Indigenous and tribal peoples' health (The Lancet-Lowitja Institute Global Collaboration): a population study.

BACKGROUND: International studies of the health of Indigenous and tribal peoples provide important public health insights. Reliable data are required for the development of policy and health services. Previous studies document poorer outcomes for Indigenous peoples compared with benchmark populations, but have been restricted in their coverage of countries or the range of health indicators. Our objective is to describe the health and social status of Indigenous and tribal peoples relative to benchmark populations from a sample of countries. METHODS: Collaborators with expertise in Indigenous health data systems were identified for each country. Data were obtained for population, life expectancy at birth, infant mortality, low and high birthweight, maternal mortality, nutritional status, educational attainment, and economic status. Data sources consisted of governmental data, data from non-governmental organisations such as UNICEF, and other research. Absolute and relative differences were calculated. FINDINGS: Our data (23 countries, 28 populations) provide evidence of poorer health and social outcomes for Indigenous peoples than for non-Indigenous populations. However, this is not uniformly the case, and the size of the rate difference varies. We document poorer outcomes for Indigenous populations for: life expectancy at birth for 16 of 18 populations with a difference greater than 1 year in 15 populations; infant mortality rate for 18 of 19 populations with a rate difference greater than one per 1000 livebirths in 16 populations; maternal mortality in ten populations; low birthweight with the rate difference greater than 2% in three populations; high birthweight with the rate difference greater than 2% in one population; child malnutrition for ten of 16 populations with a difference greater than 10% in five populations; child obesity for eight of 12 populations with a difference greater than 5% in four populations; adult obesity for seven of 13 populations with a difference greater than 10% in four populations; educational attainment for 26 of 27 populations with a difference greater than 1% in 24 populations; and economic status for 15 of 18 populations with a difference greater than 1% in 14 populations. INTERPRETATION: We systematically collated data across a broader sample of countries and indicators than done in previous studies. Taking into account the UN Sustainable Development Goals, we recommend that national governments develop targeted policy responses to Indigenous health, improving access to health services, and Indigenous data within national surveillance systems. FUNDING: The Lowitja Institute.

Compartment syndrome of the foot: A case report.

Background: Exercise-induced compartment syndrome is a condition characterized by elevated pressure within a muscle compartment, resulting from repetitive loading or participation in sports activities. Primarily affecting the medial compartment of the foot, this rare condition manifests as sudden-onset pain in the medial aspect of the foot, without a discernible history of trauma, occurring during or after physical exertion. Diagnosis is primarily clinical in nature, as diagnostic imaging techniques provide limited utility. Conclusions: Exercise-induced compartment syndrome is a rare syndrome with prolonged implications such as contractures, claw toes, muscle weakness, and sensory neuropathy. Hence, it is imperative for orthopedic surgeons to be familiar with this condition in order to facilitate timely diagnosis and treatment.

Results of the transition from posterolateral to anterior minimally invasive approach for total hip arthroplasty.

BACKGROUND: The anterior minimally invasive (AMI) approach reduces soft tissue damage, risk of dislocation and enhances recovery, but it is associated with certain complications. The aim of this study is to compare the outcomes of patients who underwent total hip arthroplasty (THA) through posterolateral (PL) and AMI approaches performed by the same surgeon, in order to determine the learning curve associated with this new approach. METHODS: This retrospective cohort study included patients who underwent THA via PL and AMI approach between 2017 and 2022, with a minimum follow-up of 1 year. Hip fracture and oncologic patients were excluded. Demographic variables, functional scores and perioperative complications were assessed. A bivariate analysis was performed to identify differences between groups. RESULTS: Data of 124 AMI and 120 PL patients were analyzed. Demographic characteristics among groups were homogeneous. Functional outcomes at 3 months were superior for AMI (Oxford: 43 vs. 38; p < 0.05), no dislocations were identified (0% vs. 4.2%; p < 0.05) and no differences in the transfusion rate were found (6.5% AMI vs. 6.7% PL; p = 0.996). Infection rate was 4% for AMI and 3.4% for PL (p = 0.572). Surgical time was shorter for the PL approach, but the median surgical time of the last 25 AMI cases was shorter. CONCLUSIONS: The AMI approach is an excellent alternative for patients requiring THA. Although surgical time and perioperative bleeding were greater during the learning curve, this approach offers improved functional outcomes and a lower dislocation rate, without significant differences in transfusion and infection outcomes, demonstrating that responsible innovation and safe implementation of new techniques is possible.

