Organoid-Based Assessment of Metal-Organic Framework (MOF) Nanomedicines for Ex Vivo Cancer Therapy.

Nanomaterials have been extensively exploited in tumor treatment, leading to numerous innovative strategies for cancer therapy. While nanomedicines present immense potential, their application in cancer therapy is characterized by significant complexity and unpredictability, especially regarding biocompatibility and anticancer efficiency. These considerations underscore the essential need for the development of ex vivo research models, which provide invaluable insights and understanding into the biosafety and efficacy of nanomedicines in oncology. Fortunately, the emergence of organoid technology offers a novel approach to the preclinical evaluation of the anticancer efficacy of nanomedicines in vitro. Hence, in this study, we constructed intestine and hepatocyte organoid models (Intestine-orgs and Hep-orgs) for assessing intestinal and hepatic toxicity at the microtissue level. We utilized three typical metal-organic frameworks (MOFs), ZIF-8, ZIF-67, and MIL-125, as nanomedicines to further detect their interactions with organoids. Subsequently, the MIL-125 with biocompatibility loaded methotrexate (MTX), forming the nanomedicine (MIL-125-PEG-MTX), indicated a high loading efficiency (82%) and a well-release capability in an acid microenvironment. More importantly, the anticancer effect of the nanomedicine was investigated using an in vitro patient-derived organoids (PDOs) model, achieving inhibition rates of 48% and 78% for PDO-1 and PDO-2, respectively, demonstrating that PDOs could predict clinical response and facilitate prospective therapeutic selection. These achievements presented great potential for organoid-based ex vivo models for nano theragnostic evaluation in biosafety and function.

In-vitro and in-vivo assessment of pH-responsive core-shell nanocarrier system for sequential delivery of methotrexate and 5-fluorouracil for the treatment of breast cancer.

Breast cancer (BC) is one of the leading fatal diseases affecting females worldwide. Despite the presence of tremendous chemotherapeutic agents, the resistance emergence directs the recent research towards synergistic drugs' combination along with encapsulation inside biocompatible smart nanocarriers. Methotrexate (MTX) and 5-fluorouracil (Fu) are effective against BC and have sequential synergistic activity. In this study, a core-shell nanocarrier composed of mesoporous silica nanoparticles (MSN) as the core and zeolitic imidazolate framework-8 nano metal organic frameworks (ZIF-8 NMOF) as the shell was developed and loaded with Fu and MTX, respectively. The developed nanostructure; Fu-MSN@MTX-NMOF was validated by several characterization techniques and conferred high drugs' entrapment efficiency (EE%). In-vitro assessment revealed a pH-responsive drug release pattern in the acidic pH where MTX was released followed by Fu. The cytotoxicity evaluation indicated enhanced anticancer effect of the Fu-MSN@MTX-NMOF relative to the free drugs in addition to time-dependent fortified cytotoxic effect due to the sequential drugs' release. The in-vivo anticancer efficiency was examined using Ehrlich ascites carcinoma (EAC) animal model where the anticancer effect of the developed Fu-MSN@MTX-NMOF was compared to the sequentially administrated free drugs. The results revealed enhanced anti-tumor effect while maintaining the normal functions of the vital organs as the heart, kidney and liver.

Assessment of Ante- and Postnatal Development of the Offspring of Male Rats Crossed in Delayed Periods after Treatment with Methotrexate in Low Doses.

We studied ante- and postnatal development of the offspring of intact female rats crossed with males injected with low doses of methotrexate 3 and 6 months before mating. The time of crossing corresponded to the manifestation of the cytostatic effect on spermatogonial stem cells. The offspring of methotrexate-treated males was characterized by increased preimplantation losses and fetal growth restriction in the antenatal period and inhibition of physical development, delayed formation of sensory-motor reflexes, and impaired learning abilities in the postnatal period.

An MMP-2 Responsive Nanotheranostic Probe Enabled Synergistic Therapy of Rheumatoid Arthritis and MR/CT Assessment of Therapeutic Response In Situ.

