or in vivo. MNs can be designed to incorporate appropriate structural materials as well as therapeutics or formulations with tailored physicochemical properties. This platform technique has been applied to deliver drugs both locally and systemically in applications ranging from vaccination to diabetes and cancer therap. As an alternative to hypodermic needles, coated polymer microneedles (MNs) are able to deliver drugs to subcutaneous tissues after being inserted into the skin. The dip-coating process is a versatile, rapid fabricating method that can form coated MNs in a short time. However, it is still a challenge to fabricate coated MNs with homogeneous and precise drug doses in the dip-coating process. This review article focuses on recent and potential future developments in microneedle technologies. This will include the detailing of progress made in microneedle design, an exploration of the challenges faced in this field and potential forward strategies to embrace the exploitation of microneedle methodologies, while considering the inherent safety aspects of such therapeutic tools. The clinical potential and future translation of MNs are also discussed.

Medical students generally learn to calculate drug doses using paper problems containing numerical information. In contrast, once qualified, they have to extract the relevant information from treatment guidelines and use equipment, such as syringes, to dose patients. We compared students’ success in calculating drug doses using those different approaches. After receiving relevant training, 239 consenting first year students were randomised into four groups. Groups 1 and 2 had to calculate a dose, while groups 3 and 4 had to both calculate and then prepare a dose using a syringe and a labelled bottle of medicine. We gave groups 1 and 3 numerical dosage information. Groups 2 and 4 had to extract this information from guidelines. We compared success between groups using a chi-square test. Groups 1 and 3 outperformed groups 2 and 4. Availability of equipment seemed to be related to the improved success between groups 2 and 4, but this was not significant. Students who did not speak English at home were three times more likely to answer incorrectly than English-speaking students. Students who had equipment were more likely than students who did not have equipment to use appropriate units and propose realistic quantities. In light of these findings, we recommend that medical student training and assessment should include both extraction of embedded dosage information from guidelines and use of the equipment used in dosing.

Background Inconsistent doses and schemes are commonly used in older patients receiving cancer chemotherapy. We performed this study in patients with cancer and age ≥ 70 years to determine the frequency of undertreatment and overtreatment as well as factors influencing the decision to modify chemotherapy doses. Patients and Methods Patients aged ≥70 years starting new chemotherapy regimens were prospectively included in a multicentre study. The schedule and drug doses were determined by the treating oncologist. Pre-chemotherapy assessment included sociodemographics, treatment details and geriatric assessment (GA) variables. Association between these factors and undertreatment (use of less intensive cancer treatment [LICT] in a fit patient) or overtreatment (use of standard cancer treatment in an unfit older patient) were examined by multivariate logistic regression. Results Three- hundred ninety-seven patients were included, 43% of whom received LICT. If not adjusted for GA, toxicity did not differ between those receiving LICT (38%) or standard doses of chemotherapy (37%). If the dose of chemotherapy was analyzed according to the results of GA 61 (15%) patients had been undertreated and 133 (34%) had been overtreated. Undertreatment was related with increasing age and decreased renal function. Factors related with overtreatment were younger age, curative intention of treatment, prescription of G-CSF as primary prophylaxis and adequate cognitive status. Overtreated patients had more grade 3–4 toxicity than those receiving treatment adapted to fragility (42% vs 31%; p Conclusions The use of chemotherapy without considering GA leads to overtreatment more commonly than undertreatment in older patients with cancer. Oncologists should take into account the results of GA to stratify patients and to avoid under or overtreatment.

Cancer patients are considered one of the most vulnerable to infection with Corona virus (COVID-19), especially who are elderly, multiple comorbidities, and are often immunosuppressed by their cancer or therapy. The immune system of cancer patients is very weak compared to the healthy individuals, so, morbidity and mortality of any serious infections expected to be high among them. This research aims to study the impact of COVID-19 pandemic on cancer patients practices in Saudi Arabia (KSA) and compare with the result in Egypt. It was conducted through a well-structured questionnaire, among cancer patients either online (KSA) or paper questionnaire (Egypt). The questionnaire consists of 16 questions about Scio-demographic and changes in time and method of treatment (chemotherapy and radiotherapy), postponed of surgical operations. Our results showed significant differences between KSA and Egypt hospital practices; cancer department was affected by postponed appointment (54.8% & 63.3%), diagnosis (32.7% & 60%) and treatment of cancer patients (37.1% & 63.3%) respectively. Also, postponed of chemotherapy/radiotherapy (56.8% & 73.3%), surgical operations (45% & 43.3%), an increase in the deterioration of cancer by (35.5% & 23.3%), switching from parenteral injection to oral (27.8% & 56.7%) and changing in the drug doses (19.5% & 40%) in KSA and Egypt respectively. We can conclude that management of cancer patients during COVID-19 pandemic of great importance and so, switching from parenteral to oral, prolongation of the treatment period and postponed of some surgical operations gave a good opportunity to maintain adequate care of cancer patient with minimum exposure of patients to infection.

Transdermal delivery of drugs is a current alternative route of administration for systemic actions because of a whole series of unarguable advantages, including high compliance due to its noninvasive, pain-free and simple use, as well as reductions in drug doses and the consequent reductions in side effects. However, most candidate drugs encounter the problem of low drug permeability though the skin barrier. One of the simplest means of enhancing skin permeability consists of introducing a permeability enhancer (penetrator) into the medicinal formulation. The aim of the present review was to consider different types of chemical permeability enhancers presented in the literature in recent years. A classification of permeability enhancers is provided and possible mechanisms of action are indicated.

Gestational trophoblastic disease is a rare tumor highly sensitive to systemic drug therapy. The standard regimens of chemotherapy of I and II lines for patients in the high-risk group for gestational trophoblastic disease are the EMA-CO, EMA-EP and TP/TE regimens, which have been demonstrated to be effective and require adherence to drug doses and intervals of administration. If these criteria are not met, the risk of developing resistance with an unfavorable outcome for patients is extremely high. The situation is extremely difficult when a patient has an absolute allergic intolerance to one of the components of standard regimens, which is presented in a clinical case.