Cross-cultural translation and validation of the Spanish version of the patellofemoral pain and osteoarthritis subscale of the KOOS (KOOS-PF).

OBJECTIVE: The aim of this study was to translate to Spanish the patellofemoral pain and osteoarthritis subscale of the knee injury and osteoarthritis outcome score (KOOS-PF) and validate this Spanish version of a disease-specific patient-reported outcome measure (PROM) for patellofemoral pain. RESULTS: The KOOS-PF was translated to Spanish and sixty patients with patellofemoral pain and/or osteoarthritis accepted to complete the questionnaire. 1-week later 58 patients answered the questions again for the test-retest reliability validation and finally 55 patients completed 1-month later for the responsiveness assessment. The Spanish version showed very good internal consistency (Cronbach's alpha: 0.93) and test-retest reliability (intraclass correlation coefficient: 0.82). Responsiveness was confirmed, showing a strong correlation with the global rating of change (GROC) score (r 0.64). The minimal detectable change was 11.1 points, the minimal important change was 17.2 points, and there were no floor or ceiling effects for the score.

Performing point-of-care molecular testing for SARS-CoV-2 with RNA extraction and isothermal amplification.

To respond to the urgent need for COVID-19 testing, countries perform nucleic acid amplification tests (NAAT) for the detection of SARS-CoV-2 in centralized laboratories. Real-time RT-PCR (Reverse transcription-Polymerase Chain Reaction), used to amplify and detect the viral RNA., is considered, as the current gold standard for diagnostics. It is an efficient process, but the complex engineering required for automated RNA extraction and temperature cycling makes it incompatible for use in point of care settings [1]. In the present work, by harnessing progress made in the past two decades in isothermal amplification and paper microfluidics, we created a portable test, in which SARS-CoV-2 RNA is extracted, amplified isothermally by RT-LAMP (Loop-mediated Isothermal Amplification), and detected using intercalating dyes or fluorescent probes. Depending on the viral load in the tested samples, the detection takes between twenty minutes and one hour. Using a set of 16 pools of naso-pharyngal swab eluates, we estimated a limit of detection comparable to real-time RT-PCR (i.e. 1 genome copies per microliter of clinical sample) and no cross-reaction with eight major respiratory viruses currently circulating in Europe. We designed and fabricated an easy-to-use portable device called "COVIDISC" to carry out the test at the point of care. The low cost of the materials along with the absence of complex equipment will expedite the widespread dissemination of this device. What is proposed here is a new efficient tool to help managing the pandemics.

In vitro antifungal activities of bis(alkylpyridinium)alkane compounds against pathogenic yeasts and molds.

Ten bis(alkylpyridinium)alkane compounds were tested for antifungal activity against 19 species (26 isolates) of yeasts and molds. We then determined the MICs and minimum fungicidal concentrations (MFCs) of four of the most active compounds (compounds 1, 4, 5, and 8) against 80 Candida and 20 cryptococcal isolates, in comparison with the MICs of amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, and caspofungin, using Clinical Laboratory and Standards Institutes broth microdulition M27-A3 (yeasts) or M38-A2 (filamentous fungi) susceptibility protocols. The compounds were more potent against Candida and Cryptococcus spp. (MIC range, 0.74 to 27.9 microg/ml) than molds (0.74 to 59.7 microg/ml). MICs against Exophiala were 0.37 to 5.9 microg/ml and as low as 1.48 microg/ml for Scedosporium but >or=25 microg/ml for zygomycetes, Aspergillus, and Fusarium spp. Compounds 1, 4, 5, and 8 exhibited good fungicidal activity against Candida and Cryptococcus, except for Candida parapsilosis (MICs of >44 mug/ml). Geometric mean (GM) MICs were similar to those of amphotericin B and lower than or comparable to fluconazole GM MICs but 10- to 100-fold greater than those for the other azoles. GM MICs against Candida glabrata were <1 microg/ml, significantly lower than fluconazole GM MICs (P<0.001) and similar to those of itraconazole, posaconazole, and voriconazole (GM MIC range of 0.4 to 1.23 microg/ml). The GM MIC of compound 4 against Candida guilliermondii was lower than that of fluconazole (1.69 microg/ml versus 7.48 microg/ml; P=0.012). MICs against Cryptococcus neoformans and Cryptococcus gattii were similar to those of fluconazole. The GM MIC of compound 4 was significantly higher for C. neoformans (3.83 mug/ml versus 1.81 microg/ml for C. gattii; P=0.015). This study has identified clinically relevant in vitro antifungal activities of novel bisalkypyridinium alkane compounds.

