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Bruno P A Cammue - One of the best experts on this subject based on the ideXlab platform.
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Repurposing Toremifene for Treatment of Oral Bacterial Infections.
Antimicrobial agents and chemotherapy, 2017Co-Authors: Evelien Gerits, Katrijn De Brucker, Katleen Vandamme, Bruno P A Cammue, Karin Thevissen, Valerie Defraine, Kaat De Cremer, Serge Beullens, Maarten Fauvart, Natalie VerstraetenAbstract:ABSTRACT The spread of antibiotic resistance and the challenges associated with antiseptics such as chlorhexidine have necessitated a search for new antibacterial agents against oral bacterial pathogens. As a result of failing traditional approaches, drug repurposing has emerged as a novel paradigm to find new antibacterial agents. In this study, we examined the effects of the FDA-approved anticancer agent Toremifene against the oral bacteria Porphyromonas gingivalis and Streptococcus mutans. We found that the drug was able to inhibit the growth of both pathogens, as well as prevent biofilm formation, at concentrations ranging from 12.5 to 25 μM. Moreover, Toremifene was shown to eradicate preformed biofilms at concentrations ranging from 25 to 50 μM. In addition, we found that Toremifene prevents P. gingivalis and S. mutans biofilm formation on titanium surfaces. A time-kill study indicated that Toremifene is bactericidal against S. mutans. Macromolecular synthesis assays revealed that treatment with Toremifene does not cause preferential inhibition of DNA, RNA, or protein synthesis pathways, indicating membrane-damaging activity. Biophysical studies using fluorescent probes and fluorescence microscopy further confirmed the membrane-damaging mode of action. Taken together, our results suggest that the anticancer agent Toremifene is a suitable candidate for further investigation for the development of new treatment strategies for oral bacterial infections.
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oral administration of the broad spectrum antibiofilm compound Toremifene inhibits candida albicans and staphylococcus aureus biofilm formation in vivo
Antimicrobial Agents and Chemotherapy, 2014Co-Authors: Kaat De Cremer, Nicolas Delattin, Katrijn De Brucker, Evelien Gerits, Natalie Verstraeten, Annelies Peeters, Sona Kucharikova, Jan Michiels, Patrick Van Dijck, Bruno P A CammueAbstract:ABSTRACT We here report on the in vitro activity of Toremifene to inhibit biofilm formation of different fungal and bacterial pathogens, including Candida albicans, Candida glabrata, Candida dubliniensis, Candida krusei, Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis. We validated the in vivo efficacy of orally administered Toremifene against C. albicans and S. aureus biofilm formation in a rat subcutaneous catheter model. Combined, our results demonstrate the potential of Toremifene as a broad-spectrum oral antibiofilm compound.
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repurposing as a means to increase the activity of amphotericin b and caspofungin against candida albicans biofilms
Journal of Antimicrobial Chemotherapy, 2014Co-Authors: Nicolas Delattin, Katrijn De Brucker, Katleen Vandamme, Els M K Meert, Arnaud Marchand, Patrick Chaltin, Bruno P A Cammue, Karin ThevissenAbstract:Results: Pre-incubation of C. albicans biofilms with subinhibitory concentrations of the enhancers drospirenone, perhexiline maleate or Toremifene citrate significantly increased the activity of amphotericin B or caspofungin (FICI ,0.5) against C. albicans and Candida glabrata biofilms. Moreover, these enhancers did not affect the growth potential of osteoblasts. Interestingly, Toremifene citrate also enhanced theinvitro activity of caspofungin in a mixed biofilm consisting ofC.albicans andStaphylococcusepidermidis. Furthermore, we demonstrate synergy between Toremifene citrate and caspofungin in an in vivo worm C. albicans biofilm infection model. Conclusions: Our data demonstrate an in vitro and in vivo enhancement of the antibiofilm activity of caspofungin by Toremifene citrate. Furthermore, our results pave the way for implant-related applications of the identified enhancers.