OBJECTIVE To establish weight-based dose bands for commonly used oral medicines, given in liquid forms, for children in the UK that could be used for prescribing and administering accurate and safe drug doses. METHODS A list of commonly prescribed, oral liquid medications was established from the medication dispensing database of four UK hospitals and a primary care database. The evidence base of currently used dose regimens for each drug was identified from paediatric reference books, summary of product characteristics and the literature. Then, weight-based dose bands were developed and a modified Delphi process was used to achieve healthcare professional consensus about the suggested dose bands for each drug. RESULTS Forty-six experts in paediatric medicines participated in the Delphi process (mean years of experience 17.3 ± 9.4 [standard deviation]) and assessed 45 oral liquid drugs in total. Four categories of weight-based dose bands were established: drugs with two dose bands (17.8%, 8/45), drugs with three dose bands (64.4%, 29/45), drugs with four dose bands (15.6%, 7/45) and drugs with five dose bands (2.2%, 1/45). The 46 participants reached consensus on all the suggested dose bands for 53.3% (24/45) of the drugs. Consensus was reached in the first round of the Delphi process for 91.7% (22/24) of the drugs and after two rounds for two drugs. No agreement was achieved on any of the suggested dose bands for 26.7% (12/45) of the drugs. CONCLUSION This study provides healthcare professionals with a set of recommended weight-based dose bands for commonly prescribed oral liquid drugs for children. These bands could establish the basis for change in clinical practice to reduce dosing errors and improve healthcare for children.

Background Failure of patients' adherence to medications has been a big issue for both physicians and patients; not only it does affect the patients' health but also it affects the financial status of the hospital and the patient. Objective This investigation aims to explore the prevalence and the factors affecting the compliance of patients with chronic conditions to their medications. Materials and methods An online survey was distributed to patients who had chronic conditions and lived in the main cities of Saudi Arabia. The questionnaire included sections about the patients' general characters, type of chronic disease, the pattern of prescribed medications' usage, and factors affecting compliance of patients toward their medications. Data was collected in a predesigned excel sheet, and analysis was executed through SPSS program version 26. Results 301 patients responded to this questionnaire. The lowest incidence of missing pills was among patients with heart failure, followed by chronic kidney disease, whereas the highest frequency of missing pills was among patients with vitamin D deficiency, followed by hyperlipidemia. 38.5% of the patients used mobile applications as reminders for the administration of their medications. 50% of the patients who use reminders take more than four pills a day. 48.2% of the patients stopped medications without consulting their doctors, where 20.9% stopped one medication for less than a month. 57.5% forgot to take drug doses in a year, with a mean of 8.55 ± 26.3 forgotten doses. Females, patients aging between 31 and 45 years old, obese, married, illiterate, self-employed, those who follow with military hospitals, exercising regularly, and ex-smoker all showed a higher incidence of noncompliance to medications. The main reason for noncompliance was forgetfulness in 60% of patients. 63.2% of the patients did not have a GP to help them with medications compliance. Conclusion The compliance of Saudi patients toward their chronic medications requires improvement. Similar studies in other areas in Saudi Arabia are recommended.

BACKGROUND Acute kidney injury (AKI) is common but not often recognized. Early recognition and management may improve patient outcomes. METHODS This is a prospective, nonrandomized study of clinical decision support (CDS) system [combining electronic alert and standardized care pathway (SCP)] to evaluate AKI detection and progression in hospitalized children. The study was done in three phases: pre-, intervention (CDS) and post. During CDS, text-page with AKI stage and link to SCP was sent to patient's contact provider at diagnosis of AKI using creatinine. The SCP provided guidelines on AKI management [AEIOU: Assess cause of AKI, Evaluate drug doses, Intake-Output charting, Optimize volume status, Urine dipstick]. RESULTS In all, 239 episodes of AKI in 225 patients (97 females, 43.1%) were analyzed. Proportion of patients with decrease in the stage of AKI after onset was 71.4% for CDS vs. 64.4% for pre- and 55% for post-CDS phases (p = 0.3). Documentation of AKI was higher during CDS (74.3% CDS vs. 47.5% pre- and 57.5% post-, p

The decoding of the DNA structure and development of new molecular methods of its analysis, as well as identification of specific genomic changes responsible for malignant transformation, have become the turning points in elaboration of novel anti-tumour drugs directed against molecular and genetic targets of tumor growth. Transition from empirical screening of agents inhibiting tumour cell proliferation to molecule-targeted analytical methods has raised a number of serious methodological issues regarding preclinical evaluation of novel medicines. The objective of this paper was to analyse general principles and features of preclinical efficacy and safety studies of different classes of modern anti-tumour drugs with a view to improve existing national guidelines. The paper reviews various aspects of preclinical studies of different classes of anti-tumour drugs (small molecule chemotherapy drugs, hormones and hormone antagonists, alkylating agents and antimetabolites, microbial and herbal medicines, as well as monoclonal antibodies). The article explores general principles of studying the drugs’ pharmacological activity in vitro, ex vivo, and in vivo, and evaluating their pharmacokinetic parameters. It describes various methods and models of research, summarises specific aspects of determination of genotoxicity, carcinogenicity, reproductive toxicity, mutagenicity, acute and chronic toxicity of various groups of medicines. It also lists criteria for selecting drug doses for toxicokinetic studies. The need for harmonisation of national requirements for conducting preclinical studies with the European standards entails alignment of terminology and further development of general algorithms for selecting doses and determining the necessary scope of research. The use of biomarkers in preclinical studies will make it possible to exclude inefficient compounds from further research.

