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1.
J Pharm Sci ; 109(1): 863-870, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31654660

RESUMO

Pancreatic islet transplantation is a promising advanced therapy that has been used to treat patients suffering from diabetes type 1. Traditionally, pancreatic islets are infused via the portal vein, which is subsequently intended to engraft in the liver. Severe immunosuppressive treatments are necessary, however, to prevent rejection of the transplanted islets. Novel approaches therefore have focused on encapsulation of the islets in biomaterial implants which can protect the islets and offer an organ-like environment. Vascularization of the device's surface is a prerequisite for the survival and proper functioning of transplanted pancreatic islets. We are pursuing a prevascularization strategy by incorporation of vascular endothelial growth factor (VEGF)-loaded microspheres in 3-dimensional printed poly(dimethylsiloxane)-based devices prior to their prospective loading with transplanted cells. Microspheres (~50 µm) were based on poly(ε-caprolactone-PEG-ε-caprolactone)-b-poly(L-lactide) multiblock copolymers and were loaded with 10 µg VEGF/mg microspheres, and subsequently dispersed in a hyaluronic acid carrier liquid. In vitro release studies at 37°C demonstrated continuous release of fully bioactive VEGF for 4 weeks. In conclusion, our results demonstrate that incorporation of VEGF-releasing microspheres ensures adequate release of VEGF for a time window of 4 weeks, which is attractive in view of the vascularization of artificial pancreas implants.

2.
Biomacromolecules ; 21(1): 73-88, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31500418

RESUMO

Combining multiple stimuli-responsive functionalities into the polymer design is an attractive approach to improve nucleic acid delivery. However, more in-depth fundamental understanding how the multiple functionalities in the polymer structures are influencing polyplex formation and stability is essential for the rational development of such delivery systems. Therefore, in this study the structure and dynamics of thermosensitive polyplexes were investigated by tracking the behavior of labeled plasmid DNA (pDNA) and polymer with time-resolved fluorescence spectroscopy using fluorescence resonance energy transfer (FRET). The successful synthesis of a heterofunctional poly(ethylene glycol) (PEG) macroinitiator containing both an atom transfer radical polymerization (ATRP) and reversible addition-fragmentation chain-transfer (RAFT) initiator is reported. The use of this novel PEG macroinitiator allows for the controlled polymerization of cationic and thermosensitive linear triblock copolymers and labeling of the chain-end with a fluorescent dye by maleimide-thiol chemistry. The polymers consisted of a thermosensitive poly(N-isopropylacrylamide) (PNIPAM, N), hydrophilic PEG (P), and cationic poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA, D) block, further referred to as NPD. Polymer block D chain-ends were labeled with Cy3, while pDNA was labeled with FITC. The thermosensitive NPD polymers were used to prepare pDNA polyplexes, and the effect of the N/P charge ratio, temperature, and composition of the triblock copolymer on the polyplex properties were investigated, taking nonthermosensitive PD polymers as the control. FRET was observed both at 4 and 37 °C, indicating that the introduction of the thermosensitive PNIPAM block did not compromise the polyplex structure even above the polymer's cloud point. Furthermore, FRET results showed that the NPD- and PD-based polyplexes have a less dense core compared to polyplexes based on cationic homopolymers (such as PEI) as reported before. The polyplexes showed to have a dynamic character meaning that the polymer chains can exchange between the polyplex core and shell. Mobility of the polymers allow their uniform redistribution within the polyplex and this feature has been reported to be favorable in the context of pDNA release and subsequent improved transfection efficiency, compared to nondynamic formulations.

3.
ACS Omega ; 4(7): 11481-11492, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31460253

RESUMO

Vascular endothelial growth factor (VEGF) is the major regulating factor for the formation of new blood vessels, also known as angiogenesis. VEGF is often incorporated in synthetic scaffolds to promote vascularization and to enhance the survival of cells that have been seeded in these devices. Such applications require sustained local delivery of VEGF of around 4 weeks for stable blood vessel formation. Most delivery systems for VEGF only provide short-term release for a couple of days, followed by a release phase with very low VEGF release. We now have developed VEGF-loaded polymeric microspheres that provide sustained release of bioactive VEGF for 4 weeks. Blends of two swellable poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone)-b-poly(l-lactide) ([PCL-PEG-PCL]-b-[PLLA])-based multiblock copolymers with different PEG content and PEG molecular weight were used to prepare the microspheres. Loading of the microspheres was established by a solvent evaporation-based membrane emulsification method. The resulting VEGF-loaded microspheres had average sizes of 40-50 µm and a narrow size distribution. Optimized formulations of a 50:50 blend of the two multiblock copolymers had an average VEGF loading of 0.79 ± 0.09%, representing a high average VEGF loading efficiency of 78 ± 16%. These microspheres released VEGF continuously over 4 weeks in phosphate-buffered saline pH 7.4 at 37 °C. This release profile was preserved after repeated and long-term storage at -20 °C for up to 9 months, thereby demonstrating excellent storage stability. VEGF release was governed by diffusion through the water-filled polymer matrix, depending on PEG molecular weight and PEG content of the polymers. The bioactivity of the released VEGF was retained within the experimental error in the 4-week release window, as demonstrated using a human umbilical vein endothelial cells proliferation assay. Thus, the microspheres prepared in this study are suitable for embedment in polymeric scaffolds with the aim of promoting their functional vascularization.