This study reports a facile and green synthesis of a new multifunctional nanotheranostic probe for the synergistic therapy of rheumatoid arthritis (RA) and in situ assessment of therapeutic response. The probe is synthesized through a one-step self-assembly of two exquisitely designed peptide-amphiphilic block copolymers (PEG-DTIPA-KGPLGVRK-MTX and Pal-GGGGHHHHD-TCZ) under mild conditions, requiring minimal energy input. The resultant probe demonstrates excellent biocompatibility, water solubility, and colloidal stability. It exhibits a strong IL-6R targeting ability toward inflamed joints, and releases drugs in an MMP-2-responsive manner. The co-loading of methotrexate(MTX) and tocilizumab (TCZ) into the probe enables synergistic RA therapy with improved efficacy by simultaneously decreasing the activity of adenosine synthetase and interfering with the binding of IL-6 to its receptor. In addition, the resultant probe exhibits a high r1 relaxation rate (7.00 mm-1  s-1 ) and X-ray absorption capability (69.04 Hu mm-1 ), enabling sensitive MR and CT dual-modal imaging for simultaneous evaluation of synovial thickness and bone erosion. Both in vitro experiments using lipopolysaccharide-treated RAW264.7 cells and in vivo experiments using collagen-induced arthritis mice demonstrate the probe's high effectiveness in synergistically inhibiting inflammation. This study provides new insights into RA theranostics, therapeutic monitoring, the design of multifunctional theranostic probes, and beyond.

Eficacia y seguridad de guselkumab y secukinumab en pacientes adultos con psoriasis vulgar severa, no respondedores a terapia tópica y sistémica convencional y no tributario a terapia biológica antagonista al factor de necrosis tumoral por antecedente de neoplasia maligna / Efficacy and safety of guselkumab and secukinumab in adult patients with severe psoriasis vulgaris, non-responsive to conventional topical and systemic therapy and not amenable to biological therapy antagonistic to tumor necrosis factor due to a history of malignancy