Sociodemographic factors associated with the consumption of ultra-processed foods in Colombia.

OBJECTIVE: To analyze the consumption of ultra-processed foods in the Colombian population across sociodemographic factors. METHODS: We used data from the 2005 National Survey of the Nutritional Status in Colombia. Food consumption was assessed using a 24-hour food recall in 38,643 individuals. The food items were classified according to the degree and extent of industrial processing using the NOVA classification. RESULTS: The mean calorie contribution of ultra-processed foods ranged from 0.2% in the lowest quintile of consumers to 41.1% in the highest quintile of consumers. The greatest increases were due to the consumption of industrialized breads, sweet and savory snacks, sugary drinks, processed meats, and confectionery. No major differences were found in the consumption of ultra-processed foods between men and women. We observed significant differences by age, socioeconomic status, area of residence, and geographic region. Children and adolescents showed a higher intake of ultra-processed foods, almost double that of participants over 50 years of age. Children consumed significantly more snacks, confectionery products, processed cereals, milk-based drinks and desserts. Participants over 50 years consumed fewer products from these sub-groups of ultra-processed foods but had the highest consumption of industrialized bread. Individuals from urban areas, those with high socioeconomic status, participants residing in the Bogotá region had 1.5 to 1.7 times higher calorie intake from ultra-processed foods compared with those from a lower socioeconomic status and those residing in rural regions. CONCLUSION: In Colombia, industrialized bread is the ultra-processed product that is most easily assimilated into the traditional diet, along with snacks and sugary drinks. Children and adolescents residing in urban areas and households with greater purchasing power have some of the highest intakes of ultra-processed foods in the country.

Synthesis, antifungal, haemolytic and cytotoxic activities of a series of bis(alkylpyridinium)alkanes.

A series of bis(alkylpyridinium)alkanes with a twelve carbon spacer between the positive charges was synthesised and their antifungal activity has been investigated. Compounds with 2-pentyl, 4-pentyl, 4-hexyl, 4-octyl, 4-propylbenzene, 3,4-dipentyl, 4-(5'-nonyl) and 3-methyl,4-pentyl head groups were the most potent antifungal agents with MICs in the range of 1.4-2.7 microM against reference strains of both Cryptococcus neoformans and Candida albicans.

Retears of the Rotator Cuff: An Ultrasonographic Assessment During the First Postoperative Year.

BACKGROUND: Surgical repair of rotator cuff (RC) tears is an effective treatment option. However, the prevalence of recurrent ruptures is high. HYPOTHESIS: Recurrent tears are a frequent complication of surgical repair of RC tears. Their incidence might be influenced by factors such as the patient's age and size of the initial tear. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Data from 90 adult patients who underwent arthroscopic RC repair between 2014 and 2017 and underwent an ultrasound examination 6 to 12 months after surgery were analyzed retrospectively. Massive tears were repaired using a double-row technique, and nonmassive tears were repaired with a single-row technique. Clinical records were reviewed for demographic information. RESULTS: All patients (57.8% women; 42.2% men) were older than 18 years (mean, 58.9 years). Of these patients, 30.0% (27/90) had massive tears, which were primarily found in patients ≥60 years (74.1%; 20/27). Complete healing was seen in 74.5% of all repairs during follow-up. A total of 23 patients (25.5%) had retears (13 complete; 10 partial), which were diagnosed by ultrasound imaging 6 to 12 months after the initial surgery. The occurrence of retears was more prevalent in patients with massive tears than in patients with nonmassive tears (40.7% vs 19.0%, respectively); the difference was statistically significant (P = .03). Reruptures occurred in 50.0% of patients older than 60 years with massive tears. Although patients older than 60 years had more recurrent tears (32.6%) compared with younger patients (18.2%), the difference was not statistically significant (P = .12). CONCLUSION: One-quarter of the patients who had undergone surgical repair of an RC tear had recurrent ruptures. There was a statistically significant association between the initial massive tear and a retear. Patients older than 60 years showed a higher recurrence rate, but this difference lacked statistical significance. Reruptures occurred in 50.0% of patients older than 60 years with massive tears.