4.
PLoS Negl Trop Dis ; 12(12): e0006758, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30522129

RESUMO

BACKGROUND: Regular preventive chemotherapy (PCT) targeting high-risk populations is an effective way to control STH in the short term, but sustainable long-term STH control is expected to require improved access to water, sanitation, and hygiene (WASH). However, experimental studies have not been able to conclusively demonstrate the benefit of WASH in preventing STH (re-)infections. We investigated the impact of WASH on STH infections during and after PCT using mathematical modelling. METHODS AND FINDINGS: We use the individual-based transmission model WORMSIM to predict the short and long-term impact of WASH on STH transmission in contexts with and without PCT. We distinguish two WASH modalities: sanitation, which reduces individuals' contributions to environmental contamination; and hygiene, which reduces individuals' exposure to infection. We simulate the impact of varying levels of uptake and effectiveness of each WASH modality, as well as their combined impact. Clearly, sanitation and hygiene interventions have little observable short-term impact on STH infections levels in the context of PCT. However, in the long term, both are pivotal to sustain control or eliminate infection levels after scaling down or stopping PCT. The impact of hygiene is determined more by the effectiveness of the intervention than its overall uptake, whereas the impact of sanitation depends more directly on the product of uptake and the effectiveness. INTERPRETATION: The impact of WASH interventions on STH transmission highly depends on the worm species, WASH modality, and uptake and effectiveness of the intervention. Also, the impact of WASH is difficult to measure in the context of ongoing PCT programmes. Still, we show a clear added benefit of WASH to sustain the gains made by PCT in the long term, such that PCT may be scaled down or even stopped altogether. To safely stop or scale down PCT, policy for WASH and PCT should be integrated.


Assuntos
Helmintíase/prevenção & controle , Helmintos/fisiologia , Higiene , Saneamento , Solo/parasitologia , Água/parasitologia , Animais , Feminino , Helmintíase/transmissão , Humanos , Masculino , Modelos Teóricos
5.
Pharm Res ; 35(11): 226, 2018 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-30280277

RESUMO

PURPOSE: Filgrastim, a recombinant human granulocyte-colony stimulating factor, is widely used to treat congenital and acquired neutropenia. Following patent expiration of the innovator filgrastim product, biosimilar filgrastim products have been approved in the EU and shown to be comparable with the innovator with respect to quality, safety and efficacy. In less regulated markets, copy filgrastim products are available but data about their quality are scarce. In the present study, we provide a head-to-head comparative study on the quality of biosimilar and copy filgrastim products. METHODS: Innovator filgrastim product, Neupogen®, two EU-licensed biosimilars, Zarzio® and Tevagrastim®, and two copy filgrastim products, Biocilin® and PDgrastim®, were subjected to peptide mapping, circular dichroism spectroscopy, fluorescence spectroscopy, sodium dodecyl sulfate polyacrylamide gel electrophoresis, high performance size-exclusion chromatography, reversed-phase ultra-performance liquid chromatography, endotoxin test, flow imaging microscopy and in vitro potency assay. RESULTS: Zarzio® and Tevagrastim® have comparable quality to Neupogen®, while Biocilin® showed a significantly lower and PDgrastim® a higher specific activity. Moreover, PDgrastim® showed a higher level of impurities and a lower thermo stability than the other products. CONCLUSIONS: Except for the deviating specific activities of the two copy filgrastim products, we found no substantial differences in product quality between the filgrastim products studied.


Assuntos
Medicamentos Biossimilares/química , Filgrastim/química , Fármacos Hematológicos/química , Medicamentos Biossimilares/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Contaminação de Medicamentos , Estabilidade de Medicamentos , Filgrastim/farmacologia , Fármacos Hematológicos/farmacologia , Humanos , Estabilidade Proteica
6.
PLoS One ; 13(9): e0202924, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30180203

RESUMO

BACKGROUND: Human papillomavirus (HPV) vaccination and the implementation of primary HPV screening in the Netherlands will lead to a lower cervical disease burden. For evaluation and further improvement of prevention, it is important to estimate the magnitude and timing of health benefits of current and alternative vaccination strategies such as vaccination of boys or adults. METHODS AND FINDINGS: We evaluated the impact of the current girls-only vaccination program and alternative strategies on cervical disease burden among the first four vaccinated five-year birth cohorts, given the context of primary HPV screening. We integrated the existing microsimulation models STDSIM (HPV transmission model) and MISCAN-Cervix (cervical cancer screening model). Alternative vaccination strategies include: improved vaccination uptake, including routine boys vaccination, and offering adult vaccination at sexual health clinics. Our models show that the current vaccination program is estimated to reduce cervical cancers and cancer deaths by about 35% compared to primary HPV screening in the absence of vaccination. The number needed to vaccinate (NNV) to gain 1 life year is 45. The most efficient alternative vaccination strategies are: 1) improving coverage of girls to 80% (NNV = 42); and 2) routine vaccination for girls and boys at 80% coverage (incremental NNV = 155), with cervical cancer mortality reductions estimated at 50% and 60% respectively. CONCLUSIONS: While the current program already substantially reduces cervical cancer incidence and mortality, prevention can be further improved by increasing vaccination uptake and extending vaccination to boys. As not all cervical cancer deaths will be prevented, screening participation should still be encouraged.