Objective: To describe the frequency and characteristics of adverse drug events in pediatric inpatients in a Brazilian tertiary teaching hospital. Methods: A cross-sectional study was conducted by retrospective and manual chart review of 240 pediatric admissions to identify adverse drug events using 17 triggers. When triggers were detected in the chart, reviewers investigated the chart in depth to decide whether an event occurred. Consensus about the occurrence of the event was obtained in meeting with a healthcare team. Events were classified by harm category and drugs were classified according to the Anatomical Therapeutic Chemical Classification. Patients who had suffered were compared to those who had not experienced events using the chi-squared test and the Mann-Whitney U test. Results: A total of 62 adverse events were found, and 18.8% of the patients had at least one event. Adverse events rates were 25.83 per 100 admissions, 20.27 per 1000 patient-days, 25.94 per 1000 drugs, and 2.12 per 1000 drug doses. All events found were classified as temporary harm, and cardiovascular drugs were most frequently related to events. Groups of patients with and without event were segregated (p < 0.05) by the length of stay, number of drugs, and drug doses. Conclusion: The use of triggers demonstrated its utility in a pediatric setting by identifying harm. Adverse events rates were found to be higher than those of previous studies, but the harm rate was lower than other studies. This study enables the measurement of adverse events in order to define strategies to mitigate or reduce harm. Resumo Objetivo: Descrever a frequência e as características dos eventos adversos a medicamentos em pacientes pediátricos internados em um hospital universitário terciário brasileiro. Métodos: Foi realizado um estudo transversal por meio da análise retrospectiva e manual de prontuários de 240 internações pediátricas para identificar eventos adversos a medicamentos utilizando 17 rastreadores. Quando foram identificados rastreadores no prontuário, os analistas investigaram extensivamente o prontuário para decidir a respeito da existência de um evento. O consenso sobre a ocorrência do evento foi obtido em reunião com uma equipe de profissionais da saúde. Os eventos foram classificados por categoria de dano e os medicamentos foram classificados de acordo com a Classificação Anatômica Terapêutico-Química. Os pacientes que sofreram eventos adventos foram comparados aos que não apresentaram eventos adversos, com o teste qui-quadrado e o teste U de Mann-Whitney. Resultados: Verificou-se um total de 62 eventos adversos e 18,8% dos pacientes apresentaram ao menos evento. As taxas de eventos adversos foram de 25,83 por 100 internações, 20,27 por 1.000 pacientes/dia, 25,94 por 1.000 medicamentos e 2,12 por 1.000 doses de medicamentos. Todos os eventos encontrados foram classificados como dano temporário e os medicamentos cardiovasculares foram frequentemente associados aos eventos. Grupos de pacientes com e sem eventos apresentaram diferenças (p < 0,05) em relação ao tempo de internação, número e doses de medicamentos. Conclusão: O uso de rastreadores demonstrou sua utilidade no contexto pediátrico ao identificar danos. As taxas de eventos adversos foram maiores do que as taxas de estudos anteriores, porém a categoria de dano foi menor que em outros estudos. Este estudo possibilita a medição dos eventos adversos a fim de definir estratégias para minimizar ou reduzir os danos.

Fatty acid amide hydrolase (FAAH) is a key enzyme in the endocannabinoid system. N-(3,4-Dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[11C]methylphenyl)thiazol-2-yl]-1-carboxamide ([11C]DFMC) was developed as an irreversible-type positron emission tomography (PET) tracer for FAAH. Here, we attempted to noninvasively estimate rate constant k3 (rate of transfer to the specifically-bound compartment) as a direct index for FAAH in the rat brain. First, the two-tissue compartment model analysis including three parameters [K1−k3, two-tissue compartment model for the irreversible-type radiotracer (2TCMi)] in PET study with [11C]DFMC was conducted, which provided 0.21 ± 0.04 ml·cm−3·min−1 of the net uptake value (Ki), an indirect index for FAAH, in the FAAH-richest region (the cingulate cortex). Subsequently, to noninvasively estimate Ki value, the reference model analysis (Patlak graphical analysis reference model) was tried using a time-activity curve of the spinal cord. In that result, the noninvasive Ki value (KREF) was concisely estimated with high correlation (r > 0.95) to Ki values based on 2TCMi. Using estimated KREF value, we tried to obtain calculated-k3 based on previously defined equations. The calculated k3 was successfully estimated with high correlation (r = 0.95) to direct k3 in 2TCMi. Finally, the dose relationship study using calculated k3 demonstrated that in vivo ED50 value of [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate, a major inhibitor of FAAH, was 66.4 µg/kg in rat brain. In conclusion, we proposed the calculated k3 as an alternative index corresponding to regional FAAH concentrations and suggested that PET with [11C]DFMC enables occupancy study for new pharmaceuticals targeting FAAH. SIGNIFICANCE STATEMENT In the present study, we proposed calculated k3 as an alternative index corresponding with fatty acid amide hydrolase concentration. By using calculated k3, in vivo ED50 of [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate was successfully estimated to be 66.4 µg/kg for rats. Thus, we demonstrated the pharmacological utility of positron emission tomography with N-(3,4-dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[11C]methylphenyl)thiazol-2-yl]-1-carboxamide.

Treatment of neurodegenerative diseases or other central nervous system (CNS) disorders has always been a significant challenge. The nature of the blood-brain barrier (BBB) limits the penetration of therapeutic molecules to the brain after oral or parenteral administration, which, in combination with hepatic metabolism and drug elimination and inactivation during its journey in the systemic circulation, decreases the efficacy of the treatment, requires high drug doses and often induces adverse side effects. Nose-to-brain drug delivery allows the direct transport of therapeutic molecules by bypassing the BBB and increases drug concentration in the brain. The present review describes mechanisms of nose-to-brain drug delivery and discusses recent advances in this area with especial emphasis on nanotechnology-based approaches.

Objectives: To estimate the frequency of manipulations of all tablets and capsules prescribed for children in a teaching and tertiary children's hospital in China over the course of 1 month. Moreover, hypothetical reduction of manipulation according to the availability of low-strength tablets/capsules licensed by the Chinese National Medical Products Administration (CNMPA) was evaluated.Methods: Information on all tablets and capsules prescribed in the hospital from March 17 to April 16, 2019 was collected. It was assumed that tablets or capsules were manipulated if the prescribed dose would have required only a proportion of the intact dose form. Manipulation typically includes splitting or crushing tablets, opening capsules and dispersing in water, or combinations of these method. Moreover, we defined an “avoidable manipulation,” when the dose could be rounded and/or when alternative products with a reduced strength or in liquid formulation were available in the hospital, and a “inappropriate manipulation,” which involved manipulated medications with a direct contraindication for any manipulation, such as those with a narrow therapeutic index or hazardous ingredients, or modified release dosage-forms. The frequencies of total, avoidable, and inappropriate manipulation were estimated, along with the hypothetical reduction of manipulation according to the availability of CNMPA-approved drug doses.Results: A total of 17,123 prescriptions for 142 medications were identified to have required a manipulation among 78,366 prescriptions administered during the study period, with 43 different proportions of subdivisions, ranging from a 19/20 to 1/180 product strength reduction. Half, quarter, and trisection were the most common subdivisions administered. Overall, 19% of the manipulated prescriptions were determined to be avoidable, and 19% of the manipulations involved medications with a clear recommendation to not manipulate. In addition, 21% of the manipulated prescriptions could have been potentially avoided if all of the approved preparations with the lowest strength would have been available at the hospital. Any manipulations undertaken were carried out by pharmacists and family care givers.Conclusions: More than 20% of tablets and capsules prescriptions need manipulated, included a high incidence of avoidable and inappropriate manipulation.