Synthesis and Evaluation of a Series of Bis(pentylpyridinium) Compounds as Antifungal Agents.

A series of bis(4-pentylpyridinium) compounds with a variety of spacers between the pyridinium headgroups was synthesised, and the antifungal activity of these compounds was investigated. Lengthening the alkyl spacer between the pentylpyridinium headgroups from 12 to 16 methylene units resulted in increased antifungal activity against C. neoformans and C. albicans, but also resulted in increased hemolytic activity and cytotoxicity against mammalian cells. However, inclusion of an ortho-substituted benzene ring in the centre of the alkyl spacer resulted in decreased cytotoxicity and hemolytic activity, while maintaining antifungal potency. Replacement of the alkyl and aromatic-containing spacers by more hydrophilic ethylene glycol groups resulted in a loss of antifungal activity. Some of the compounds inhibited fungal PLB1 activity, but the low correlation of this inhibition with antifungal potency indicates PLB1 inhibition is unlikely to be the predominant mode of antifungal action of this class of compounds, with preliminary studies suggesting they may act via disruption of fungal mitochondrial function.

Correlation of antifungal activity with fungal phospholipase inhibition using a series of bisquaternary ammonium salts.

A series of bisquaternary ammonium salts with a 12-carbon spacer between the positive charges were synthesized, and their antifungal activity has been investigated. Compounds with butyl, pentyl, and isopentyl headgroups were the most potent antifungal agents with MICs in the range of 2.2-5.5 microM against both Cryptococcus neoformans and Candida albicans. The antifungal activity of these compounds correlated with their inhibition of cryptococcal phospholipase B1 (PLB1), a newly identified virulence factor. This indicates that the mode of action of these compounds may be inhibition of the fungal PLB1 enzyme, further validating this enzyme as a target for the development of novel antifungal therapies.

Sociodemographic factors associated with the consumption of ultra-processed foods in Colombia / Factores sociodemográficos asociados al consumo de alimentos ultraprocesados en Colombia

ABSTRACT OBJECTIVE To analyze the consumption of ultra-processed foods in the Colombian population across sociodemographic factors. METHODS We used data from the 2005 National Survey of the Nutritional Status in Colombia. Food consumption was assessed using a 24-hour food recall in 38,643 individuals. The food items were classified according to the degree and extent of industrial processing using the NOVA classification. RESULTS The mean calorie contribution of ultra-processed foods ranged from 0.2% in the lowest quintile of consumers to 41.1% in the highest quintile of consumers. The greatest increases were due to the consumption of industrialized breads, sweet and savory snacks, sugary drinks, processed meats, and confectionery. No major differences were found in the consumption of ultra-processed foods between men and women. We observed significant differences by age, socioeconomic status, area of residence, and geographic region. Children and adolescents showed a higher intake of ultra-processed foods, almost double that of participants over 50 years of age. Children consumed significantly more snacks, confectionery products, processed cereals, milk-based drinks and desserts. Participants over 50 years consumed fewer products from these sub-groups of ultra-processed foods but had the highest consumption of industrialized bread. Individuals from urban areas, those with high socioeconomic status, participants residing in the Bogotá region had 1.5 to 1.7 times higher calorie intake from ultra-processed foods compared with those from a lower socioeconomic status and those residing in rural regions. CONCLUSION In Colombia, industrialized bread is the ultra-processed product that is most easily assimilated into the traditional diet, along with snacks and sugary drinks. Children and adolescents residing in urban areas and households with greater purchasing power have some of the highest intakes of ultra-processed foods in the country.