Assuntos
Programas de Rastreamento , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus , Vacinação , Adulto , Idoso , Criança , Estudos de Coortes , Feminino , Papillomavirus Humano 16 , Papillomavirus Humano 18 , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/transmissão , Vacinação/métodos
7.
Mol Pharm ; 15(9): 3786-3795, 2018 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-30063364

RESUMO

The aim of the study is to investigate the uptake by and transport through Caco-2 cells of two mixed micelle formulations (based on egg phosphatidylcholine and glycocholic acid) of vitamin K, i.e., with and without DSPE-PEG2000. The uptake of vitamin K and fluorescently labeled mixed micelles with and without PEG coating showed similar kinetics and their uptake ratio remained constant over time. Together with the fact that an inhibitor of scavenger receptor B1 (BLT-1) decreased cellular uptake of vitamin K by ∼80% compared to the uptake in the absence of this inhibitor, we conclude that both types of micelles loaded with vitamin K can be taken up intactly by Caco-2 cells via this scavenger receptor. The amount of vitamin K in chylomicrons fraction from Caco-2 cell monolayers further indicates that mixed micelles (with or without PEGylation) are likely packed into chylomicrons after internalization by Caco-2 cells. Uptake of vitamin K from PEGylated mixed micelles increased four- to five-fold at simulated gastrointestinal conditions. In conclusion, PEGylated mixed micelles are stable upon exposure to simulated gastric conditions, and as a result, they do show overall a higher cellular uptake efficiency of vitamin K as compared to mixed micelles without PEG coating.


Assuntos
Micelas , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Vitamina K/química , Vitamina K/farmacologia , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Humanos , Receptores Depuradores Classe B/metabolismo
8.
PLoS Negl Trop Dis ; 12(3): e0006250, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29534061

RESUMO

BACKGROUND: The control or elimination of neglected tropical diseases (NTDs) has targets defined by the WHO for 2020, reinforced by the 2012 London Declaration. We estimated the economic impact to individuals of meeting these targets for human African trypanosomiasis, leprosy, visceral leishmaniasis and Chagas disease, NTDs controlled or eliminated by innovative and intensified disease management (IDM). METHODS: A systematic literature review identified information on productivity loss and out-of-pocket payments (OPPs) related to these NTDs, which were combined with projections of the number of people suffering from each NTD, country and year for 2011-2020 and 2021-2030. The ideal scenario in which the WHO's 2020 targets are met was compared with a counterfactual scenario that assumed the situation of 1990 stayed unaltered. Economic benefit equaled the difference between the two scenarios. Values are reported in 2005 US$, purchasing power parity-adjusted, discounted at 3% per annum from 2010. Probabilistic sensitivity analyses were used to quantify the degree of uncertainty around the base-case impact estimate. RESULTS: The total global productivity gained for the four IDM-NTDs was I$ 23.1 (I$ 15.9 -I$ 34.0) billion in 2011-2020 and I$ 35.9 (I$ 25.0 -I$ 51.9) billion in 2021-2030 (2.5th and 97.5th percentiles in brackets), corresponding to US$ 10.7 billion (US$ 7.4 -US$ 15.7) and US$ 16.6 billion (US$ 11.6 -US$ 24.0). Reduction in OPPs was I$ 14 billion (US$ 6.7 billion) and I$ 18 billion (US$ 10.4 billion) for the same periods. CONCLUSIONS: We faced important limitations to our work, such as finding no OPPs for leprosy. We had to combine limited data from various sources, heterogeneous background, and of variable quality. Nevertheless, based on conservative assumptions and subsequent uncertainty analyses, we estimate that the benefits of achieving the targets are considerable. Under plausible scenarios, the economic benefits far exceed the necessary investments by endemic country governments and their development partners. Given the higher frequency of NTDs among the poorest households, these investments represent good value for money in the effort to improve well-being, distribute the world's prosperity more equitably and reduce inequity.