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Oral Administration of the Broad-Spectrum Antibiofilm Compound Toremifene Inhibits Candida albicans and Staphylococcus aureus Biofilm Formation In Vivo
'American Society for Microbiology', 2014Co-Authors: De Cremer Kaat, Gerits Evelien, De Brucker Katrijn, Verstraeten Natalie, Delattin Nicolas, Peeters Annelies, Kucharikova Sona, Michiels Jan, Van Dijck Patrick, Bruno P A CammueAbstract:We here report on the in vitro activity of Toremifene to inhibit biofilm formation of different fungal and bacterial pathogens, including Candida albicans, Candida glabrata, Candida dubliniensis, Candida krusei, Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis. We validated the in vivo efficacy of orally administered Toremifene against C. albicans and S. aureus biofilm formation in a rat subcutaneous catheter model. Combined, our results demonstrate the potential of Toremifene as a broad-spectrum oral antibiofilm compound.status: publishe
Antti Yliurpo - One of the best experts on this subject based on the ideXlab platform.
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silica xerogel carrier material for controlled release of Toremifene citrate
International Journal of Pharmaceutics, 2000Co-Authors: Manja Ahola, Pirjo Kortesuo, Ilkka Kangasniemi, Juha Kiesvaara, Antti YliurpoAbstract:Sol-gel processed silica xerogel was used as a carrier material for Toremifene citrate in order to develop an implantable controlled release formulation which could be localised to a desired site providing targeted and long-lasting disease control and resulting in a reduced amount of drug needed. Toremifene citrate, an anti-estrogenic compound, was incorporated into silica xerogel matrixes during polycondensation of organic silicate, tetraethyl ortho silicate (TEOS). The effects of drug amount, drying temperature and polyethylene glycol (PEG) on the release rate of Toremifene citrate and degradation of the silica xerogel matrixes were investigated. Addition of PEG (Mw 4600/10 000) decreased the specific surface area of the matrix and lowered the release rate of the drug. Reducing the amount of drug in the matrix also decreased the release rate of Toremifene citrate. However, drying temperature did not affect the release rate of silica or Toremifene citrate. The release profiles of Toremifene citrate were according to zero order kinetics, suggesting that drug release was controlled by erosion of the silica xerogel matrix. These results suggest that the Toremifene citrate release rate can be controlled to some extent by adding (PEG) or by varying the amount of drug in the silica xerogel matrix.
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silica xerogel as an implantable carrier for controlled drug delivery evaluation of drug distribution and tissue effects after implantation
Biomaterials, 2000Co-Authors: Pirjo Kortesuo, Manja Ahola, Ilkka Kangasniemi, Antti Yliurpo, Stefan Karlsson, Juha KiesvaaraAbstract:The purpose of the present study was to examine controlled delivery of Toremifene citrate from subcutaneously implanted silica xerogel carrier and to evaluate silica xerogel related tissue effects after implantation. Toremifene citrate was incorporated into hydrolyzed silica sol in a room temperature process. Toremifene citrate treated silica xerogel implants were tested both in vitro and in vivo using healthy mice. Silica xerogel with tritium-labelled Toremifene was implanted subcutaneously in mice for 42 d. To determine the amount of tritiated Toremifene remaining in the silica discs at the implantation site, the discs were excised periodically and radioactivity measured. The amount of tritiated Toremifene in the implant after 42 d was still about 16% and the amount of silica xerogel about 25%. In a histopathological study silica xerogel did not show any tissue irritation at the site of the implantation. A fibrotic capsule was formed around the implant. No silica xerogel related histological changes in liver, kidney, lymph nodes and uterus were observed during the implantation period. The silica xerogel discs showed a sustained release of Toremifene citrate over 42 d. Histologically, Toremifene-related changes in the uterus were also detectable at all studied time points. These findings suggest that silica xerogel is a promising carrier material for implantable controlled drug delivery system.
