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Effects of intraventricular methotrexate administration on Cuprizone-induced demyelination in mice  [PDF]
Andre M. Mueller,Adam Nassery,Massimiliano Cristofanilli
Frontiers in Molecular Neuroscience , 2013, DOI: 10.3389/fnmol.2013.00034
Abstract: We previously showed that intrathecal administration of methotrexate slowed disability progression in multiple sclerosis (MS) patients with progressive disease. In general MS patients with progressive disease respond poorly to anti-inflammatory therapies. In order to better understand the mechanism by which methotrexate is protective in progressive MS, we analyzed its impact on the non-inflammatory cuprizone-induced demyelination model. When low-dose methotrexate was administered intracerebroventricularly it reduced demyelination and accumulation of GFAP+ reactive astrocytes in the corpus callosum. Administration of methotrexate after the withdrawal of cuprizone neither delayed remyelination nor influenced the number of astrocytes in the corpus callosum suggesting that methotrexate does not interfere with repair processes in the CNS. Moreover, methotrexate increased the expression of IGF1 in vitro and in vivo, a factor known to protect oligodendrocytes and limit the activation of astrocytes. Our studies show that methotrexate has an impact on pathogenic process in a demyelination model whose pathophysiological basis is not primarily related to inflammatory mechanisms, similar to neurodegenerative mechanisms associated with progressive MS. The pronounced inhibitory influence of methotrexate on the accumulation of astrocytes in the corpus callosum suggests that intrathecal methotrexate modulates astroglial activation in progressive MS possibly by promoting CNS production of IGF1.
Novel formulation of a methotrexate derivative with a lipid nanoemulsion  [cached]
Moura JA,Valduga CJ,Tavares ER,Kretzer IF
International Journal of Nanomedicine , 2011,
Abstract: Juliana A Moura1, Claudete J Valduga2, Elaine R Tavares1, Iara F Kretzer1,4, Durvanei A Maria3, Raul C Maranh o1,4 1Heart Institute of the Medical School Hospital, University of S o Paulo; 2Bandeirante University of S o Paulo; 3Butantan Institute, 4Faculty of Pharmaceutical Sciences of the University of S o Paulo, S o Paulo, Brazil Background: Lipid nanoemulsions that bind to low-density lipoprotein receptors can concentrate chemotherapeutic agents in tissues with low-density lipoprotein receptor overexpression and decrease the toxicity of the treatment. The aim of this study was to develop a new formulation using a lipophilic derivative of methotrexate, ie, didodecyl methotrexate (ddMTX), associated with a lipid nanoemulsion (ddMTX-LDE). Methods: ddMTX was synthesized by an esterification reaction between methotrexate and dodecyl bromide. The lipid nanoemulsion was prepared by four hours of ultrasonication of a mixture of phosphatidylcholine, triolein, and cholesteryloleate. Association of ddMTX with the lipid nanoemulsion was performed by additional cosonication of ddMTX with the previously prepared lipid nanoemulsion. Formulation stability was evaluated, and cell uptake, cytotoxicity, and acute animal toxicity studies were performed. Results: The yield of ddMTX incorporation was 98% and the particle size of LDE-ddMTX was 60 nm. After 48 hours of incubation with plasma, approximately 28% ddMTX was released from the lipid nanoemulsion. The formulation remained stable for at least 45 days at 4°C. Cytotoxicity of LDE-ddMTX against K562 and HL60 neoplastic cells was higher than for methotrexate (50% inhibitory concentration [IC50] 1.6 versus 18.2 mM and 0.2 versus 26 mM, respectively), and cellular uptake of LDE-ddMTX was 90-fold higher than that of methotrexate in K562 cells and 75-fold in HL60 cells. Toxicity of LDE-ddMTX, administered at escalating doses, was higher than for methotrexate (LD50 115 mg/kg versus 470 mg/kg; maximum tolerated dose 47 mg/kg versus 94 mg/kg) in mice. However, the hematological toxicity of LDE-ddMTX was lower than for methotrexate. Conclusion: LDE-ddMTX was stable, and uptake of the formulation by neoplastic cells was remarkably greater than of methotrexate, which resulted in markedly greater cytotoxicity. LDE-ddMTX is thus a promising formulation to be tested in future animal models of cancer or rheumatic disease, wherein methotrexate is widely used. Keywords: nanoparticles, methotrexate, didodecyl methotrexate, drug delivery, cholesterol