Assuntos
Erradicação de Doenças/economia , Saúde Global/estatística & dados numéricos , Doenças Negligenciadas/economia , Doenças Negligenciadas/epidemiologia , Doenças Negligenciadas/prevenção & controle , Gerenciamento Clínico , Saúde Global/economia , Gastos em Saúde , Humanos , Pobreza , Literatura de Revisão como Assunto
9.
PLoS Negl Trop Dis ; 11(1): e0005289, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28103243

RESUMO

BACKGROUND: Lymphatic filariasis (LF), onchocerciasis, schistosomiasis, soil-transmitted helminths (STH) and trachoma represent the five most prevalent neglected tropical diseases (NTDs). They can be controlled or eliminated by means of safe and cost-effective interventions delivered through programs of Mass Drug Administration (MDA)-also named Preventive Chemotherapy (PCT). The WHO defined targets for NTD control/elimination by 2020, reinforced by the 2012 London Declaration, which, if achieved, would result in dramatic health gains. We estimated the potential economic benefit of achieving these targets, focusing specifically on productivity and out-of-pocket payments. METHODS: Productivity loss was calculated by combining disease frequency with productivity loss from the disease, from the perspective of affected individuals. Productivity gain was calculated by deducting the total loss expected in the target achievement scenario from the loss in a counterfactual scenario where it was assumed the pre-intervention situation in 1990 regarding NTDs would continue unabated until 2030. Economic benefits from out-of-pocket payments (OPPs) were calculated similarly. Benefits are reported in 2005 US$ (purchasing power parity-adjusted and discounted at 3% per annum from 2010). Sensitivity analyses were used to assess the influence of changes in input parameters. RESULTS: The economic benefit from productivity gain was estimated to be I$251 billion in 2011-2020 and I$313 billion in 2021-2030, considerably greater than the total OPPs averted of I$0.72 billion and I$0.96 billion in the same periods. The net benefit is expected to be US$ 27.4 and US$ 42.8 for every dollar invested during the same periods. Impact varies between NTDs and regions, since it is determined by disease prevalence and extent of disease-related productivity loss. CONCLUSION: Achieving the PCT-NTD targets for 2020 will yield significant economic benefits to affected individuals. Despite large uncertainty, these benefits far exceed the investment required by governments and their development partners within all reasonable scenarios. Given the concentration of the NTDs among the poorest households, these investments represent good value for money in efforts to share the world's prosperity and reduce inequity.


Assuntos
Quimioprevenção/economia , Helmintíase/prevenção & controle , Doenças Negligenciadas/economia , Doenças Negligenciadas/prevenção & controle , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/economia , Análise Custo-Benefício , Helmintíase/tratamento farmacológico , Helmintíase/economia , Humanos , Doenças Negligenciadas/tratamento farmacológico , Fatores Socioeconômicos , Medicina Tropical/economia
10.
J Infect Dis ; 214(6): 854-61, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27330051

RESUMO

BACKGROUND: Expanding routine human papillomavirus (HPV) vaccination to adults could be an effective strategy to improve prevention of HPV infection and cervical cancer. METHODS: We evaluated the following adult vaccination strategies for women only and for both women and men in addition to the current girls-only vaccination program in the Netherlands, using the established STDSIM microsimulation model: one-time mass campaign, vaccination at the first cervical cancer screening visit, vaccination at sexual health clinics, and combinations of these strategies. RESULTS: The estimated impact of expanding routine vaccination to adult women is modest, with the largest incremental reductions in the incidence of HPV infection occurring when offering vaccination both at the cervical cancer screening visit and during sexually transmitted infection (STI) consultations (about 20% lower after 50 years for both HPV-16 and HPV-18). Adding male vaccination during STI consultations leads to more-substantial incidence reductions: 63% for HPV-16 and 84% for HPV-18. The incremental number needed to vaccinate among women is 5.48, compared with 0.90 for the current vaccination program. CONCLUSIONS: Offering vaccination to adults, especially at cervical cancer screening visits (for women) and during STI consultations (for both sexes), would substantially reduce HPV incidence and would be an efficient policy option to improve HPV prevention and subsequently avert cervical and possibly male HPV-related cancers.


Assuntos
Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/imunologia , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/prevenção & controle , Vacinação/estatística & dados numéricos , Adolescente , Adulto , Feminino , Humanos , Esquemas de Imunização , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Países Baixos/epidemiologia , Infecções por Papillomavirus/complicações , Adulto Jovem
11.
PLoS Negl Trop Dis ; 10(2): e0004386, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26890362