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in vitro evaluation of biodegradable e caprolactone co d l lactide silica xerogel composites containing Toremifene citrate
International Journal of Pharmaceutics, 1999Co-Authors: Manja Ahola, Pirjo Kortesuo, Juha Kiesvaara, Jaana Rich, Jukka Seppala, Antti YliurpoAbstract:Abstract Poly(e-caprolactone-co- d,l -lactide) polymers were blended with Toremifene citrate or with Toremifene citrate impregnated silica xerogel in order to develop a controlled release formulation. The copolymers were synthesized by bulk polymerization and characterized by nuclear magnetic resonance, size exclusion chromatography and differential scanning calorimetry analyses. The in vitro release of Toremifene citrate, an antiestrogenic compound, and silica was carried out in simulated body fluid (pH 7.4) containing 0.5 wt% sodium dodecylsulphate at 34°C. The in vitro release studies indicate that the release flux of Toremifene citrate increases with increasing weight fraction of caprolactone in the copolymer. Silica xerogel had a minor enhancing effect on the release rate of Toremifene citrate. Copolymers containing larger amounts of d,l -lactide (PLA–CL20 and PLA–CL40 copolymers) were not suitable matrices for the delivery of Toremifene citrate in a controlled manner because of the burst effect. The fraction of Toremifene citrate released from PLA–CL80 matrix increased with the increasing loading of Toremifene citrate. The results of the study indicate that the in vitro release of Toremifene citrate can be adjusted by varying the polymer composition and also the initial drug loading.
Juha Kiesvaara - One of the best experts on this subject based on the ideXlab platform.
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silica xerogel carrier material for controlled release of Toremifene citrate
International Journal of Pharmaceutics, 2000Co-Authors: Manja Ahola, Pirjo Kortesuo, Ilkka Kangasniemi, Juha Kiesvaara, Antti YliurpoAbstract:Sol-gel processed silica xerogel was used as a carrier material for Toremifene citrate in order to develop an implantable controlled release formulation which could be localised to a desired site providing targeted and long-lasting disease control and resulting in a reduced amount of drug needed. Toremifene citrate, an anti-estrogenic compound, was incorporated into silica xerogel matrixes during polycondensation of organic silicate, tetraethyl ortho silicate (TEOS). The effects of drug amount, drying temperature and polyethylene glycol (PEG) on the release rate of Toremifene citrate and degradation of the silica xerogel matrixes were investigated. Addition of PEG (Mw 4600/10 000) decreased the specific surface area of the matrix and lowered the release rate of the drug. Reducing the amount of drug in the matrix also decreased the release rate of Toremifene citrate. However, drying temperature did not affect the release rate of silica or Toremifene citrate. The release profiles of Toremifene citrate were according to zero order kinetics, suggesting that drug release was controlled by erosion of the silica xerogel matrix. These results suggest that the Toremifene citrate release rate can be controlled to some extent by adding (PEG) or by varying the amount of drug in the silica xerogel matrix.
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silica xerogel as an implantable carrier for controlled drug delivery evaluation of drug distribution and tissue effects after implantation
Biomaterials, 2000Co-Authors: Pirjo Kortesuo, Manja Ahola, Ilkka Kangasniemi, Antti Yliurpo, Stefan Karlsson, Juha KiesvaaraAbstract:The purpose of the present study was to examine controlled delivery of Toremifene citrate from subcutaneously implanted silica xerogel carrier and to evaluate silica xerogel related tissue effects after implantation. Toremifene citrate was incorporated into hydrolyzed silica sol in a room temperature process. Toremifene citrate treated silica xerogel implants were tested both in vitro and in vivo using healthy mice. Silica xerogel with tritium-labelled Toremifene was implanted subcutaneously in mice for 42 d. To determine the amount of tritiated Toremifene remaining in the silica discs at the implantation site, the discs were excised periodically and radioactivity measured. The amount of tritiated Toremifene in the implant after 42 d was still about 16% and the amount of silica xerogel about 25%. In a histopathological study silica xerogel did not show any tissue irritation at the site of the implantation. A fibrotic capsule was formed around the implant. No silica xerogel related histological changes in liver, kidney, lymph nodes and uterus were observed during the implantation period. The silica xerogel discs showed a sustained release of Toremifene citrate over 42 d. Histologically, Toremifene-related changes in the uterus were also detectable at all studied time points. These findings suggest that silica xerogel is a promising carrier material for implantable controlled drug delivery system.