Novel formulation of a methotrexate derivative with a lipid nanoemulsion
Moura JA, Valduga CJ, Tavares ER, Kretzer IF, Maria DA, Maranhao RC
International Journal of Nanomedicine , 2011, DOI: http://dx.doi.org/10.2147/IJN.S18039
Abstract: vel formulation of a methotrexate derivative with a lipid nanoemulsion Original Research (3820) Total Article Views Authors: Moura JA, Valduga CJ, Tavares ER, Kretzer IF, Maria DA, Maranhao RC Published Date October 2011 Volume 2011:6 Pages 2285 - 2295 DOI: http://dx.doi.org/10.2147/IJN.S18039 Juliana A Moura1, Claudete J Valduga2, Elaine R Tavares1, Iara F Kretzer1,4, Durvanei A Maria3, Raul C Maranh o1,4 1Heart Institute of the Medical School Hospital, University of S o Paulo; 2Bandeirante University of S o Paulo; 3Butantan Institute, 4Faculty of Pharmaceutical Sciences of the University of S o Paulo, S o Paulo, Brazil Background: Lipid nanoemulsions that bind to low-density lipoprotein receptors can concentrate chemotherapeutic agents in tissues with low-density lipoprotein receptor overexpression and decrease the toxicity of the treatment. The aim of this study was to develop a new formulation using a lipophilic derivative of methotrexate, ie, didodecyl methotrexate (ddMTX), associated with a lipid nanoemulsion (ddMTX-LDE). Methods: ddMTX was synthesized by an esterification reaction between methotrexate and dodecyl bromide. The lipid nanoemulsion was prepared by four hours of ultrasonication of a mixture of phosphatidylcholine, triolein, and cholesteryloleate. Association of ddMTX with the lipid nanoemulsion was performed by additional cosonication of ddMTX with the previously prepared lipid nanoemulsion. Formulation stability was evaluated, and cell uptake, cytotoxicity, and acute animal toxicity studies were performed. Results: The yield of ddMTX incorporation was 98% and the particle size of LDE-ddMTX was 60 nm. After 48 hours of incubation with plasma, approximately 28% ddMTX was released from the lipid nanoemulsion. The formulation remained stable for at least 45 days at 4°C. Cytotoxicity of LDE-ddMTX against K562 and HL60 neoplastic cells was higher than for methotrexate (50% inhibitory concentration [IC50] 1.6 versus 18.2 mM and 0.2 versus 26 mM, respectively), and cellular uptake of LDE-ddMTX was 90-fold higher than that of methotrexate in K562 cells and 75-fold in HL60 cells. Toxicity of LDE-ddMTX, administered at escalating doses, was higher than for methotrexate (LD50 115 mg/kg versus 470 mg/kg; maximum tolerated dose 47 mg/kg versus 94 mg/kg) in mice. However, the hematological toxicity of LDE-ddMTX was lower than for methotrexate. Conclusion: LDE-ddMTX was stable, and uptake of the formulation by neoplastic cells was remarkably greater than of methotrexate, which resulted in markedly greater cytotoxicity. LDE-ddMTX is thus a promising formulation to be tested in future animal models of cancer or rheumatic disease, wherein methotrexate is widely used.
Low-dose methotrexate administration in the management of cervical pregnancy  [cached]
Christine E. Reissmann,Tamme W. Goecke,Matthias W. Beckmann,Ralf L. Schild
Journal of the Turkish-German Gynecological Association , 2009,
Abstract: Objective: Cervical pregnancy is a rare form of ectopic pregnancy. There is the risk of hysterectomy when this type of ectopic pregnancy is managed with surgery. An established form of conservative treatment is the administration of methotrexate (MTX). We demonstrate the effectiveness of a low-dose MTX regimen. Materials and Methods: Case analysis of cervical pregnancies at a tertiary referral center at an University Hospital. Six patients presented with cervical or isthmocervical pregnancies. Low-dose of MTX was administered intravenously. Secondary surgical intervention was carried out when needed. The main outcome measures were to preserve childbearing capacity using conservative treatment partly followed by curettage for cervical pregnancyResults: Six patients received conservative treatment with MTX in a low-dose regimen. During the course of conservative treatment with MTX, three patients underwent curettage. One of these patients also received an intra-amniotic administration in addition to systemic administration of MTX. Conclusions: Systemic low-dose methotrexate treatment is an effective form of primary treatment, with a low rate of side effects.