RESUMO

BACKGROUND: The London Declaration (2012) was formulated to support and focus the control and elimination of ten neglected tropical diseases (NTDs), with targets for 2020 as formulated by the WHO Roadmap. Five NTDs (lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminths and trachoma) are to be controlled by preventive chemotherapy (PCT), and four (Chagas' disease, human African trypanosomiasis, leprosy and visceral leishmaniasis) by innovative and intensified disease management (IDM). Guinea worm, virtually eradicated, is not considered here. We aim to estimate the global health impact of meeting these targets in terms of averted morbidity, mortality, and disability adjusted life years (DALYs). METHODS: The Global Burden of Disease (GBD) 2010 study provides prevalence and burden estimates for all nine NTDs in 1990 and 2010, by country, age and sex, which were taken as the basis for our calculations. Estimates for other years were obtained by interpolating between 1990 (or the start-year of large-scale control efforts) and 2010, and further extrapolating until 2030, such that the 2020 targets were met. The NTD disease manifestations considered in the GBD study were analyzed as either reversible or irreversible. Health impacts were assessed by comparing the results of achieving the targets with the counterfactual, construed as the health burden had the 1990 (or 2010 if higher) situation continued unabated. PRINCIPLE FINDINGS/CONCLUSIONS: Our calculations show that meeting the targets will lead to about 600 million averted DALYs in the period 2011-2030, nearly equally distributed between PCT and IDM-NTDs, with the health gain amongst PCT-NTDs mostly (96%) due to averted disability and amongst IDM-NTDs largely (95%) from averted mortality. These health gains include about 150 million averted irreversible disease manifestations (e.g. blindness) and 5 million averted deaths. Control of soil-transmitted helminths accounts for one third of all averted DALYs. We conclude that the projected health impact of the London Declaration justifies the required efforts.


Assuntos
Erradicação de Doenças/métodos , Doenças Negligenciadas/prevenção & controle , Saúde Global , Humanos , Doenças Negligenciadas/epidemiologia , Doenças Negligenciadas/mortalidade , Anos de Vida Ajustados por Qualidade de Vida , Medicina Tropical
12.
Parasit Vectors ; 8: 541, 2015 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-26489659

RESUMO

BACKGROUND: Globally, hookworms infect 440 million people in developing countries. Especially children and women of childbearing age are at risk of developing anaemia as a result of infection. To control hookworm infection and disease (i.e. reduce the prevalence of medium and heavy infection to <1 %), the World Health Organization has set the target to provide annual or semi-annual preventive chemotherapy (PC) with albendazole (ALB) or mebendazole (MEB) to at least 75 % of all children and women of childbearing age in endemic areas by 2020. Here, we predict the feasibility of achieving <1 % prevalence of medium and heavy infection, based on simulations with an individual-based model. METHODS: We developed WORMSIM, a new generalized individual-based modelling framework for transmission and control of helminths, and quantified it for hookworm transmission based on published data. We simulated the impact of standard and more intense PC strategies on trends in hookworm infection, and explored the potential additional impact of interventions that improve access to water, sanitation, and hygiene (WASH). The individual-based framework allowed us to take account of inter-individual heterogeneities in exposure and contribution to transmission of infection, as well as in participation in successive PC rounds. RESULTS: We predict that in low and medium endemic areas, current PC strategies (including targeting of WCBA) will achieve control of hookworm infection (i.e. the parasitological target) within 2 years. In highly endemic areas, control can be achieved with semi-annual PC with ALB at 90 % coverage, combined with interventions that reduce host contributions to the environmental reservoir of infection by 50 %. More intense PC strategies (high frequency and coverage) can help speed up control of hookworm infection, and may be necessary in some extremely highly endemic settings, but are not a panacea against systematic non-participation to PC. CONCLUSIONS: Control of hookworm infection by 2020 is feasible with current PC strategies (including targeting of WCBA). In highly endemic areas, PC should be combined with health education and/or WASH interventions.


Assuntos
Anti-Helmínticos/administração & dosagem , Quimioprevenção/métodos , Transmissão de Doença Infecciosa/prevenção & controle , Infecções por Uncinaria/tratamento farmacológico , Infecções por Uncinaria/prevenção & controle , Albendazol/administração & dosagem , Infecções por Uncinaria/epidemiologia , Humanos , Mebendazol/administração & dosagem , Modelos Teóricos , Prevalência
13.
Vaccine ; 33(41): 5357-5364, 2015 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-26348405

RESUMO

BACKGROUND: Mathematical modelling is used to estimate the effectiveness of HPV vaccination. These estimates depend strongly on herd immunity and thus on naturally acquired immunity, a mechanism of which little is known. We estimated the impact of different vaccination strategies on HPV-16 and HPV-18 transmission and cervical cancer incidence in the Netherlands, considering different acquired immunity mechanisms. METHODS: We used the STDSIM microsimulation model, and considered two mechanisms for acquired immunity after infection: (I) full immunity with variable duration; (II) cumulatively decreasing susceptibility to reinfection. Girls aged 13-16 years received vaccination (94.7% efficacy for HPV-16 and 92.3% for HPV-18) during a once-off catch-up campaign with 50% coverage, followed by annual vaccination of 12-year-old girls (60% coverage). Alternative vaccination scenarios included increased coverage, including boys, and lower vaccine efficacy. RESULTS: HPV-16 incidence reduced by 64% under mechanism I and 75% under mechanism II; HPV-18 incidence reduced by 58% and 73%, respectively, and these reductions lead to 48-56% fewer cervical cancer cases. Increasing coverage can lead to over 96% reduction in HPV incidence. Vaccinating boys reduced incidence by 79-89% for HPV-16 and 83-98% for HPV-18 in women. CONCLUSIONS: Effectiveness estimates of HPV vaccination differ slightly between different acquired immunity mechanisms, yet these differences are unlikely to affect policy decisions. Offering vaccination to boys as well may be considered to further reduce cancer incidence.