Information regarding the pharmacokinetics of oral sildenafil in dogs with pulmonary hypertension is limited. In this study, we examined the pharmacokinetics of oral sildenafil in a canine model of chronic embolic pulmonary hypertension (CEPH). The CEPH model was developed by repeatedly injecting microspheres into the pulmonary arteries. The pharmacokinetics of oral sildenafil at 1, 2 and 4 mg/kg was evaluated using four dogs with pulmonary hypertension in the fasted state. The plasma concentrations of sildenafil were determined using high-performance liquid chromatography, and pharmacokinetic parameters were calculated using a noncompartmental analysis. Sildenafil was well tolerated in this study. Proportional increments in the maximum plasma concentration and area under the curve extrapolated to infinity at drug doses of 1, 2 and 4 mg/kg were detected using a power model analysis. No significant differences were observed among the three doses in the time to maximum plasma concentration. The mean residence time and elimination half-life were slightly but significantly higher at a dose of 4 mg/kg than at a dose of 1 mg/kg.

Oesophageal stents have been widely used to prevent occlusion or stenosis in the treatment of oesophageal cancers. However, stent restenosis caused by tumour ingrowth occurs frequently after stent placement. Incorporating anti-cancer drugs into endoluminal stents is a promising strategy to provide a sustained release of drugs to oesophageal malignant tissues while prolonging the retention of the stent and relieving dysphagia. Recognizing the potential of 3D printing to produce personalised stents with patient specific geometries, we herein report the development of a drug-loaded 3D printed stent for the sustained local delivery of 5-fluorouracil (5-FU) to treat oesophageal cancer. The 3D printed drug-eluting stents (DESs) were fabricated via fused deposition modelling using 5-FU-loaded polyurethane filament. Determination of the 5-FU in the filament and stent (>97%) confirmed that minimal degradation of the drug occurred during the thermal extrusion and 3D printing processes. The physicochemical properties of the stents were investigated using photoacoustic Fourier-transform infrared (PA-FTIR) spectrophotometry, X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA) and mechanical testing. In vitro release studies revealed that the drug-loaded stents provided a sustained release of 5-FU over a period of 110 days and allowed the constant diffusion of 5-FU when in contact with oesophageal mucosa. Furthermore, the 3D printed stents exhibited good stability following sterilization with gamma or UV irradiation, and during accelerated storage. This study demonstrates that 3D printing is a powerful tool for manufacturing DESs which could easily be customized to provide personalized, patient specific geometries and drug doses. Refereed/Peer-reviewed

This study aimed to construct an optimal algorithm for initial dose settings of vancomycin (VCM) using machine learning (ML) with decision tree (DT) analysis. Patients who were administered intravenous VCM and underwent therapeutic drug monitoring (TDM) at the Hokkaido University Hospital were enrolled. The study period was November 2011 to March 2019. In total, 654 patients were included in the study. Patients were divided into two groups, training (patients who received VCM from November 2011 to December 2017; n = 496) and testing (patients who received VCM from January 2018 to March 2019; n = 158) groups. For the training group, DT analysis of the classification and regression tree algorithm was performed to construct an algorithm (called DT algorithm) for the initial dose settings of VCM. For the testing group, the rates of attaining the VCM therapeutic range (trough value = 10-15 and 10-20 mg/L) with the DT algorithm and three conventional dose-setting methods were compared for model evaluation. The DT algorithm was constructed to be used for patients with estimated glomerular filtration rate >= 50 mL/min and body weight >= 40 kg. As a result, the recommended daily doses ranged from 20.0 to 58.1 mg/kg. In model evaluation, the DT algorithm obtained the highest rates of attaining the VCM therapeutic range compared to conventional dose-setting methods. Therefore, our DT algorithm can be applied to clinical practice. In addition, ML is useful for setting drug doses.

Objective: A large-scale capture method was developed to enable sterilisation of a macropod population in western Sydney from 2005 to 2018. Methods: Until March 2007, free ranging eastern grey kangaroos and red kangaroos were herded into purpose-built 15 m diameter capture yards (CYs) for darting with a projectile syringe. From March 2007 onwards, animals were free-range darted in large areas without herding. Kangaroos were darted with 1.33–5.10 mg/kg tiletamine/zolazepam and 0.01–0.02 mg/kg medetomidine, ± 0.03 mg/kg acepromazine. Deaths were monitored. Population counts were performed annually. Results: There were 5825 capture events involving 3963 kangaroos. Over 85% of all captures occurred from 2005 to 2008. Of all reported deaths (n = 523), 135 were attributed to ill health. Musculoskeletal injuries incurred during capture were the main project-related cause of death (n = 116). Post capture myopathy was uncommonly diagnosed following capture (n = 19). Conclusion: The herding and capture method enabled a large number of kangaroos to be mobilised and captured with low mortality rates, and the use of CYs resulted in fewer capture-related injuries and deaths than free-range capture. The drug doses and combinations used for darting were safe and effective, and the capture technique was successfully applied to a population management project.

Typical methods used in cancer treatment, including chemotherapy, are debilitating because of the various adverse side effects experienced by cancer patients. The free drug injected into the patient at given doses affects both healthy and cancerous cells. Therefore, novel methods are being researched to ensure the selectivity of the treatment. The purpose of this study is to test the release of a model fluorescent drug, calcein, from echogenic stealth liposomes, triggered by lowfrequency pulsed ultrasound. Several experimental parameters related to the ultrasound (US) and the investigated liposomes were varied in order to examine their effect on the acoustic release. Upon analysis of experimental results, the study concluded that release can be maximized by optimizing the sonication frequency, power density, and US pulse duration. When a non-isothermal chamber is used to conduct the experiments, it is important to have longer ‘Off’ than ‘On’ US periods in order to avoid overheating the liposomes. Applying such pulsation pattern can also be utilized to achieve slower release rates, which safely meet the desired drug levels at the end of the session. Our study also concluded that optimizing the liposome concentration is vital to delivering desired drug doses. Additionally, the type of lipids used in the synthesis should be carefully selected to produce stable yet acoustically sensitive liposomes capable of releasing at desired rates.