RESUMEN OBJETIVO Analizar el consumo de alimentos ultraprocessados en la población colombiana según factores sociodemográficos. MÉTODOS Se usaron datos de la Encuesta Nacional de la Situación Nutricional en Colombia del año 2005. El consumo de alimentos se evaluó por medio de recordatorio 24 horas en 38.643 individuos. Los ítems alimentarios se clasificaron según el grado y extensión de procesamiento industrial usando la propuesta NOVA. RESULTADOS La contribución promedio de calorías de los alimentos ultraprocesados varió del 0,2% en el primer quintil al 41,1% en el ultimo quintil. Los mayores incrementos se dieron por el consumo de panes industrializados, snacks dulces y salados, las bebidas azucaradas, las carnes procesadas y los productos de confitería. No hubo grandes diferencias en el consumo de alimentos ultraprocesados entre hombres y mujeres. Se observaron diferencias significativas por edad, estatus socioeconómico, área de residencia y región geográfica. Los niños y adolescentes presentaron mayor ingesta de alimentos ultraprocesados, casi el doble que los participantes mayores de 50 años. Los niños consumieron significativamente mayor cantidad de snacks, productos de confitería, cereales procesados, bebidas a base de leche y postres. Mientras que los participantes mayores de 50 años consumieron menor cantidad de productos de estos subgrupos de alimentos ultraprocesados, pero tenían el consumo más alto de pan industrializado. Los habitantes urbanos, con alto estatus socioeconómico, que residían en la región de Bogotá tenían entre 1,5 a 1,7 más veces de ingesta calórica de alimentos ultraprocesados en comparación con sus contrapartes de bajo estatus socioeconómico, y sus contrapartes rurales. CONCLUSIÓN En Colombia, el pan industrializado es el alimento ultraprocesado más fácilmente asimilable en la dieta tradicional, junto con los snacks y las bebidas azucaradas. Los niños y adolescentes residentes en zonas urbanas y hogares con mayor poder adquisitivo fueron más vulnerables en el consumo de alimentos ultraprocesados.

Fracturas en niños: experiencia en un centro de alta complejidad del suroccidente Colombiano / Fractures in children: experience in a tertiary referral hospital in South west Colombia

Resumen Introducción: Es importante conocer las características demográficas y clínicas de las fracturas en niños para mejorar las estrategias de prevención y tratamiento en estos pacientes. Objetivos: Describir las fracturas en niños y sus características epidemiológicas. Metodología: Estudio tipo corte transversal desde enero 2014 hasta diciembre 2017. Pacientes menores de 18 años que consultaron por fracturas a una clínica en Colombia fueron incluidos. Se incluyeron datos demográficos, lugar donde ocurrió el trauma, huesos fracturados y tipo de tratamiento. Se evaluó la distribución por género y grupo etario. La fuente de información fue la historia clínica. Se utilizaron medidas de tendencia central y dispersión para agrupar los datos. Se calculó la incidencia de fracturas por cada 1000 niños/ año. Este estudio recibió aval del comité de ética de la institución. Resultados: Hubo 2436 niños fracturados, 65.6% (n=1597) ocurrieron en hombres. La mayoría fueron entre 6-11 años (40.7%, n=991), luego entre 12-17 años (36.4%, n=887) y finalmente, menores de 6 años (22.9%, n=558). La localización de la fractura más frecuente entre 0-5 años fue el húmero (30.6%, n=171), seguido por el radio (29%, n=162) y la clavícula (15.9%, n=89); entre 6-11 años fue el radio (45.2%, n=448), seguido por el húmero (18%, n=178) y el cúbito (16.6%, n=165); y entre 12-17 años fue el radio (34.6%, n=307), seguido por los huesos de la mano (22.7%, n=201) y los huesos del pie (10.8%, n=96). Requirieron manejo quirúrgico 30.9% de los niños fracturados (n=752). La incidencia de fracturas fue de 29.7/1000 niños por año. Conclusión: Las fracturas en niños se presentan con mayor frecuencia en el género masculino. Los huesos fracturados varían dependiendo del grupo etario, con un porcentaje importante del radio en todos los grupos. La mayoría se manejan de forma conservadora.