Assuntos
Alphapapillomavirus/imunologia , Imunidade Inata , Modelos Teóricos , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Adolescente , Adulto , Feminino , História do Século XXI , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/história , Infecções por Papillomavirus/transmissão , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/etiologia , Adulto Jovem
14.
Am J Prev Med ; 49(4): 605-13, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26232897

RESUMO

INTRODUCTION: Individual and environmental factors dynamically interact in shaping income inequalities in healthy food consumption. The agent-based model, Health Behaviors Simulation (HEBSIM), was developed to describe income inequalities in healthy food consumption. It simulates interactions between households and their environment. HEBSIM was used to explore the impact of interventions aimed at reducing food consumption inequalities. METHODS: HEBSIM includes households and food outlets. Households are characterized by location, composition, income, and preference for food. Decisions about where to shop for food (fruit/vegetable stores, supermarkets, or discount supermarkets) and whether to visit fast food outlets are based on distance, price, and food preference. Food outlets can close and new food outlets can enter the system. Three interventions to reduce healthy food consumption inequalities were tested: (1) eliminating residential segregation; (2) lowering the prices of healthy food; and (3) providing health education. HEBSIM was quantified using data from Statistics Netherlands, Statistics Eindhoven, and the GLOBE study (2011). RESULTS: The model mimicked food consumption in Eindhoven. High-income households visited healthy food shops more often than low-income households. Eliminating residential segregation had the largest impact in reducing income inequalities in food consumption, but resulted partly from a worsening in healthy food consumption in high-income households. Lowering prices and health education could also substantially reduce inequalities. Most interventions took 5-10 years to reach their (almost) full effects. CONCLUSIONS: HEBSIM is a promising tool for studying dynamic interactions between households and their environment and for assessing the impact of interventions on income inequalities in food consumption.


Assuntos
Abastecimento de Alimentos/economia , Alimentos/economia , Renda , Análise de Sistemas , Educação em Saúde
15.
PLoS One ; 10(2): e0116618, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25642941

RESUMO

BACKGROUND: Knowledge of the natural history of human papillomavirus (HPV), in particular the role of immunity, is crucial in estimating the (cost-) effectiveness of HPV vaccination and cervical cancer screening strategies, because naturally acquired immunity after clearing an infection may already protect part of the risk population against new HPV infections. METHODS: We used STDSIM, an established stochastic microsimulation model, quantified to the Netherlands. We explored different assumptions regarding the natural history of HPV-16 and HPV-18, and estimated the transmission probabilities and durations of acquired immunity necessary to reproduce age-specific prevalence. RESULTS: A model without acquired immunity cannot reproduce the age-specific patterns of HPV. Also, it is necessary to assume a high degree of individual variation in the duration of infection and acquired immunity. According to the model estimates, on average 20% of women are immune for HPV-16 and 15% for HPV-18. After an HPV-16 infection, 50% are immune for less than 1 year, whereas 20% exceed 30 years. For HPV-18, up to 12% of the individuals are immune for less than 1 year, and about 50% over 30 years. Almost half of all women will never acquire HPV-16 or HPV-18. CONCLUSIONS: Acquired immunity likely plays a major role in HPV epidemiology, but its duration shows substantial variation. Combined with the lifetime risk, this explains to a large extent why many women will never develop cervical cancer.


Assuntos
Imunidade Adaptativa , Papillomavirus Humano 16/fisiologia , Papillomavirus Humano 18/fisiologia , Modelos Biológicos , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/transmissão , Adolescente , Adulto , Infecções por Chlamydia/imunologia , Infecções por Chlamydia/transmissão , Feminino , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Processos Estocásticos , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/virologia , Adulto Jovem
16.
PLoS One ; 9(12): e115886, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25545677

RESUMO

The African Programme for Onchocerciasis Control (APOC) is currently shifting its focus from morbidity control to elimination of infection. To enhance the likelihood of elimination and speed up its achievement, programs may consider to increase the frequency of ivermectin mass treatment from annual to 6-monthly or even higher. In a computer simulation study, we examined the potential impact of increasing the mass treatment frequency for different settings. With the ONCHOSIM model, we simulated 92,610 scenarios pertaining to different assumptions about transmission conditions, history of mass treatment, the future mass treatment strategy, and ivermectin efficacy. Simulation results were used to determine the minimum remaining program duration and number of treatment rounds required to achieve 99% probability of elimination. Doubling the frequency of treatment from yearly to 6-monthly or 3-monthly was predicted to reduce remaining program duration by about 40% or 60%, respectively. These reductions come at a cost of additional treatment rounds, especially in case of 3-monthly mass treatment. Also, aforementioned reductions are highly dependent on maintained coverage, and could be completely nullified if coverage of mass treatment were to fall in the future. In low coverage settings, increasing treatment coverage is almost just as effective as increasing treatment frequency. We conclude that 6-monthly mass treatment may only be worth the effort in situations where annual treatment is expected to take a long time to achieve elimination in spite of good treatment coverage, e.g. because of unfavorable transmission conditions or because mass treatment started recently.