Ufasomes Mediated Cutaneous Delivery of Dexamethasone: Formulation and Evaluation of Anti-Inflammatory Activity by Carrageenin-Induced Rat Paw Edema Model  [PDF]
Rajkamal Mittal,Arvind Sharma,Sandeep Arora
Journal of Pharmaceutics , 2013, DOI: 10.1155/2013/680580
Abstract: The purpose of study is to formulate and evaluate ufasomal gel of dexamethasone. Ufasomal suspension was made by sonication method using different concentrations of Span 80, Span 20 and cholesterol along with 25 mg of drug. Ufasomal gel was formulated by hydration method using carbopol 940. Ufasomal vesicles appeared as spherical and multilamellar under Transmission Electron Microscope. Ufasomal formulation prepared with drug to oleic acid molar ratio 8:2 (UF-2) produced greater number of vesicles and greater entrapment efficiency. UF-2 was optimized for further evaluation. The transdermal permeation and skin partitioning of from optimized formulation was significantly higher ( ) as compared to plain drug and plain gel formulation which is due to presence of surfactant acting as permeation enhancer. Permeation of optimized formulation was found to be about 4.7 times higher than plain drug gel. Anti-inflammatory activity evaluated by inhibition Carrageenan induced rat paw edema model. Significant reduction of edema ( ) was observed in comparison to the commercial product. Hence oleic acid based vesicles can be used as alternate carrier for topical delivery. 1. Introduction Dexamethasone is a glucocorticoid with a relevant clinical use mainly due to its anti-inflammatory and immunosuppressive effects. However, the great number of side effects, such as hypertension, hydroelectrolytic disorders, hyperglycemia, peptic ulcers, and glucosuria, restricts the use of dexamethasone in prolonged therapy [1]. Topical administration of dexamethasone is clinically used for the treatment of many ocular disorders, or diseases, like uveitis, [2] allergic conjunctivitis, [3] and corneal postoperative period, [4] as well as for the treatment of skin disorders such as atopic dermatitis, [5, 6] allergic dermatitis, eczematous dermatitis, [6, 7] psoriasis, acne rosacea, [8] and phimosis [9]. Over the last years many efforts have been made not only to improve the efficacy and bioavailability of drugs but also to reduce their adverse effects by means of the development of novel drug carrier systems [10]. In the past few decades, considerable attention has been focused on the development of new drug delivery system (NDDS). When the new drug or existing drug is given by altering the formulation and administered through different route, this process is called the novel drug delivery system. The NDDS should ideally fulfill two prerequisites. Firstly, it should deliver the drug at a rate directed by the needs of the body, over the period of treatment. Secondly, it should channel the
pH and salivary sodium bicarbonate during the administration protocol for methotrexate in children with leukemia
Rojas de Morales,Thais; Navas,Rita; Viera,Ninoska; álvarez,Carmen Julia; Chaparro,Neira; Griman,Dariana;
Medicina Oral, Patología Oral y Cirugía Bucal (Internet) , 2007,
Abstract: objective: to analyze the behavior of ph and sodium bicarbonate (nahco3) in the saliva of patients with leukemia during the administration protocol for methotrexate (mtx). materials and methods: a controlled clinical essay was carried out on 23 patients between 4 and 18 years of age with high-risk acute lymphoblastic leukemia. sampling was carried out at to: basal condition; t1: 12 hours after intravenous administration of sodium bicarbonate, before administering mtx and t2: 3 hours after administering mtx, the time of maximum concentration. chiron-diagnostic 378? equipment was used to determine ph and sodium bicarbonate. the data was interpreted using analysis of variance at the 5% significance level. results: the highest values of sodium bicarbonate were observed at t2, with salivary ph levels remaining within neutrality ranges, diminishing slightly in t1. conclusion. in this study, the dose of sodium bicarbonate considered in the administration protocol of 3 g /m2 mtx, kept sodium bicarbonate levels in saliva at normal levels and ph neutral.
Study of pharmacokinetics and tissue distribution of liposomal brucine for dermal administration  [cached]
Yang B-C,Chu Z-F,Zhu S,Wang L-J
International Journal of Nanomedicine , 2011,
Abstract: Bai-Can Yang1, Zhi-Feng Chu1, Sha Zhu1, Li-Jun Wang1, Yu-Hong Feng1, Feng-Hua Li1, Chang-Sheng Liu2, Yuan Yuan21Pharmacy Department of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Key Laboratory for Ultrafine Materials of Ministry of Education, and Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai, People’s Republic of ChinaObjective: To evaluate the pharmacokinetics and tissue distribution of liposomal brucine (LB) for dermal application.Methods: Pharmacokinetics and tissue distribution were studied by in vivo animal testing. High performance liquid chromatography (HPLC) was used to detect the concentration of brucine in rats’ skin, plasma and various tissues.Results: After dermal administration, LB was absorbed rapidly in the skin and could be detected after 0.5 hours. After 36 hours, levels were too low to be detected. In plasma, levels were also too low to be detected after 36 hours. The concentration of LB reached 50% of the maximum in all tissues except the brain, peaking after 1.5 hours but still detectable after 12 hours.Conclusion: The concentration of LB was high in skin at the application site. LB was quickly absorbed into tissues through the blood circulation and widely distributed throughout the whole body. There was no obvious toxicity and LB did not readily accumulate in tissues and organs. It showed local potency but low overall systemic toxicity.Keywords: liposomal brucine, dermal administration, pharmacokinetics, tissue distribution