Abstract Introduction: It is important to know the demographic and clinical characteristics of fractures in children to improve prevention and treatment strategies in these patients. Objectives: To describe fractures in children and their epidemiological characteristics. Methodology: Cross-sectional study performed between January 2014 and December 2017. Patients under 18 years old with fractures who consulted to a hospital in Colombia were included. Demographic data, the location where the trauma occurred, fractured bones and type of treatment were included. Age and gender distribution were analyzed. Medical records were the source of information. Central tendency and dispersion measures were used to group the data. Incidence of fractures per 1000 children / year was calculated. This study received approval from the institution's ethics committee. Results: There were 2436 children with fractures, 65.6% (n=1597) occurred in males. Most fractures were in children between 6-11 years old (40.7%, n=991), followed by 12-17 years old (36.4%, n=887) and finally by children under 6 years old (22.9%, n=558). For the group under 6 years, most fractures occurred in humerus (30.6%, n=171), followed by radius (29%, n=162) and clavicle (15.9%, n=89); between 6-11 years old it was in radius (45.2%, n=448), followed by humerus (18%, n=178) and ulna (16.6%, n=165); and between 12-17 years it was in radio (34.6%, n=307), followed by bones of the hand (22.7%, n=201) and bones of the foot (10.8%, n=96). Surgical treatment was required in 30.9% (n=752) of the patients. The incidence of fractures was 29.7/1000 children per year. Conclusions: Fractures in children occur more frequently in males. The fractured bones differ depending on the age group; however, radius fractures represent an important proportion in all groups. Most fractures in children are treated in a conservative manner.

Lipophilic adamantyl- or deferasirox-based conjugates of desferrioxamine B have enhanced neuroprotective capacity: implications for Parkinson disease.

Parkinson disease (PD) is a neurodegenerative disease characterized by death of dopaminergic neurons in the substantia nigra region of the brain. Iron content is also elevated in this region in PD and is implicated in the pathobiology of the disease. Desferrioxamine B (DFOB) is a high-affinity iron chelator and has shown efficacy in animal models of Parkinson disease. The high water solubility of DFOB, however, attenuates its ability to enter the brain. In this study, we have conjugated DFOB to derivatives of adamantane or the clinical iron chelator deferasirox to produce lipophilic compounds designed to increase the bioavailability of DFOB to brain cells. We found that the novel compounds are highly effective in preventing iron-mediated paraquat and hydrogen peroxide toxicity in neuronal-like BE2-M17 dopaminergic cells, primary neurons, and iron-loaded or glutathione-depleted primary astrocytes. The compounds also alleviated paraquat toxicity in BE2-M17 cells that express the PD-causing A30P mutation of α-synuclein. This protection was ∼66-fold more potent than DFOB alone and also more effective than other cell-permeative metal chelators, clioquinol and phenanthroline. These results demonstrate that increasing the bioavailability of DFOB through the conjugation of lipophilic fragments greatly enhances its protective capacity. These novel compounds have potential as therapeutics for the treatment of PD and other conditions of Fe dyshomeostasis.

The many faces of the adamantyl group in drug design.

Adamantyl-based compounds are used clinically for the treatment of neurological conditions, as anti-viral agents and as agents against type 2 diabetes. The value of the adamantyl group in drug design is multidimensional. The hydrophobic substituent constant for the adamantyl group has been estimated from the calculated partition coefficients (clogP values) of 31 adamantyl-bearing compounds in the clinic or in development as πadamantyl=3.1, which indicates that the logP value of a compound with high water solubility (logP<<0) could be moved with an adamantyl-based modification to a region that is more clinically useful. The steric bulk of the adamantyl group can: (i) restrict or modulate intramolecular reactivity; and (ii) impede the access of hydrolytic enzymes, thereby increasing drug stability and plasma half life. The value of the adamantyl group in drug design has been recognized most recently in the design of agents to treat iron overload disease (in development), malaria (in clinical trials) and type 2 diabetes (in the clinic).