Paediatric medical emergencies can be distressing for the child, parent and clinician alike. This paper aims to remind those in primary dental care how to manage these emergencies safely and effectively. Topics covered include paediatric airway management, basic life support, defibrillation, choking, asthma, paediatric emergency drug doses and epilepsy.

Although educators frequently act as if curricula are as standardized as drug doses (300 mg of PBL t.i.d.), such is not the case. As a case in point, at its inception, Problem Based Learning was hailed as a major curriculum innovation, with the promise of enormous gains in learning outcomes. Very quickly, ecclesiastical debates arose as what was true PBL and what was "modified PBL". Ironically, systematic reviews conducted fairly early in its evolution showed that the gains in learning outcome from PBL were neither large nor uniform (Vernon and Blake in Acad Med 68:550-563, 1993), and the most consistent finding was greater student satisfaction. In this paper, we review five decades of experience with the first PBL curriculum at McMaster. We point out how the curriculum has evolved, both theoretically and practically, in response to external influences, based both on empirical evidence and practical demands. We describe these changes in four broad domains-theoretical rationale, the curriculum, assessment and admissions.

Most medical therapies require repeated, sequential administration of therapeutic agents in well-defined intervals and over extended time windows. Typically, the patient is in charge of applying the individual drug doses, and insufficient patient compliance reduces the efficiency of the treatment. Therefore, the development of a smart delivery mechanism releasing therapeutic agents in a pre-defined, time-controlled fashion would be beneficial for many medical treatments. Here, we present a DNA-mediated release cascade which allows for precisely controlling the sequential delivery of several different nanoparticles. By using complementary DNA sequences, nanoparticle aggregates are created, embedded into distinct layers of a hydrogel and released by triggering aggregate dispersal. This mechanism is compatible with physiological conditions as the release cascade is initiated by exposing the nanoparticle-loaded gel to physiological salt concentrations. Moreover, we show that the reservoir hydrogel can be enriched with biopolymers to receive charge-selective release properties towards small molecules - without interfering with the DNA-based release cascade. Owing to the excellent reproducibility, precision and effectiveness of the presented mechanism, a similar DNA-mediated release avalanche may lead to the development of autonomous and robust delivery systems, which minimize the possibility of pharmaceutical therapy failure due to patient non-compliance.

INTRODUCTION: Identification of optimal drug doses and drug combinations is crucial for optimized treatment of tuberculosis. AREAS COVERED: An unprecedented level of research activity involving multiple approaches is seeking to improve tuberculosis treatment. This report is a review of the quantitative methods currently used on clinical data sets to identify drug exposure targets and optimal drug combinations for tuberculosis treatment. A high-level summary of the methods, including the strengths and weaknesses of each method and potential methodological improvements is presented. Methods incorporating data generated from multiple sources such as in vitro and clinical studies, and their potential to provide better estimates of pharmacokinetic/pharmacodynamic (PK/PD) targets, are discussed. PK/PD relationships identified are compared between different studies and data analysis methods. EXPERT OPINION: The relationships between drug exposures and tuberculosis treatment outcomes are complex and require analytical methods capable of handling the multidimensional nature of the relationships. The choice of a method is guided by its complexity, interpretability of results, and type of data available.

Objectives To investigate the rounding of prescribed drug doses for paediatric administration. Methods A cross-sectional medication chart review was conducted at a UK paediatric hospital. Proposed administration dose volumes were calculated for prescribed doses using available manufactured liquids measured with oral and intravenous syringes. Resulting percentage deviations in doses administered were calculated. Results Of 2031 doses observed, 524 (25.8%) required rounding. The majority of which were for children aged 1–12 months. Twenty-seven rounded doses deviated from the prescribed dose by more than 10%. Conclusion This study highlights the impact of dose-rounding in paediatrics and the need for standardisation.

In this paper we present a mathematical analysis of a pharmacological ODE model for target mediated drug disposition (TMDD). It is known that solutions of this model undergo four qualitatively different phases. In this paper we provide a mathematical identification of these separate phases by viewing the TMDD model as a singular perturbed system. Our analysis is based on geometric singular perturbation theory and we believe that this approach systemizes-and sheds further light on-the scalings arguments used by previous authors. In particular, we present a novel description of the third phase through a distinguished solution of a nonlinear differential equation. We also describe the solution curve for large values of initial drug doses and recover, en route, a result by Aston et al. (J Math Biol 68(6):1453-1478, 2014) on rebounding using our alternative perturbation approach. Finally, from our main result we derive a new method for estimating the parameters of the system in the event that detailed data is available. Ideally our approach to the TMDD model should stimulate further research into applications of these methods to more complicated models in pharmacology.

Preventing microbial colonization or infections that cause offensive smells may lead to odor reduction. As both anaerobic and aerobic bacteria cause the release of malodor from wounds, the most direct way of avoiding or eliminating wound odor is to prevent or eradicate the responsible infection through the debridement of necrotic tissues. However, some burn patients with malodorous wounds are unable to undergo debridement due to systemic conditions, especially in the acute stage. Moreover, the optimal drug doses and dressings to ensure the efficacy and cost-effectiveness of odorous burn wound management is unclear. The purpose of this commentary is to outline the odor management options available for burn patients, focusing on topical strategies. Numerous potential therapies for treating odorous wounds after burn injuries are suggested.