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in vitro evaluation of biodegradable e caprolactone co d l lactide silica xerogel composites containing Toremifene citrate
International Journal of Pharmaceutics, 1999Co-Authors: Manja Ahola, Pirjo Kortesuo, Juha Kiesvaara, Jaana Rich, Jukka Seppala, Antti YliurpoAbstract:Abstract Poly(e-caprolactone-co- d,l -lactide) polymers were blended with Toremifene citrate or with Toremifene citrate impregnated silica xerogel in order to develop a controlled release formulation. The copolymers were synthesized by bulk polymerization and characterized by nuclear magnetic resonance, size exclusion chromatography and differential scanning calorimetry analyses. The in vitro release of Toremifene citrate, an antiestrogenic compound, and silica was carried out in simulated body fluid (pH 7.4) containing 0.5 wt% sodium dodecylsulphate at 34°C. The in vitro release studies indicate that the release flux of Toremifene citrate increases with increasing weight fraction of caprolactone in the copolymer. Silica xerogel had a minor enhancing effect on the release rate of Toremifene citrate. Copolymers containing larger amounts of d,l -lactide (PLA–CL20 and PLA–CL40 copolymers) were not suitable matrices for the delivery of Toremifene citrate in a controlled manner because of the burst effect. The fraction of Toremifene citrate released from PLA–CL80 matrix increased with the increasing loading of Toremifene citrate. The results of the study indicate that the in vitro release of Toremifene citrate can be adjusted by varying the polymer composition and also the initial drug loading.
Lauri Kangas - One of the best experts on this subject based on the ideXlab platform.
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The effect of Toremifene on bone and uterine histology and on bone resorption in ovariectomised rats.
Pharmacology & toxicology, 1999Co-Authors: Stefan Karlsson, Eero Mäntylä, Y. Hirsimäki, Seija Niemi, Lauri Nieminen, Kirsti Nieminen, Lauri KangasAbstract:The effect of the selective oestrogen receptor modulator, Toremifene, to inhibit ovariectomy-induced bone loss was studied in rats. The oral doses were 0.3, 3.0 or 30 mg/kg/day for 2 months. 17beta-oestradiol (5 microg/kg/day, subcutaneously) was used as positive control. One group was also treated with a combination of 17beta-oestradiol (5 microg/kg) and Toremifene (3.0 mg/kg). Biochemical markers were urinary hydroxyproline and calcium (adjusted with urinary creatinine levels) and the serum level of pyridinoline cross-linked carboxy terminal telopeptide, a bone specific collagen breakdown product. The femoral and sternal trabecular bone thickness served as histological parameters. Ovarectomy increased the levels of hydroxyproline and pyrodinoline and decreased the trabecular bone thickness compared to the sham-operated control group. This was inhibited by both test compounds but 17beta-oestradiol was more efficient. Toremifene did not reverse the ovariectomy-induced reduction of urinary calcium but inhibited the 17beta-oestradiol-related increase. When administered together with oestradiol, Toremifene did not reverse the positive effect of 17beta-oestradiol on bone, however Toremifene reversed the oestradiol-related uterothrophic effects. These findings indicate that the antagonistic features of Toremifene dominate in the rat uterus the agonistic properties do in the bone.