ANTECEDENTES: En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N° 111-IETSI-ESSALUD-2021 y ampliada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N° 97-IETSI-ESSALUD2022, se ha elaborado el presente dictamen, el cual expone la evaluación de la eficacia y seguridad de guselkumab y secukinumab en pacientes adultos con psoriasis vulgar severa, no respondedores a terapia tópica y sistémica convencional y no tributario a terapia biológica antagonista al factor de necrosis tumoral disponible en EsSalud por antecedente de neoplasia maligna, en comparación de la mejor terapia de soporte. Así, la médica Evelyn Giuliana Castro Vargas, especialista en dermatología, a través del Comité Farmacoterapéutico del Hospital Nacional Alberto Sabogal Sologuren y siguiendo la Directiva N° 003-IETSI-ESSALUD-2016, envía al Instituto de Evaluación de Tecnologías en Salud e Investigación - IETSI la solicitud de autorización de uso del producto farmacéutico guselkumab no incluido en el Petitorio Farmacológico de EsSalud. ASPECTOS GENERALES La psoriasis es una enfermedad dermatológica inflamatoria crónica no transmisible que afecta aproximadamente del 1 % al 3 % de la población mundial (Augustin et al., 2010) con una prevalencia de alrededor del 2.5 % en el Perú (Rodríguez-Zúñiga, 2016). Esta enfermedad es considerada como un problema de salud pública y de elevada carga para la sociedad (Parisi et al., 2013), lo que se explica por su alto riesgo de morbilidad y porque deteriora la calidad de vida y la salud mental de las personas que lo padecen (Boehnoke & Schón, 2015). El fenotipo de psoriasis más común es la psoriasis vulgar, que se caracteriza por la presencia de placas eritematosas, gruesas y escamosas que se presentan mayormente en cuero cabelludo, glúteos, tronco y extremidades (codos y rodillas). La psoriasis suele clasificarse en leve, moderada y severa, según la clinimetría de las mediciones del Psoriasis Area and Severity Index (PASI), la Body surface area (BSA) y la calidad de vida medida a partir del Dermatology Life Quality Index (DLQI) (Finlay, 2015; Robinson et al., 2012). Es decir, la enfermedad severa se define por tener más de 10 puntos en el PASI, más del 10 % de la superficie corporal (BSA) afectada por la enfermedad, o más de 10 puntos en el DLQI (Strober et al., 2019). Los tratamientos para los pacientes con psoriasis vulgar severa tienen como objetivo lograr una reducción de por lo menos el 75 % o 90 % de la severidad de enfermedad inicial medida por la escala PASI (i.e. PASI75 o PASI90, respectivamente) luego de al menos tres meses de tratamiento efectivo (Belinchón Romero et al., 2021). Asimismo, se considera que, si después de 16 a 24 semanas de la aplicación de un esquema terapéutico efectivo no se ha logrado por lo menos alcanzar el PASI75 con DLQI < 5 o un PASI90, se considera que el paciente no ha respondido al tratamiento (i.e. falla terapéutica) (Aschoff et al., 2021). Así, entre los tratamientos disponibles para la psoriasis tenemos la terapia tópica que se utiliza en los casos de psoriasis leve a moderada', y la terapia sistémica, en casos de psoriasis de moderada a severa2. Dentro de la terapia sistémica, tenemos a los agentes sistémicos convencionales (metotrexato, ciclosporina o acitretina) y la terapia biológica. Ésta última se utiliza generalmente en los casos de falla al tratamiento con agentes sistémicos convencionales (Gisondi et al., 2017). Las terapias biológicas se clasifican según el mecanismo de acción, es decir, según la inhibición dirigida a citoquinas específicas del sistema inmune, tales como el factor de necrosis tumoral alfa (TNF), la interleucina (IL) 17 (IL17) y la IL23 (Fellner, 2016). METODOLOGIA: Se realizó una búsqueda bibliográfica exhaustiva con el objetivo de identificar la mejor evidencia sobre la eficacia y seguridad de guselkumab y secukinumab en pacientes adultos con psoriasis vulgar severa no respondedores a terapia tópica y sistémica convencional y no tributario a terapia biológica anti TNF disponibles en EsSalud por antecedente de neoplasia maligna. La búsqueda se realizó en las bases de datos bibliográficas de PubMed, The Cochrane Library, Web of Science y LILACS (Literatura Latinoamericana y del Caribe en Ciencias 'de la Salud). Asimismo, se realizó una búsqueda dentro de la información generada en las páginas web de grupos o instituciones que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), tales como: el National Institute for Health and Care Excellence (NICE), la Agency for Healthcare Research and Quality's (AHRQ), la Scottish Intercollegiate Guidelines Network (SIGN), la New Zealand Guidelines Group (NZGG), la National Health and Medical Research Council (NHMRC), el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI), el Centro Nacional de Excelencia Tecnológica en Salud (CENETEC), la Canadian Agency for Drugs and Technologies in Health (CADTH), el Scottish Medicines Consortium (SMC), la Haute Authorité de Santé (HAS), el Institute for Quality and Efficiency in Health Care (IQWiG), la Comissáo Nacional de lncorporagáo de Tecnologías no Sistema Único de Saúde (CONITEC), el Institute for Clinical and Economic Review (ICER) y en la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA). Además, se realizó una búsqueda de las guías en las principales instituciones o sociedades especializadas en dermatología y en psoriasis, tales como la American Academy of Dermatology (AAD), la British Association of Dermatologists (BAD), la European Academy of Dermatology and Venereology (EADV), y la International Psoriasis Council (IPC). Adicionalmente, se llevó a cabo una búsqueda manual en el motor de búsqueda Google utilizando los términos: "Psoriasis guidelines"; revisando documentos de interés en las diez primeras páginas. Finalmente, se realizó una búsqueda adicional en la página web de registro de ensayos clínicos (EC) www.clinicaltrials.gov, para identificar EC en curso o aún no publicados. RESULTADOS: Luego de la búsqueda bibliográfica hasta diciembre de 2022, se identificaron: una GPC de la BAD publicada en el 2020 (Smith et al., 2020); y una RS con MA en red (Sbidian et al., 2022) publicada en el 2022 que fue seleccionada como evidencia indirecta para responder a la pregunta PICO del presente dictamen. CONCLUSIÓN: Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación aprueba el uso de guselkumab en pacientes adultos con psoriasis vulgar severa, no respondedores a terapia tópica y sistémica convencional y no tributario a terapia biológica anti TNF antecedente de neoplasia maligna, como producto farmacéutico no incluido en el Petitorio Farmacológico de EsSalud, según lo establecido en el Anexo N° 1. La vigencia del presente informe preliminar es de un año a partir de la fecha de publicación. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de mayor evidencia que pueda surgir en el tempo.