OBJECTIVES CYP3A5 and ABCB1 are highly implicated in the pharmacokinetics and pharmacodynamics of immunosuppressive agents, such as calcineurin inhibitors and mammalian target of rapamycin inhibitors. The polymorphisms of their coding genes play important roles in the interindividual and intraindividual differences of bioavailability of these drugs. In this study, our objective was to investigate, in a Lebanese population,the frequency of ABCB1C3435T (rs1045642) and CYP3A5*3 (rs776746) polymorphisms and to compare the results to preexisting data from other populations. MATERIALS AND METHODS We determined the frequencies of the allelic variants of interest for 1824 Lebanese participants, and we compared these results with those from other major ethnic groups. RESULTS The allelic frequencies were 91.4% (C) and 8.6% (T) for CYP3A5*3 and 50.8% (T) and 49.2% (C) for ABCB1 C3435T. Our results were significantly different from most other world populations, except the European population. CONCLUSIONS The frequencies of gene variants of interest in our Lebanese population were similar to those found in European populations. Most of our study population were CYP3A5*3 carriers, and more than half may have a lower P-glycoprotein efflux pump. These characteristics might render Lebanese transplant recipients more prone to the development of drug toxicity and in need of lower drug doses.

Tissue-on-chip systems represent promising platforms for monitoring and controlling tissue functions in vitro for various purposes in biomedical research. The two-dimensional (2D) layouts of these constructs constrain the types of interactions that can be studied and limit their relevance to three-dimensional (3D) tissues. The development of 3D electronic scaffolds and microphysiological devices with geometries and functions tailored to realistic 3D tissues has the potential to create important possibilities in advanced sensing and control. This study presents classes of compliant 3D frameworks that incorporate microscale strain sensors for high-sensitivity measurements of contractile forces of engineered optogenetic muscle tissue rings, supported by quantitative simulations. Compared with traditional approaches based on optical microscopy, these 3D mechanical frameworks and sensing systems can measure not only motions but also contractile forces with high accuracy and high temporal resolution. Results of active tension force measurements of engineered muscle rings under different stimulation conditions in long-term monitoring settings for over 5 wk and in response to various chemical and drug doses demonstrate the utility of such platforms in sensing and modulation of muscle and other tissues. Possibilities for applications range from drug screening and disease modeling to biohybrid robotic engineering.

Multiple sclerosis (MS) can sometimes cause uncommon pseudotumoural lesions that produce atypical symptoms, such as motor epileptic seizures which are often pharmacoresistant. In these cases, accurate diagnosis is essential for correct therapy, even if unconventional. We present the case of a brain tumour in a 40-year-old relapsing-remitting MS patient who presented with pharmacoresistant seizures which eventually responded to nabiximols. After various therapeutic approaches, delta-9-tetrahydrocannabinol therapy was introduced with good results. Spasticity improved, pain decreased and we observed a reduction in the number of daily seizures. It is possible that delta-9-tetrahydrocannabinol can enhance the efficacy of anti-epilepsy therapy. Learning points The patient experienced fewer daily focal motor crises after the administration of nabiximols in the morning.The correct combination of symptomatic drugs can optimize a specific multiple sclerosis (MS) therapy even if the real cause of symptoms is a primary brain tumour and not MS.The addition of nabiximols to the therapeutic program allowed anti-epilepsy drug doses to be reduced and improved the patient's cognitive impairment.

Nanoparticles (NPs) in the biomedical field are known for many decades as carriers for drugs that are used to overcome biological barriers and reduce drug doses to be administrated. Some types of NPs can interact with external stimuli, such as electromagnetic radiations, promoting interesting effects (e.g., hyperthermia) or even modifying the interactions between electromagnetic field and the biological system (e.g., electroporation). For these reasons, at present these nanomaterial applications are intensively studied, especially for drugs that manifest relevant side effects, for which it is necessary to find alternatives in order to reduce the effective dose. In this review, the main electromagnetic-induced effects are deeply analyzed, with a particular focus on the activation of hyperthermia and electroporation phenomena, showing the enhanced biological performance resulting from an engineered/tailored design of the nanoparticle characteristics. Moreover, the possibility of integrating these nanofillers in polymeric matrices (e.g., electrospun membranes) is described and discussed in light of promising applications resulting from new transdermal drug delivery systems with controllable morphology and release kinetics controlled by a suitable stimulation of the interacting systems (nanofiller and interacting cells).

Background In the light of the Gosport Independent Panel Report (June 2018), we conducted a comparison of continuous subcutaneous infusions (CSCI) at end of life in hospital and hospice settings. Methods Retrospective case note review of all patients who died at a university teaching hospital and local hospice in April 2018. Results 26/34(76%) hospice patients died on an infusion in comparison to 34/86(40%) hospital patients. Select drug dose ranges were: 21/26(81%) had been on a regular opioid prior to starting an infusion in hospice, in comparison to 6/30(20%) in hospital. Median survival after starting a CSCI: 3 days in hospice, 2 days in hospital. Although recognition and discussion of dying was often recorded, documentation around starting a CSCI was poor in hospital. In the hospice, all patients had a documented indication and 24/26(92%) had a documented rationale for starting doses. While documentation of discussion with patients, family and between doctors was good, discussion with nursing staff was poorly documented in both settings. Conclusions Higher drug doses used in the hospice setting could be attributed to more complex symptom control needs and interestingly did not seem to have a negative effect on survival. This comparative review highlights areas for improvement: documentation of discussion with family about starting a CSCI, indication and rationale for starting doses in hospital and documentation of discussion with the wider team in both settings. These are likely to apply to other hospices and hospitals.

Metered dose inhalers (MDIs) are the mainstay of asthma and COPD therapy worldwide. MDIs are pocket-size hand-held drug delivery devices utilizing the energy of compressed propellant(s) for the aerosol generation. They have the drug in solution or suspension in the propellant(s), or a mixture of propellant(s) and co-solvent(s). MDIs deliver small metered drug doses either directly, or via add-on devices to the patients, like spacers or Valved Holding Chambers (VHCs) that can be used with a fast mask for children. Add-on devices hold the aerosol to eliminate the problem with correct synchronisation of dose release and inhalation. They also provide the possibility to inhale a single dose in multiple breaths. Alternatively, breath-actuated MDIs have been developed. MDIs have the disadvantage that the currently used hydrofluoroalkane (HFA) propellants contribute to the greenhouse effect and re-formulation of the drug formulations on short notice with more environment-friendly propellants may be necessary.