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Endocrine mechanism of action of Toremifene at the level of the central nervous system in advanced breast cancer patients
Cancer chemotherapy and pharmacology, 1998Co-Authors: Irene Számel, Lauri Kangas, I. Hindy, Barna Budai, A. Hajba, Risto LammintaustaAbstract:Purpose: To differentiate the antagonistic and agonistic effect of Toremifene at the level of the hypothalamus-hypophysis axis a leutinizing hormone-releasing hormone (LHRH) test was performed during a phase II clinical trial. Methods: In 15 postmenopausal patients with advanced breast cancer, follicle-stimulating hormone (FSH) and LH release – induced by an LHRH agonist (Suprefact injection, 0.5 mg s.c.) – was monitored during a 16-week period of Toremifene treatment (60 mg/day p.o.). Prolactin, estradiol, and sex hormone-binding globulin (SHBG) levels were also measured. The functional test was carried out prior to Toremifene therapy and then 4, 8, 12, and 16 weeks afterward. Results: The drug sensitized the pituitary to the action of the gonadotrophins; the LHRH-induced FSH and LH release showed a considerably increasing tendency during the Toremifene therapy. Estradiol levels decreased statistically significantly and SHBG levels showed a statistically significant increase. A decreased level of prolactin is the sign of an antiestrogenic effect of Toremifene on the hypophysis and, as a result, provides evidence for a direct influence of Toremifene upon the pituitary. An increase in LH and prolactin release in response to the LHRH test was characteristic in the responders. Conclusion: According to the LHRH test, the antagonistic effect of Toremifene seems to be more dominant than the concomitantly existing agonistic property. Neither clinical nor endocrinological side effects could be observed at the level of the CNS during a prolonged period of Toremifene administration.
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Antioxidant properties of the triphenylethylene antiestrogen drug Toremifene.
Naunyn-Schmiedeberg's Archives of Pharmacology, 1997Co-Authors: Markku Ahotupa, Eero Mäntylä, Lauri KangasAbstract:The aim of the present study was to investigate antioxidativity of the triphenylethylene antiestrogen Toremifene. Toremifene and its structural analogues were studied for their ability to inhibit chain reactions of lipid peroxidation and to act as scavengers of free radicals in vitro, and the effects of Toremifene were compared to those of the estrogens, tamoxifen and known antioxidants. Moreover, the in vivo antioxidativity of Toremifene was tested in a long-term experiment with rats. The ability of Toremifene to prevent lipid peroxidation was assayed in two different test systems. In the first assay (initiated with ascorbate/ADP-FeCl3, detection by the formation of TBA-reactive material) Toremifene was found to act as an efficient membrane antioxidant with an IC50-value (18 μM) comparable to that of tamoxifen (26 μM) and α-tocopherol (43 μM). Toremifene derivatives 4-hydroxyToremifene (IC50 = 8 μM) and Fc 1159 (IC50 = 31 μM), as well as diethylstilbestrol (IC50 = 17 μM) were also active while estradiol showed only weak antioxidativity (IC50 = 300 μM) in this test system. In the other assay (peroxidation initiated with t-butylhydroperoxide, detection by luminol-enhanced chemiluminescence) Toremifene prevented lipid peroxidation only at high concentrations (IC50 = 450 μM) but the metabolite 4-hydroxyToremifene (IC50 = 0.18 μM), estradiol (IC50 = 4.6 μM) and diethylstilbestrol (IC50 = 1.7 μM) showed potent antioxidant activity. The potency of 4-hydroxyToremifene even exeeded that of α-tocopherol (IC50 = 2.0 μM) and butylated hydroxyanisole (IC50 = 1.1 μM). Toremifene was found to have some superoxide anion but no peroxyl radical scavenging activity. Interestingly, diethylstilbestrol turned out to be a potent scavenger of peroxyl radicals. Treatment of female Sprague-Dawley rats with Toremifene (12 or 48 mg/kg) was found to decrease serum levels of lipid peroxides. This was seen at various time points (2 days, 5 weeks, 6 and 12 months) during long-term administration of Toremifene to rats, and results obtained with two different methods (diene conjugation, TBA-reactive material) gave similar results. The present study thus showed that (i) like steroidal estrogens and tamoxifen Toremifene is a potent membrane antioxidant in vitro, (ii) the antioxidant action of Toremifene is not due to scavenging of free radicals and, importantly, (iii) Toremifene acts antioxidatively also in living organisms in vivo.