Towards establishment of a plant-based model to assess the novel anti-cancerous lead molecule(s): An in silico, in vivo and in vitro assessment of some potential anti-cancerous drugs on Lathyrus sativus L.

The drug development process is one of the important aspects of medical biology. The classical lead identification strategy in the way of drug development based on animal cell is time-consuming, expensive and involving ethical issues. The following study aims to develop a novel plant-based screening of drugs. Study shows the efficacy of certain anti-cancerous drugs (Pemetrexed, 5-Fluorouracil, Methotrexate, Topotecan and Etoposide) on a plant-based (Lathyrus sativus L.) system. Two important characteristics of cancer cells were observed in the colchicine-treated polyploid cell and the callus, where the chromosome numbers were unusual and the division of cells were uncontrolled respectively. With increasing concentration, the drugs significantly reduced the mitotic index, ploidy level and callus growth. Increasing Pemetrexed concentration decreased the plant DHFR activity. A decrease in total RNA content was observed in 5-FU and Methotrexate with increasing concentrations of the drugs. Etoposide and Topotecan inhibited plant topoisomerase II and topoisomerase I activities, which was justified through plasmid nicking and comet assay, respectively. Molecular and biochemical study revealed similar results to the animal system. The in silico study had been done, and the structural similarity of drug binding domains of L. sativus and human beings had also been established. The binding site of the selected drugs to the domains of plant target proteins was also determined. Experimental results are significant in terms of the efficacy of known anti-cancerous drugs on the plant-based system. The proposed assay system is a cost-effective, convenient and less time-consuming process for primary screening of anti-cancerous lead molecules.

An economic analysis comparing health care resource use and cost of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin versus gemcitabine and cisplatin as neoadjuvant therapy for muscle invasive bladder cancer.

PURPOSE: To compare healthcare resource utilization (HRU) and costs associated with dose-dense methotrexate, vinblastine, doxorubicin, cisplatin (ddMVAC) and gemcitabine, cisplatin (GC) as neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC). METHODS: Patient treated at Dana-Farber Cancer Institute from 2010 to 2019 were identified. HRU data on chemotherapy administered, supportive medications, patient monitoring, clinic, infusion, emergency department (ED) visits and hospitalization were collected retrospectively. Unit costs for HRU components were obtained from the Centers for Medicare and Medicaid Website and HRU was compared between groups using quantile regression analysis. RESULTS: 137 patients were included; 51 received ddMVAC and 86 GC. Baseline characteristics were similar, except lower mean age (P < 0.001) and higher proportion of ECOG-PS = 0 (P < 0.001) for ddMVAC. ddMVAC required more granulocyte-colony stimulating factor support (P < 0.001), central line placement (P = 0.017), cardiac imaging (P < 0.001), and infusion visits (P < 0.001), whereas GC required more clinic visits. ED visits were higher for ddMVAC (P = 0.048), while chemotherapy cycle delays and hospitalization days were higher for GC (P = 0.008). After adjusting for ECOG-PS and age, the cost per patient was approximately 41% lower (95%CI: 28% to 52%; P < 0.001) for GC vs. ddMVAC, which translated to a median adjusted cost savings of $7,410 (95%CI: $5,474-$9,347) per patient. CONCLUSIONS: Although excess HRU did not clearly favor one regimen, adjusting for PS and age indicated lower costs with GC vs. ddMVAC. Given the similar cumulative cisplatin delivery with both regimens, the associated values and costs supports the preferential selection of GC in the neoadjuvant setting of MIBC.

Assessment of HBEC-5i endothelial cell line cultivated in astrocyte conditioned medium as a human blood-brain barrier model for ABC drug transport studies.