Conjugates of desferrioxamine B (DFOB) with derivatives of adamantane or with orally available chelators as potential agents for treating iron overload.

Desferrioxamine B (DFOB) conjugates with adamantane-1-carboxylic acid, 3-hydroxyadamantane-1-carboxylic acid, 3,5-dimethyladamantane-1-carboxylic acid, adamantane-1-acetic acid, 4-methylphenoxyacetic acid, 3-hydroxy-2-methyl-4-oxo-1-pyridineacetic acid (N-acetic acid derivative of deferiprone), or 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid (deferasirox) were prepared and the integrity of Fe(III) binding of the compounds was established from electrospray ionization mass spectrometry and RP-HPLC measurements. The extent of intracellular (59)Fe mobilized by the DFOB-3,5-dimethyladamantane-1-carboxylic acid adduct was 3-fold greater than DFOB alone, and the IC(50) value of this adduct was 6- or 15-fold greater than DFOB in two different cell types. The relationship between logP and (59)Fe mobilization for the DFOB conjugates showed that maximal mobilization of intracellular (59)Fe occurred at a logP value approximately 2.3. This parameter, rather than the affinity for Fe(III), appears to influence the extent of intracellular (59)Fe mobilization. The low toxicity-high Fe mobilization efficacy of selected adamantane-based DFOB conjugates underscores the potential of these compounds to treat iron overload disease in patients with transfusional-dependent disorders such as beta-thalassemia.

Synthesis, antifungal and antimicrobial activity of alkylphospholipids.

The antifungal, antibacterial and haemolytic activity of a series of alkylphosphocholines (e.g., miltefosine) and alkylglycerophosphocholines (e.g., edelfosine) has been investigated. These compound classes exhibit significant antifungal and moderate antibacterial activities. Several new alkylphosphocholine derivatives with amide or ester bonds in the alkyl chain have been synthesised. These compounds show much lower haemolytic activity than miltefosine. Alkylphosphocholines and alkylglycerophosphocholines show significant promise as novel orally available antifungal and antibacterial therapeutics.

Hexadecylphosphocholine (miltefosine) has broad-spectrum fungicidal activity and is efficacious in a mouse model of cryptococcosis.

The alkyl phosphocholine drug miltefosine is structurally similar to natural substrates of the fungal virulence determinant phospholipase B1 (PLB1), which is a potential drug target. We determined the MICs of miltefosine against key fungal pathogens, correlated antifungal activity with inhibition of the PLB1 activities (PLB, lysophospholipase [LPL], and lysophospholipase-transacylase [LPTA]), and investigated its efficacy in a mouse model of disseminated cryptococcosis. Miltefosine inhibited secreted cryptococcal LPTA activity by 35% at the subhemolytic concentration of 25 microM (10.2 microg/ml) and was inactive against mammalian pancreatic phospholipase A2 (PLA2). At 250 microM, cytosolic PLB, LPL, and LPTA activities were inhibited by 25%, 51%, and 77%, respectively. The MICs at which 90% of isolates were inhibited (MIC90s) against Candida albicans, Candida glabrata, Candida krusei, Cryptococcus neoformans, Cryptococcus gattii, Aspergillus fumigatus, Fusarium solani, Scedosporium prolificans, and Scedosporium apiospermum were 2 to 4 microg/ml. The MICs of miltefosine against Candida tropicalis (n = 8) were 2 to 4 microg/ml, those against Aspergillus terreus and Candida parapsilosis were 8 microg/ml (MIC90), and those against Aspergillus flavus (n = 8) were 2 to 16 microg/ml. Miltefosine was fungicidal for C. neoformans, with rates of killing of 2 log units within 4 h at 7.0 microM (2.8 microg/ml). Miltefosine given orally to mice on days 1 to 5 after intravenous infection with C. neoformans delayed the development of illness and mortality and significantly reduced the brain cryptococcal burden. We conclude that miltefosine has broad-spectrum antifungal activity and is active in vivo in a mouse model of disseminated cryptococcosis. The relatively small inhibitory effect on PLB1 enzyme activities at concentrations exceeding the MIC by 2 to 20 times suggests that PLB1 inhibition is not the only mechanism of the antifungal effect.