Assuntos
Erradicação de Doenças , Ivermectina/administração & dosagem , Ivermectina/uso terapêutico , Modelos Biológicos , Oncocercose/tratamento farmacológico , Oncocercose/prevenção & controle , África/epidemiologia , Animais , Simulação por Computador , Humanos , Ivermectina/provisão & distribução , Onchocerca volvulus , Oncocercose/epidemiologia , Oncocercose/parasitologia , Probabilidade , Pele/parasitologia , Fatores de Tempo , Resultado do Tratamento
17.
Lancet Glob Health ; 2(1): e23-34, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25104632

RESUMO

BACKGROUND: New WHO guidelines recommend initiation of antiretroviral therapy for HIV-positive adults with CD4 counts of 500 cells per µL or less, a higher threshold than was previously recommended. Country decision makers have to decide whether to further expand eligibility for antiretroviral therapy accordingly. We aimed to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy and expanded treatment coverage. METHODS: We used several independent mathematical models in four settings-South Africa (generalised epidemic, moderate antiretroviral therapy coverage), Zambia (generalised epidemic, high antiretroviral therapy coverage), India (concentrated epidemic, moderate antiretroviral therapy coverage), and Vietnam (concentrated epidemic, low antiretroviral therapy coverage)-to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy under scenarios of existing and expanded treatment coverage, with results projected over 20 years. Analyses assessed the extension of eligibility to include individuals with CD4 counts of 500 cells per µL or less, or all HIV-positive adults, compared with the previous (2010) recommendation of initiation with CD4 counts of 350 cells per µL or less. We assessed costs from a health-system perspective, and calculated the incremental cost (in US$) per disability-adjusted life-year (DALY) averted to compare competing strategies. Strategies were regarded very cost effective if the cost per DALY averted was less than the country's 2012 per-head gross domestic product (GDP; South Africa: $8040; Zambia: $1425; India: $1489; Vietnam: $1407) and cost effective if the cost per DALY averted was less than three times the per-head GDP. FINDINGS: In South Africa, the cost per DALY averted of extending eligibility for antiretroviral therapy to adult patients with CD4 counts of 500 cells per µL or less ranged from $237 to $1691 per DALY averted compared with 2010 guidelines. In Zambia, expansion of eligibility to adults with a CD4 count threshold of 500 cells per µL ranged from improving health outcomes while reducing costs (ie, dominating the previous guidelines) to $749 per DALY averted. In both countries results were similar for expansion of eligibility to all HIV-positive adults, and when substantially expanded treatment coverage was assumed. Expansion of treatment coverage in the general population was also cost effective. In India, the cost for extending eligibility to all HIV-positive adults ranged from $131 to $241 per DALY averted, and in Vietnam extending eligibility to patients with CD4 counts of 500 cells per µL or less cost $290 per DALY averted. In concentrated epidemics, expanded access for key populations was also cost effective. INTERPRETATION: Our estimates suggest that earlier eligibility for antiretroviral therapy is very cost effective in low-income and middle-income settings, although these estimates should be revisited when more data become available. Scaling up antiretroviral therapy through earlier eligibility and expanded coverage should be considered alongside other high-priority health interventions competing for health budgets. FUNDING: Bill & Melinda Gates Foundation, WHO.


Assuntos
Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Adulto , Terapia Antirretroviral de Alta Atividade/economia , Contagem de Linfócito CD4 , Análise Custo-Benefício , Definição da Elegibilidade/métodos , Feminino , Infecções por HIV/imunologia , Custos de Cuidados de Saúde , Humanos , Índia , Masculino , Modelos Teóricos , Anos de Vida Ajustados por Qualidade de Vida , África do Sul , Vietnã , Zâmbia
18.
J Pharm Pharmacol ; 66(9): 1339-46, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24730468

RESUMO

OBJECTIVES: The aim of this study is to establish the inhibitory effects of 14 commonly used complementary and alternative medicines (CAM) on the metabolism of cytochrome P450 2C9 (CYP2C9) substrates 7-methoxy-4-trifluoromethyl coumarine (MFC) and tolbutamide. CYP2C9 is important for the metabolism of numerous drugs and inhibition of this enzyme by CAM could result in elevated plasma levels of drugs that are CYP2C9 substrates. Especially for anticancer drugs, which have a narrow therapeutic window, small changes in their plasma levels could easily result in clinically relevant toxicities. METHODS: The effects of CAM on CYP2C9-mediated metabolism of MFC were assessed in Supersomes, using the fluorometric CYP2C9 inhibition assay. In human liver microsomes (HLM) the inhibition of CYP2C9-mediated metabolism of tolbutamide was determined, using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). KEY FINDINGS: The results indicated milk thistle as the most potent CYP2C9 inhibitor. For milk thistle, silybin (main constituent of milk thistle) was mainly responsible for the inhibition of CY2C9. CONCLUSIONS: Milk thistle and green tea were confirmed as potent inhibitors of CYP2C9-mediated metabolism of multiple substrates in vitro. Clinical studies with milk thistle are recommended to establish the clinical relevance of the demonstrated CYP2C9 inhibition.


Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Camellia sinensis , Cumarínicos/metabolismo , Interações Ervas-Drogas , Cardo-Mariano/química , Extratos Vegetais/farmacologia , Tolbutamida/metabolismo , Terapias Complementares , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Silibina , Silimarina/farmacologia
19.
J Pharm Pharmacol ; 66(6): 865-74, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24392691

RESUMO

OBJECTIVE: Concomitant use of complementary and alternative medicine (CAM) and anticancer drugs can affect the pharmacokinetics of anticancer drugs by inhibiting the metabolizing enzyme cytochrome P450 3A4 (CYP3A4) (EC 1.14.13.157). Several in vitro studies determined whether CAM can inhibit CYP3A4, but these studies revealed contradictory results. A plausible explanation for these conflicting results is the use only of a single model CYP3A4 substrate in each study. Therefore, the objective was to determine the potential of selected CAM (ß-carotene, Echinacea, garlic, Ginkgo biloba, ginseng, grape seed extract, green tea extract, milk thistle, saw palmetto, valerian, vitamin B6, B12 and C) to inhibit CYP3A4-mediated metabolism of different substrates: 7-benzyloxy-4-trifluoromethyl-coumarin (BFC), midazolam and docetaxel. The effect of CAM on CYP3A4-mediated metabolism of an anticancer drug has never been determined before in vitro, which makes this study unique. The oncolytic CYP3A4 substrate docetaxel was used to establish the predictive value of the model substrates for pharmacokinetic interactions between CAM and anticancer drugs in vitro, and to more closely predict these interactions in vivo. METHODS: The inhibition of CYP3A4-mediated metabolism of 7-benzyloxy-4-trifluoromethyl-coumarin (BFC) by CAM was assessed in Supersomes, using the fluorometric CYP3A4 inhibition assay. In human liver microsomes (HLM) the inhibition of CYP3A4-mediated metabolism of midazolam and docetaxel was determined, using liquid-chromatography coupled to tandem mass spectrometry (LC-MS/MS). KEY FINDINGS: The results confirmed grape seed and green tea as potent inhibitors and milk thistle as moderate inhibitor of CYP3A4-mediated metabolism of BFC, midazolam and docetaxel. CONCLUSION: Clinical studies are required to determine the clinical relevance of the determined CYP3A4 inhibition by grape seed, green tea and milk thistle.


Assuntos
Terapias Complementares , Cumarínicos/metabolismo , Citocromo P-450 CYP3A/fisiologia , Midazolam/metabolismo , Cardo-Mariano , Taxoides/metabolismo , Docetaxel , Ginkgo biloba , Extrato de Sementes de Uva/farmacologia , Humanos , Microssomos Hepáticos/metabolismo , Chá
20.
PLoS Med ; 10(10): e1001534, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24167449

RESUMO

BACKGROUND: Expanded access to antiretroviral therapy (ART) using universal test and treat (UTT) has been suggested as a strategy to eliminate HIV in South Africa within 7 y based on an influential mathematical modeling study. However, the underlying deterministic model was criticized widely, and other modeling studies did not always confirm the study's finding. The objective of our study is to better understand the implications of different model structures and assumptions, so as to arrive at the best possible predictions of the long-term impact of UTT and the possibility of elimination of HIV. METHODS AND FINDINGS: We developed nine structurally different mathematical models of the South African HIV epidemic in a stepwise approach of increasing complexity and realism. The simplest model resembles the initial deterministic model, while the most comprehensive model is the stochastic microsimulation model STDSIM, which includes sexual networks and HIV stages with different degrees of infectiousness. We defined UTT as annual screening and immediate ART for all HIV-infected adults, starting at 13% in January 2012 and scaled up to 90% coverage by January 2019. All models predict elimination, yet those that capture more processes underlying the HIV transmission dynamics predict elimination at a later point in time, after 20 to 25 y. Importantly, the most comprehensive model predicts that the current strategy of ART at CD4 count ≤350 cells/µl will also lead to elimination, albeit 10 y later compared to UTT. Still, UTT remains cost-effective, as many additional life-years would be saved. The study's major limitations are that elimination was defined as incidence below 1/1,000 person-years rather than 0% prevalence, and drug resistance was not modeled. CONCLUSIONS: Our results confirm previous predictions that the HIV epidemic in South Africa can be eliminated through universal testing and immediate treatment at 90% coverage. However, more realistic models show that elimination is likely to occur at a much later point in time than the initial model suggested. Also, UTT is a cost-effective intervention, but less cost-effective than previously predicted because the current South African ART treatment policy alone could already drive HIV into elimination. Please see later in the article for the Editors' Summary.


Assuntos
Infecções por HIV/prevenção & controle , Modelos Teóricos , Adulto , Fármacos Anti-HIV/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , África do Sul
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