Endothelial cells are main components of the Blood-Brain Barrier (BBB) and form a tight monolayer that regulates the passage of molecules, with the ATP-Binding Cassette (ABC) transporters efflux pumps. We have developed a human in vitro model of HBEC-5i endothelial cells cultivated alone or with human astrocytes conditioned medium on insert. HBEC-5i cells showed a tight monolayer within 14 days, expressing ZO-1 and claudin 5, a low apparent permeability to small molecules, with a TEER stability during five days. The P-gp, BCRP, MRPs transporters were well expressed and functional. Accumulation and efflux ratio measurement with different ABC transporters substrates (Rhodamine 123, BCECF AM, Hoechst 33342) and inhibitors (verapamil, Ko143, probenecid and cyclosporin A) were conducted. At barrier level, the functionality of ABC transporters was three-fold enhanced in astrocyte conditioned medium. We validated our model by the transport of pharmacological substrates: caffeine, rivaroxaban, and methotrexate. The rivaroxaban and methotrexate were released with an efflux ratio >3 and were decreased by more than half with inhibitors. HBEC-5i model could be used as relevant tool in preclinical studies for assessing the permeability of therapeutic molecules to cross human BBB.

Treatment of giant-cell arteritis, a literature review.

Giant-cell arteritis (GCA) is the most common vasculitis in people aged more than 50 years. Despite the frequency of this disease, there is currently no international consensus on its therapeutic modalities. The aim of this study was to conduct a review on an international literature about the treatment of GCA, whatever the clinical pattern might be. Oral corticosteroids remain the cornerstone treatment, possibly preceded by intravenous bolus in complicated forms. In cases of glucocorticoid (GC) dependence or GC-related side effects, a GC-sparing agent may be necessary. Methotrexate is one of the most used treatments despite its low level of evidence and mild efficacy. Cyclophosphamide and tocilizumab look promising but require validation in further studies. The results for TNF-α blockers and azathioprine are disappointing. Preventing complications of prolonged corticosteroid therapy is a world challenge and the management of GC-induced osteoporosis is not the same from one country to another. There is a significant risk of arterial thrombosis, mainly at treatment onset, which may encourage to associate an antiplatelet therapy, especially in patients with other cardiovascular risk factors. Place of statins in the treatment of the disease is uncertain.

Noninvasive Electroretinography Assessment of Intravitreal Sustained-Release Methotrexate Microimplants in Rabbit Eyes.

PURPOSE: The purpose of this study is to noninvasively evaluate the safety and toxicity of a chitosan (CS) and polylactic acid (PLA)-based sustained-release methotrexate (MTX) intravitreal microimplant in normal rabbit eyes using electroretinography (ERG). METHODS: PLA-coated CS-based microimplants containing 400 µg of MTX and placebo microimplants (without drug) were surgically implanted in the vitreous of the right and the left eyes, respectively, in each of the 8 New Zealand rabbits using minimally invasive technique. At each predetermined time points (days 5, 12, 19, and 33), ERG was conducted on 2 rabbits to evaluate the safety of the microimplants administered in each eye. ERG was carried out using 2 protocols, scotopic and photopic, on each eye prior to surgery (PS) and prior to euthanasia (PE) conditions. The safety of the microimplants was assessed using statistical analysis of the ERG data (B/A ratio analysis, oscillatory potential analysis, and Naka-Rushton analysis) and subsequently quantifying and comparing functional integrity of the retina between the PS and PE conditions of each eye. RESULTS: Statistical analysis of the ERG data showed no change in retinal functional integrity because of the PLA-coated CS-based MTX microimplant and the placebo microimplant. ERG analysis also revealed absence of any evident bioelectrical dysfunction caused by the microimplants. CONCLUSION: ERGs were performed to determine whether the microimplants containing MTX and the placebo microimplants were associated with any profound retinal bioelectrical dysfunction that might be attributable to toxicity not apparent on histological studies of such eyes. The results shown in this report indicate that there were no such evident adverse effects of the microimplants or contained drug.

Antithymidylate resistance enables transgene selection and cell survival for T cells in the presence of 5-fluorouracil and antifolates.

Antithymidylates (AThy) constitute a class of drugs used in the treatment of cancers such as lung, colon, breast and pancreas. These drugs inhibit DNA synthesis by targeting the enzymes dihydrofolate reductase (DHFR) and/or thymidylate synthase (TYMS). AThys effectively inhibit cancer cells, and also inhibit T cells, preventing anticancer immunity, which might otherwise develop from AThy-induced cancer destruction. We establish that T cells expressing mutant DHFR--DHFR L22F, F31S (DHFR(FS))--and/or mutant TYMS--TYMS T51S, G52S (TYMS(SS))-effectively survive in toxic concentrations of AThys methotrexate, pemetrexed and 5-fluorouracil. Furthermore, we show that DHFR(FS) permitted rapid selection of an inducible suicide transgene in T cells. These findings demonstrate that AThy resistances prevent AThy cytotoxicity to T cells while permitting selection of important transgenes. This technological development could enhance in vitro and in vivo survival and selection of T-cell therapeutics being designed for a broad range of cancers.