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Drug Evaluation: Oncologic, Endocrine & Metabolic: Toremifene
Expert Opinion on Investigational Drugs, 1996Co-Authors: Rudolph O. Neri, Juha Ellmen, Virginia Carden, Ragab Mohamed H, Gene Resnick, Lauri KangasAbstract:Toremifene is a triphenylethylene antioestrogenic derivative, chemically and pharmacologically related to tamoxifen. In animals, Toremifene blocks the uterotrophic effect of oestradiol and, in intact animals, uterine weights are reduced, demonstrating the antioestrogenic activity of the compound. Such antioestrogenic effects are believed to underlie the antitumour actions of Toremifene in breast cancer, i.e., it competes with oestrogen for binding sites in the cancer, thus preventing the growth-stimulating effects of oestrogen. The drug is well absorbed following oral administration and the mean elimination half-life is 5 days. Toremifene is extensively metabolised and the main metabolite in human serum is N-demethylToremifene. This metabolite has a longer half-life (10 days) than Toremifene and its steady state serum concentration is about 2 times higher than that of the parent compound.Unlike tamoxifen, Toremifene is not a genotoxic carcinogen in rodent studies and, similarly, is not associated with end...
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involvement of cytochrome p450 3a enzyme family in the major metabolic pathways of Toremifene in human liver microsomes
Biochemical Pharmacology, 1994Co-Authors: Francois Berthou, Lauri Kangas, Yvonne Dreano, C Belloc, Jeancharles Gautier, Philippe BeauneAbstract:The anti-estrogen toremifen-Fc-1157a or 4-chloro-1,2-diphenyl-1-[4-[2(N,N-dimethylamino)ethoxy]-phenyl]-1- butene is now used for the treatment of breast cancer. This drug is extensively metabolized by cytochrome P450 dependent hepatic mixed function oxidase in man, yielding mainly the N-demethyl-(DMTOR), 4-hydroxy-(4OH-TOR) and deamino-hydroxy-(TOR III) Toremifene metabolites. The specific forms of cytochrome P450 involved in these oxidation reactions were examined in 32 human liver microsomal preparations previously characterized with respect to their contents of several known P450 enzymes. Toremifene was demethylated with an apparent Km of 124 microM while it was hydroxylated with an apparent Km of 139 microM. The metabolic rates were 71 +/- 56, 13 +/- 9 and 15 +/- 4 pmol/min/mg microsomal protein, respectively, for DMTOR, 4-OH-TOR and TOR III. The N-demethylation activity was strongly correlated with estradiol 2-hydroxylation (r = 0.75), nifedipine oxidation (r = 0.86), tamoxifen N-demethylation (r = 0.73), testosterone 6 beta-hydroxylation (r = 0.78) and erythromycin N-demethylation (r = 0.84), all these monooxygenase activities known to be supported by CYP3A4 isoform. Furthermore, the CYP3A content of liver microsomal samples, measured by western blot analysis using a monoclonal anti-human CYP3A4 antibody, was strongly correlated with DMTOR formation (r = 0.80). Compounds such as cyclosporin, triacetyl-oleandomycin and testosterone inhibited the N-demethylation of Toremifene metabolism at 80, 89 and 56% vs control, respectively, while the formation of TOR III was inhibited at 78, 82 and 73% vs control and the 4-hydroxylation pathway was inhibited no more than about 50% vs control. Prior incubation of microsomes with 100 microM gestodene, known to be a selective mechanism-based inhibitor of CYP3A4 in the presence of NADPH, led to 76 +/- 6 and 76 +/- 5% (N = 5 samples) reductions in the N-demethylation and formation of TOR III, respectively. Polyclonal antibody directed against human CYP3A enzymes inhibited formation of DMTOR and TOR III by 60 and 46%, respectively. The metabolism of Toremifene was not activated by alpha-naphthoflavone. Finally, the use of yeasts genetically engineered for expression of human P4501A1, 1A2, 2C9 and 3A4 allowed us to demonstrate that DMTOR and TOR III formations are mediated by P4501A and 3A4 enzymes and by contrast these enzymes are not involved in the 4-hydroxylation pathway.(ABSTRACT TRUNCATED AT 400 WORDS)
Manja Ahola - One of the best experts on this subject based on the ideXlab platform.