Study of pharmacokinetics and tissue distribution of liposomal brucine for dermal administration
Yang B-C, Chu Z-F, Zhu S, Wang L-J, Feng Y-H, Li F-H, Liu C-S, Yuan Y
International Journal of Nanomedicine , 2011, DOI: http://dx.doi.org/10.2147/IJN.S17255
Abstract: udy of pharmacokinetics and tissue distribution of liposomal brucine for dermal administration Original Research (4106) Total Article Views Authors: Yang B-C, Chu Z-F, Zhu S, Wang L-J, Feng Y-H, Li F-H, Liu C-S, Yuan Y Published Date May 2011 Volume 2011:6 Pages 1109 - 1116 DOI: http://dx.doi.org/10.2147/IJN.S17255 Bai-Can Yang1, Zhi-Feng Chu1, Sha Zhu1, Li-Jun Wang1, Yu-Hong Feng1, Feng-Hua Li1, Chang-Sheng Liu2, Yuan Yuan2 1Pharmacy Department of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Key Laboratory for Ultrafine Materials of Ministry of Education, and Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai, People’s Republic of China Objective: To evaluate the pharmacokinetics and tissue distribution of liposomal brucine (LB) for dermal application. Methods: Pharmacokinetics and tissue distribution were studied by in vivo animal testing. High performance liquid chromatography (HPLC) was used to detect the concentration of brucine in rats’ skin, plasma and various tissues. Results: After dermal administration, LB was absorbed rapidly in the skin and could be detected after 0.5 hours. After 36 hours, levels were too low to be detected. In plasma, levels were also too low to be detected after 36 hours. The concentration of LB reached 50% of the maximum in all tissues except the brain, peaking after 1.5 hours but still detectable after 12 hours. Conclusion: The concentration of LB was high in skin at the application site. LB was quickly absorbed into tissues through the blood circulation and widely distributed throughout the whole body. There was no obvious toxicity and LB did not readily accumulate in tissues and organs. It showed local potency but low overall systemic toxicity.
Formulation, Development and In-Vitro Evaluation of Mucoadhesive Buccal Patches Of Methotrexate  [PDF]
Rohit Chaudhary,,Md. Shamim Qureshi,,Jitendra Patel,Uttam Prasad Panigrahi
International Journal of Pharma Sciences and Research , 2010,
Abstract: The goal of present investigation was to design and evaluate mucoadhesive bilayered buccal devices comprising a drug containing mucoadhesive layer and a drug free backing membrane. Bilaminatd patches composed of mixture of drug (Methotrexate) and sodium alginate alone or in combination with sodium carboxy methylcellulose,Polyvinylpyrrolidine and carbopol 934 and backing membrane (Ethyl cellulose).The patches were fabricated by solvent casting technique and were evaluated for In-Vitro and Ex-Vivo drug release. The patches were evaluated for film weight uniformity, thickness, swelling index, surface pH, mucoadhesive strength and mucoadhesive time and folding endurance. A combination of sodium alginate with carbopol-934 and glycerol as plasticizer gives promising results. The optimized patch exhibit an in vitro release of 82% through cellophane membrane and 70.78 % through buccal mucosa with satisfactory mucoadhesive strength and mucoadhesive time. The release kinetics of formulation also studied .The release kinetics through cellophane membrane was Higuchi while in buccal mucosa it is zero order .From Higuchi model we can say the mechanism of drug release is diffusion control .The ex vivo also fitted to Korsmayer-Peppas equation which characterize the release mechanism. The value of n is more than one so release was non Fickinian i.e. not depends upon concentration gradient.
Changes of biochemical parameters in rat intestinal mucosa induced by methotrexate and effects of enteral administration of glutamine  [PDF]
Bajin-Kati? Katica,Stankov Karmen,Kova?evi? Zoran
Archive of Oncology , 2004, DOI: 10.2298/aoo0401035b
Abstract: BACKGROUND: Rapidly proliferating crypt cells of the intestinal epithelium, the precursors of the mature enterocytes, are extremely sensitive to the effects of cytostatic agents. We investigated the effects of the methotrexate on rat intestinal mucosa in order to get the information on biochemical indicators of intestinal damage. METHODS: Biochemical parameters were investigated in isolated intestinal mucosa of Sprague-Dawley rats, previously treated with methotrexate by intraperitoneal administration. Glutamine was dissolved in water and administered orally. RESULTS: The activity of glutaminase and alkaline phosphatase showed the enzymatic response to different doses of methotrexate. The activity of both enzymes was significantly lower in the mucosa of treated animals, compared to control group. CONCLUSION: Minimal mucosal damage and regeneration time is dose dependent and influenced by the dosage schedule of antitumor therapy.
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