Ultrasound assessment of enthesis thickening in psoriatic arthritis patients treated with adalimumab compared to methotrexate.

The objective of the study was to combine ultrasonographic (US) with clinical findings for comparing the effect of adalimumab (ADA) to methotrexate (MTX) on the thickness of tendons and enthesis in psoriatic arthritis (PsA) patients. Forty-three consecutive PsA patients were examined at baseline and after 6 and 12 weeks of treatment with ADA or MTX. The US assessment included thickness measurement of the extensor (ET) and flexor tendons (FT) of the second and third finger of both hands, plantar aponeurosis (PA) and the Achilles tendon (AT) bilaterally. Disease activity (DA) was assessed by the number of tender (TJ) and swollen joints (SJ), the number of inflamed enthesis (IE), pain assessment (PAI), and patient (PDAI) and physician (PHDAI) disease activity evaluations by visual activity score (VAS). Nineteen patients received MTX and 24 patients received ADA. All DA parameters improved in both groups. A decrease in thickness of tendons and enthesis was observed only in the ADA group, reaching a level of significance for the left AT (p = 0.01), left PA (p = 0.007), the second left FT (p = 0.04) and the third ET (p = 0.04). ADA patients showed a trend towards a better response to treatment compared to MTX patients that reach significance at week 6 of treatment for the thickness of left AT (p = 0.04), left PA (p = 0.03), the number of TJ (p = 0.0136), PAI (p = 0.0028), and PDAI (p = 0.029). ADA treatment for PsA compared to MTX significantly improved signs of DA and several US parameters. US assessment of enthesis can be an additional useful tool in the monitoring of psoriatic enthesopathy.

Modelling the cost-effectiveness of combination therapy for early, rapidly progressing rheumatoid arthritis by simulating the reversible and irreversible effects of the disease.

OBJECTIVE: To estimate the cost-effectiveness of adalimumab plus methotrexate (MTX) versus MTX monotherapy in early, aggressive rheumatoid arthritis (RA) when explicitly modelling short-term (reversible) and long-term (irreversible, ie, joint damage) disease activity and physical function. METHODS: A microsimulation model was developed to unify, in a single cost-effectiveness model, measures of reversible and irreversible disease activity and physical function based on data from the PREMIER trial. Short term, reversible disease activity was modelled using DAS28 variables, including swollen joint counts, tender joint counts, C reactive protein concentration and pain. The DAS28 variables were then used in a logistic regression to predict short-term American College of Rheumatology (ACR) responses, which informed treatment continuation and switches. Long term, irreversible, radiographically documented joint damage was modelled using modified Total Sharp Score (mTSS). The model then linked both short-term disease activity and mTSS to the Health Assessment Questionnaire score, which was used to calculate direct and indirect costs, and quality adjusted life-years (QALYs). RESULTS: When both reversible and irreversible effects of therapy were included, combination therapy was estimated to produce 6-month 50% ACR responses in 75% of patients versus 54% in MTX monotherapy. Compared to MTX monotherapy, combination therapy resulted in 2.68 and 3.04 discounted life years and QALYs gained, respectively. Combination therapy also resulted in a net increase in direct costs of £106,207 for a resulting incremental cost/QALY gain of £32,425. When indirect costs were included in the analysis, the ICER (incremental cost-effectiveness ratio) decreased to £27,238. Disregarding irreversible effects increased the incremental cost-effectiveness ratio to £78,809 (when only direct costs were included). CONCLUSIONS: Starting with adalimumab plus MTX combination therapy in early, aggressive RA is cost-effective when irreversible damage is adequately considered.

In vitro control release, cytotoxicity assessment and cellular uptake of methotrexate loaded liquid-crystalline folate nanocarrier.