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silica xerogel carrier material for controlled release of Toremifene citrate
International Journal of Pharmaceutics, 2000Co-Authors: Manja Ahola, Pirjo Kortesuo, Ilkka Kangasniemi, Juha Kiesvaara, Antti YliurpoAbstract:Sol-gel processed silica xerogel was used as a carrier material for Toremifene citrate in order to develop an implantable controlled release formulation which could be localised to a desired site providing targeted and long-lasting disease control and resulting in a reduced amount of drug needed. Toremifene citrate, an anti-estrogenic compound, was incorporated into silica xerogel matrixes during polycondensation of organic silicate, tetraethyl ortho silicate (TEOS). The effects of drug amount, drying temperature and polyethylene glycol (PEG) on the release rate of Toremifene citrate and degradation of the silica xerogel matrixes were investigated. Addition of PEG (Mw 4600/10 000) decreased the specific surface area of the matrix and lowered the release rate of the drug. Reducing the amount of drug in the matrix also decreased the release rate of Toremifene citrate. However, drying temperature did not affect the release rate of silica or Toremifene citrate. The release profiles of Toremifene citrate were according to zero order kinetics, suggesting that drug release was controlled by erosion of the silica xerogel matrix. These results suggest that the Toremifene citrate release rate can be controlled to some extent by adding (PEG) or by varying the amount of drug in the silica xerogel matrix.
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silica xerogel as an implantable carrier for controlled drug delivery evaluation of drug distribution and tissue effects after implantation
Biomaterials, 2000Co-Authors: Pirjo Kortesuo, Manja Ahola, Ilkka Kangasniemi, Antti Yliurpo, Stefan Karlsson, Juha KiesvaaraAbstract:The purpose of the present study was to examine controlled delivery of Toremifene citrate from subcutaneously implanted silica xerogel carrier and to evaluate silica xerogel related tissue effects after implantation. Toremifene citrate was incorporated into hydrolyzed silica sol in a room temperature process. Toremifene citrate treated silica xerogel implants were tested both in vitro and in vivo using healthy mice. Silica xerogel with tritium-labelled Toremifene was implanted subcutaneously in mice for 42 d. To determine the amount of tritiated Toremifene remaining in the silica discs at the implantation site, the discs were excised periodically and radioactivity measured. The amount of tritiated Toremifene in the implant after 42 d was still about 16% and the amount of silica xerogel about 25%. In a histopathological study silica xerogel did not show any tissue irritation at the site of the implantation. A fibrotic capsule was formed around the implant. No silica xerogel related histological changes in liver, kidney, lymph nodes and uterus were observed during the implantation period. The silica xerogel discs showed a sustained release of Toremifene citrate over 42 d. Histologically, Toremifene-related changes in the uterus were also detectable at all studied time points. These findings suggest that silica xerogel is a promising carrier material for implantable controlled drug delivery system.
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in vitro evaluation of biodegradable e caprolactone co d l lactide silica xerogel composites containing Toremifene citrate
International Journal of Pharmaceutics, 1999Co-Authors: Manja Ahola, Pirjo Kortesuo, Juha Kiesvaara, Jaana Rich, Jukka Seppala, Antti YliurpoAbstract:Abstract Poly(e-caprolactone-co- d,l -lactide) polymers were blended with Toremifene citrate or with Toremifene citrate impregnated silica xerogel in order to develop a controlled release formulation. The copolymers were synthesized by bulk polymerization and characterized by nuclear magnetic resonance, size exclusion chromatography and differential scanning calorimetry analyses. The in vitro release of Toremifene citrate, an antiestrogenic compound, and silica was carried out in simulated body fluid (pH 7.4) containing 0.5 wt% sodium dodecylsulphate at 34°C. The in vitro release studies indicate that the release flux of Toremifene citrate increases with increasing weight fraction of caprolactone in the copolymer. Silica xerogel had a minor enhancing effect on the release rate of Toremifene citrate. Copolymers containing larger amounts of d,l -lactide (PLA–CL20 and PLA–CL40 copolymers) were not suitable matrices for the delivery of Toremifene citrate in a controlled manner because of the burst effect. The fraction of Toremifene citrate released from PLA–CL80 matrix increased with the increasing loading of Toremifene citrate. The results of the study indicate that the in vitro release of Toremifene citrate can be adjusted by varying the polymer composition and also the initial drug loading.