Scientific reports 11(1), 14366 (2021). doi:10.1038/s41598-021-93287-5, Published by Macmillan Publishers Limited, part of Springer Nature, [London]

Human protozoan parasitic diseases are major issue of concern mainly in the tropical regions of the world. Human protozoan parasitic diseases that have high morbidity and mortality rate include malaria, leishmaniasis, and toxoplasmosis. The convetional treatments involved are not cost-effective and thus can’t be afforded by everyone. Also, vaccinations against these diseases have achieved limited success due to the incredible smartness of these protozoan parasites. Due to this, chemotherapy remains the mainstay for treatment and often high drug doses are administered leading to severe side effects and drug resistance in the parasites. The application of nanotechnology seems to be an attractive alternative approach to the conventional method. Nanoparticles are more effective as they have higher bioavailability, increased clearance rate and they can be engineered to be target-specific wherein they can affect the diseased cells only. This chapter discusses the current treatments used against these protozoan parasites and also their shortcomings. Different types of nanoparticles have been designed to target the parasites such as lipid-based, metallic/inorganic and polymeric based nanoparticles. Since nanoparticles are less toxic and can be engineered to be more effective in controlling and preventing parasitic diseases, it can show the way for future anti-parasitic treatments using nanotherapeutics.

Understanding the clinical pharmacokinetics and pharmacodynamics (PKPD) principles of anti-tuberculosis medication is critical if healthcare practitioners are to apply the safe and effective therapeutic management of these agents. One of the tools that can be applied is therapeutic drug monitoring (TDM) which allows the possibility to individualise drug doses to ensure concentrations are efficacious and not toxic. This chapter will explore when TDM should be performed together with offering some practical advice about their interpretation.

This paper presents a practical emulator of a generalised fractional-order model for gene regulation process, in an analog platform. The presented emulator is based on the second-generation current conveyor (CCII) and implemented using AD844 chips. The emulator realises a proposed generalised mathematical model for gene expression. The model sums up three different single models; the constitutive gene model, the induced gene expression under the effect of activators and repressors models. The generalised model is based on fractional-order differential equations where the concentration of the mRNA and the Protein expressed are the model variables. The study of model dynamics is detailed, and the experimental results are presented to confirm the accuracy between the practical emulator and the theoretical models. With the aid of fractional-order parameters, the proposed emulator helps test and analyse the gene regulation process. The management of drug doses and forecast of the exact timing to kill cancer cells is just an example of how to benefit from this emulator without practical animal or human tests.

Disability and even death from acute thrombosis remain a grave menace to public health. At present, the traditional drugs represented by urokinase (UK) in clinical thrombolysis can cause side effects of bleeding when the dosage is excess. Therefore, a more effective and safer method of thrombolysis is urgently needed. In this paper, a multifunctional dual-drug sequential release thrombolysis platform (UK-UH@PDA@HMSNs) consisting of polydopamine (PDA)-modified hollow mesoporous silicon (HMSNs) loading with UK and unfractionated heparin (UH) was constructed with a double physical assistance (NIR-II and bubbles). With the aid of near infrared-II (NIR-II, 1064 nm, 1.0 W cm-2) laser, the photothermal effect of PDA could be motivated to facilitate the UH release, thereby accelerating the dissolution of thrombus. Afterward, the local hyperthermia effect could expedite the phase transition of l-menthol in HMSNs to generate bubbles to promote the release of UK, thereby realizing the sequential release of two thrombolytic drugs. Importantly, this method deftly conquered the inherent obstacle that UK and UH cannot be combined directly. In vivo and in vitro experiments proved that the thrombolytic efficiency of UK-UH@PDA@HMSNs stimulated by NIR-II was nearly 3 times than that of UK alone. Collectively, the proposed dual physical assistance and sequential dual-drug delivery system significantly improved the efficiency of thrombolysis under the premise of limiting drug doses; the risk of death from intracranial hemorrhage thus could be decreased radically.

Adaptive therapy is an evolution-based treatment approach that aims to maintain tumor volume by employing minimum effective drug doses or timed drug holidays. For successful adaptive therapy outcomes, it is critical to find the optimal timing of treatment switch points. Mathematical models are ideal tools to facilitate adaptive therapy dosing and switch time points. We developed two different mathematical models to examine interactions between drug-sensitive and resistant cells in a tumor. The first model assumes genetically fixed drug-sensitive and resistant populations that compete for limited resources. Resistant cell growth is inhibited by sensitive cells. The second model considers phenotypic switching between drug-sensitive and resistant cells. We calibrated each model to fit melanoma patient biomarker changes over time and predicted patient-specific adaptive therapy schedules. Overall, the models predict that adaptive therapy would have delayed time to progression by 6-25 months compared to continuous therapy with dose rates of 6%-74% relative to continuous therapy. We identified predictive factors driving the clinical time gained by adaptive therapy. The first model predicts 6-20 months gained from continuous therapy when the initial population of sensitive cells is large enough, and when the sensitive cells have a large competitive effect on resistant cells. The second model predicts 20-25 months gained from continuous therapy when the switching rate from resistant to sensitive cells is high and the growth rate of sensitive cells is low. This study highlights that there is a range of potential patient specific benefits of adaptive therapy, depending on the underlying mechanism of resistance, and identifies tumor specific parameters that modulate this benefit.

The administration of drugs and fluid, most of which are given as the dose per kg of body weight, is a vital component in the management of the seriously injured child. Obtaining an accurate weight on arrival may not be immediately achievable because of instability, immobilisation and ongoing resuscitation. The paediatric STAG (Scottish trauma audit group) data from * hospital was used to identify patients over 12 months. Clinical notes were reviewed to assess if weight was estimated or accurately measured. 56 paediatric trauma patients who met the STAG inclusion criteria presented to * over the 12 month period. 27/56 (48%) patients had an estimated weight on arrival; 5 were estimated using the ‘old’ APLS formula, 12 using the ‘new’ formulae and for the remaining 10 the method used was unclear. Of those who initially had an estimated weight only 7/27 (26%) went on to have an accurate weight obtained at any time during their admission. In 5 patients, weight was underestimated (mean -12%) and in 2 patients, weight was overestimated (mean +19%). The weight estimation error ranged from negative 28% to positive 20%. Assessing the percentage error of estimated weight was challenging in this group of patients due to the small number on which an accurate weight was measured during this admission. Poor documentation may have been a contributing factor in some cases with the weight on a patient’s drug kardex only being clearly identified as being an ‘estimated’ value in 66% of patients. There are many implications of using an estimated weight, including errors in drug doses, fluid bolus, maintenance fluids, ventilator settings and assessment of urine output. In this cohort the estimated weight that followed them throughout their admission has implications on their immediate resuscitation and extended inpatient care and highlights the importance of obtaining an accurate weight at the time of arrival. What can we do differently? We have implemented the use of a pat-slide weighing scale by MARSDEN to get an accurate weight from time of arrival. This device enables a rapid weight to be obtained during patient transfer to the trolley.