Folate molecules self-assemble in the form of stacks to form liquid-crystalline solutions. Nanocarriers from self-assembled folates are composed of highly ordered structures, which offer high encapsulation of drug (95-98%), controlled drug release rates, active cellular uptake and biocompatibility. Recently, we have shown that the release rates of methotrexate can be controlled by varying the size of nanoparticles, cross-linking cation and cross-linking concentration. The present study reports the in vitro cytotoxic behavior of methotrexate loaded liquid-crystalline folate nanoparticles on cultured HeLa cells. Changing drug release rates can influence cytotoxicity of cancer cells. Therefore, to study the correlation of release rate and cytotoxic behavior, the effect of release controlling parameters on HeLa cells was studied through MTT assay. It is reported that by controlling the methotrexate release, the survival rates of HeLa cells can be controlled. Released methotrexate kills HeLa cells as effectively as free methotrexate solution. The co-culture based in vitro cellular uptake study through fluorescence microscopy on folate receptor positive and negative cancer cells shows that the present nanocarrier has the potential to distinguish cancer cells from normal cells. Overall, the present study reports the in vitro performance of self-assembled liquid-crystalline folate nanoparticles, which will be a platform for further in vivo studies and clinical trials.

Intensive intervention can lead to a treatment holiday from biological DMARDs in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction that causes significant morbidity and mortality. However, the combined use of methotrexate (MTX), a synthetic disease-modifying anti-rheumatic drug (sDMARD) and biological DMARDs (bDMARDs) has revolutionized treatment of RA and clinical remission or low disease activity (LDA) are now realistic targets, achieved by a large proportion of RA patients. We are now in a position to evaluate if it is possible to maintain remission or LDA while at the same time reducing the burden of treatment on the patient and healthcare system. Data are emerging from large, well-conducted studies designed to answer this question, shedding light on which patient populations and treatment algorithms can survive treatment discontinuation or tapering with low risk of disease flare. For early RA, approximately half of early RA patients could discontinue TNF-targeted bDMARDs without clinical flare and functional impairment after obtaining clinical remission by bDMARDs with MTX. In contrast, for established RA, fewer patients sustained remission or LDA after the discontinuation of bDMARDs and "deep remission" at the discontinuation was a key factor to maintain the treatment holiday of bDMARDs. Thus, this article provides a brief outline on withdrawing or tapering bDMARDs once patients have achieved remission or LDA in RA.

Tc-99 m diethylenetriamine-pentaacetic acid (DTPA): is it reliable for assessment of methotrexate-induced cumulative effect on renal filtration in rheumatoid arthritis patients?

Methotrexate (MTX) is commonly employed as the initial DMARD used for the treatment of rheumatoid arthritis (RA). We aimed to contribute to the safety profile of MTX by assessing its cumulative effect on renal filtration. A total of 52 RA adult female patients with normal baseline serum creatinine and GFR at the initial diagnosis of the disease were included. Group 1 (G1) included 30 patients (mean age 40.4 ± 4.4 years) on MTX and NSAIDS, while 22 RA patients (mean age 38.5 ± 8.2 years) who received NSAIDs only served as control group (G2). Renal function was assessed by GFR measurement using technetium diethylenetriamine-pentaacetic acid (Tc-99 m DTPA) at a point of the study time corresponding to disease duration. Twenty-one out of thirty (70 %) in G1 showed reduced GFR compared to 6/22 (27.3 %) in G2 (P = 0.007), with 3.3 ± 0.5 % annual reduction in GFR. Reduced GFR in G1 showed significant negative correlation with age (r = -0.396, P = 0.005), MTX cumulative dose (r = -0.263, P = 0.049), MTX-intake duration (r = -0.293, P = 0.031) and NSAIDs-intake duration (r = -0.344, P = 0.014). Low-dose MTX has a slow cumulative effect on renal filtration manifested by GFR reduction overtime that could be monitored by Tc-99 m DTPA.

Fraturas do fêmur proximal no idoso: estudo de custo da doença sob a perspectiva de um hospital público no Rio de Janeiro, Brasil / Hip fractures in the elderly: cost of illness study in a public hospital perspective, Rio de Janeiro, Brazil

O artigo visa a estimar o custo direto médico do tratamento hospitalar de pacientes idosos com fraturas de fêmur proximal, no Hospital Municipal Lourenço Jorge, na cidade do Rio de Janeiro. Estudo observacional, prospectivo, para estimar a utilização de recursos e custos diretos médicos associados à hospitalização por fratura de fêmur proximal em idosos, em 2007 e 2008, sob a perspectiva do prestador de serviços. Foi utilizado um instrumento de coleta de dados através do qual foram registrados recursos identificados na revisão prospectiva dos prontuários. Aos recursos utilizados foram atribuídos custos em reais (R$) baseando-se em valores do ano 2010. Foram realizadas análises descritivas dos custos e utilização de recursos, bem como avaliada a associação de variáveis clínicas e demográficas com o custo final observado. Foram incluídos 82 pacientes, 81,7 por cento do sexo feminino, idade média de 76,96 anos, hospitalização média de 12,66 dias. A mediana de custo por paciente foi de R$ 3.064,76 (IC95 por cento: 2.817,63 a 3.463,98). Hospitalização clínica e procedimento cirúrgico foram responsáveis por 65,61 por cento e 24,94 por cento dos custos, respectivamente. Pacientes submetidos ao tratamento cirúrgico até o quarto dia de hospitalização apresentaram mediana de custos menor do que pacientes submetidos após o quarto dia (R$ 2.136,31 e R$ 3.281,45, p<0,00001). Observou-se também diferença significativa nos custos finais por tipo de procedimento cirúrgico realizado. O custo do tratamento das fraturas de fêmur proximal no idoso foi significativamente maior nos pacientes submetidos à cirurgia após o quarto dia de hospitalização. Hospitalização clínica e procedimento cirúrgico foram os principais componentes do custo final observado.

This paper aims to assess direct medical costs associated to hospital treatment of hip fractures in the elderly in the Municipal Hospital Lourenço Jorge (HMLJ), Rio de Janeiro. Observational, prospective study to assess resource utilization and direct medical costs associated to elderly hip fracture hospitalization in 2007 and 2008, under the health care provider perspective. A standard data collection instrument was used to register identified resources during prospective medical charts review. The resource utilization was converted into Brazilian Real (R$), based on 2010 prices. Descriptive analysis of costs and resource utilization and their association with clinical and demographic variables were performed. Eighty two patients were included, 81.7 percent female, mean age of 76.96 years, hospitalization mean time of 12.66 days. Median total costs per patient were R$ 3,064.76 (IC95 percent: 2,817.63 - 3,463.98). Clinical hospitalization and surgical procedure were responsible for 65.61 percent and 24.94 percent of costs, respectively. Median costs for patients submitted to surgical procedure until the fourth day of hospitalization were lower than median costs for patients submitted after the fourth day (R$ 2,136.45 and R$ 3,281.45, respectively, p<0.00001). A significant difference in average costs per type of surgical procedure was also observed. Cost associated to inpatient treatment of hip fractures in the elderly was higher in patients who performed surgery after the fourth day of hospitalization. Clinical hospitalization and surgical procedure were the main cost components observed.

Early abortion in Ontario: options and costs.

OBJECTIVE: Early abortions have been predominantly surgical for many years, but medical options with comparable efficacy and safety are now available. This study compares the costs of two medical options and two surgical options. METHODS: We used a clinical model to compare the costs in Ontario of four options for early abortion: medical abortion using either mifepristone or methotrexate, and surgical abortion by vacuum aspiration in either a hospital or a free-standing clinic. The cost analysis was conducted from the perspectives of society, the health care system, and the patient. RESULTS: From all perspectives, total costs were highest for hospital surgical abortion, followed by surgical abortion in a clinic. From the patient's perspective, total costs were higher for surgical abortion but direct costs (mainly for medications) were higher for medical abortion. The total cost of mifepristone and methotrexate abortion was equal if the price of mifepristone (200 mg) was $59.52. The model was robust but was sensitive to the price of mifepristone. CONCLUSION: Early medical abortion costs less than early surgical abortion from the societal and health care system perspectives but more than surgical abortion from the patient's perspective. Surgical abortion costs more in hospitals than in free-standing clinics from the societal and health care system perspectives, but the costs are the same in both settings from the patient's perspective. No method for early abortion can be identified as best, and patients should be free to choose the option they prefer.