An application named ‘Dosing GAMA’ has developed for drug doses adjustment in patients with renal and hepar impairment. Dosing GAMA is targeted for clinical Pharmacists to calculate and make dose recommendations for patients, based on renal and hepatic conditions. This study aims to identify the appropriateness of drug dosage adjustment by using Dosing GAMA application in hospitalized patients with renal impairment and to determine the risk factors for the drug dose inappropriateness. This study was a retrospective observational descriptive study, cross-sectional design, used a consecutive sampling technique. The source of the data was Medical Record of hospitalized patients with renal impairment (creatinine clearance ≤50 mL/min) from 2018 of February till 2020 of March in the Academic Hospital of UGM. The names and the doses of the drugs were filled to Dosing GAMA application, and it would evaluate the appropriateness of drug doses. There were 570 drugs of 73 medical records included in this study. This study revealed Dosing GAMA could assess 144 drugs (25,6%) need to adjust, and 82 drugs (56,9%) were inappropriate doses. There were significant correlations of the age characteristic (p=0,000) and the creatinine clearance value (p=0,012) to the drugs dose appropriateness. There were inappropriate doses need to adjust in the hospital. So, the use of health-based technology expected for pharmacists to improve the use of drugs rationally.

For more than one hundred years, several treatments against malaria have been proposed but they have systematically failed, mainly due to the occurrence of drug resistance in part resulting from the exposure of the parasite to low drug doses. Several factors are behind this problem, including (i) the formidable barrier imposed by the Plasmodium life cycle with intracellular localization of parasites in hepatocytes and red blood cells, (ii) the adverse fluidic conditions encountered in the blood circulation that affect the interaction of molecular components with target cells, and (iii) the unfavorable physicochemical characteristics of most antimalarial drugs, which have an amphiphilic character and can be widely distributed into body tissues after administration and rapidly metabolized in the liver. To surpass these drawbacks, rather than focusing all efforts on discovering new drugs whose efficacy is quickly decreased by the parasite's evolution of resistance, the development of effective drug delivery carriers is a promising strategy. Nanomaterials have been investigated for their capacity to effectively deliver antimalarial drugs at local doses sufficiently high to kill the parasites and avoid drug resistance evolution, while maintaining a low overall dose to prevent undesirable toxic side effects. In recent years, several nanostructured systems such as liposomes, polymeric nanoparticles or dendrimers have been shown to be capable of improving the efficacy of antimalarial therapies. In this respect, nanomaterials are a promising drug delivery vehicle and can be used in therapeutic strategies designed to fight the parasite both in humans and in the mosquito vector of the disease. The chemical analyses of these nanomaterials are essential for the proposal and development of effective anti-malaria therapies. This review is intended to analyze the application of nanomaterials to improve the drug efficacy on different stages of the malaria parasites in both the human and mosquito hosts., This research was supported by grants RTI2018-094579-B-I00, PCIN-2017-100, PGC2018-097583-B-I00, PGC2018-093761-B-C31, CTQ2017-90596-REDT (Ministerio de Ciencia, Innovación y Universidades, Spain, which included FEDER funds), 2017-178 (ERA-NET Cofund EURONANOMED), 2017-SGR-908 (Generalitat de Catalunya, Spain), and E47_20R (Gobierno de Aragón-FSE). ISGlobal and IBEC are members of the CERCA Programme, Generalitat de Catalunya, and both acknowledge support from the Spanish Ministry of Science, Innovation and Universities through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000806-S). This research is part of ISGlobal's Program on the Molecular Mechanisms of Malaria, which is partially supported by the Fundación Ramón Areces. LNB-C was supported by the European Commission under Horizon 2020's Marie Skłodowska-Curie Actions COFUND scheme (712754) and by the Severo Ochoa programme of the Spanish Ministry of Science and Competitiveness, SEV-2014-0425 (2015–2019). MSA thanks the Ministerio de Ciencia, Innovación y Universidades, for her grant (BES-2016-078774)., We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).

Hair is considered an efficient tool to investigate drug-related histories; thus, the selection of the method of sample preparation is important to obtain a reliable result. The aim of this study was to compare two methods of hair preparation (cutting and pulverizing) to analyse levetiracetam concentration in hair. An additional aim was to evaluate the potential usefulness of the levetiracetam concentration measured as an index of a dosing schedule. Four groups of 12 rats were included in the experiment. Depending on the group, the rats received 10 mg/kg of levetiracetam intraperitoneally every 24, 48 and 72 hours for 30 days. The control group was not treated. At the end of the drug administration, the rats' hair was shaved, cut or pulverized and analysed by the LC/MS-MS method to determine the concentration of levetiracetam. A stronger correlation between the mean hair levetiracetam concentration in hair and the number of drug doses was found in pulverized hair than in cut hair. A smaller standard deviation between the results was obtained in the case of pulverized hair. The results indicate that pulverization gives a more reliable result of drug concentration in hair than cutting and that drug concentration in hair can reflect the scheme of levetiracetam administration.

A growing body of literature indicates that microbiota plays a significant role in the development and curability of cancer, essentially due to the microbial ability to modulate immune and inflammatory responses to cancer and therapeutic treatments. Probiotics consumption, either in the form of food or supplements, is an easy and feasible way to manipulate microbiota composition and a number of recent researches have shown that it may represent a valid approach to prevent cancer onset and progression, to improve the clinical efficacy of the current anticancer treatments, and to mitigate the harmful adverse events of chemo- and radiotherapy, which often lead to scale drug doses, to delay or interrupt treatments. In this review, we gather the main in vivo studies on the current topic, focusing on the beneficial effects and underlying mechanisms provided by bacterial and yeast probiotics and their combination, in the setting of various types of cancers and different therapeutic protocols. These findings will likely open the way to consider, in future, regular probiotics intake as an adjuvant strategy in cancer prevention and management.