Structure-activity relationships in the antiinflammatory steroids: a pattern-recognition approach

Bodor, N.; Harget, Alan J.; Phillips, Edward W.

doi:10.1021/jm00357a003

Cited by 34 publications

(17 citation statements)

References 7 publications

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“…Orabase with triamcinolone acetonide (TRCA) is an adhesive paste (KENALOG ® ) widely used as a vehicle in topical glucocorticoids therapy, but orabase losses of 85-90% of the total dose applied have been reported, 14) and another vehicle of spray-type therapeutic agent with BDP (Salcoat ® ) is for extensive stomatitis. We selected BDP as main medicament, because inflammatory effect of BDP was reported five time as strong as that of TRCA, 15) and prepared film formulation for more topical application than orabase or spray.…”

Section: Discussionmentioning

confidence: 99%

Oral Candidiasis Deteriorated by Local Application of a Glucocorticoid-Containing Film in a Mouse Model

Yanagi

Hisajima

Ishibashi

et al. 2008

Biological & Pharmaceutical Bulletin

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The anti-inflammatory agent glucocorticoid is one of the most effective and widely-used drugs for various kinds of inflammatory diseases. However, it has serious side effects, including suppression of host defense mechanisms against microbial infections. Therefore, more efficient delivery methods of glucocorticoids are required for various types of inflammatory diseases. For clinical use films containing glucocorticoids have been developed for oral inflammatory diseases, including mucosal lesions in the oral cavity. Very recently we succeeded in preparing mucoadhesive hydroxypropyl cellulose (HPC)-film containing more than 100 mg/cm 2 of beclomethasone dipropionate (BDP). Before conducting clinical research on this film, the effects of application of this film on oral infection were examined in an animal model, since it is well known that glucocorticoids predispose to oral or pharyngeal Candida infection. [1][2][3][4][5][6] In our previous papers, a murine oral candidiasis model 6) or an esopharynxial model 7) were used, allowing the examination of the effects of topical application of mucoadhesive films.In the present study, we examined the effects of BDP-and neutrophil-Candida interactions in vitro, as well as the level to which oral application of BDP-containing HPC-film predisposes towards oral candidiasis in this murine model. MATERIALS AND METHODS Film PreparationThe film was composed of one layer of HPC (150-400 cP; Wako Pure Chemical Industries, Ltd., Osaka, Japan) as the base component. To prepare BDP-containing film, BDP (Wako) was first dissolved in ethanol, HPC added, and then ethanol added to give a final volume of 30 ml per 0.9 g HPC. A 10-ml aliquot of this solution was cast using a graduated pipette at a rate of 10 ml/4 min into a flat round Teflon dish of diameter 75 mm and then dried on a clean bench overnight. These dried films were then cut into circles of diameter 30 mm for the release study or into rectangles of 0.6 cmϫ0.5 cm for the oral candidiasis study in mice.Release of BDP from the Film Measurement of BDPrelease from the BDP-containing films was performed as follows. A dissolution apparatus was modified from the original construction of Okamoto et al.8) Briefly, a 10-ml beaker was used as the receptor compartment and a piece of sample film (3-cm diameter) attached to the inner wall of the beaker using double-sided tape, to produce the donor side. An 0.1 M phosphate buffer (PB) (pH 7.0) was then added to the beaker, which was maintained at 37°C and stirred at a constant speed using a magnetic bead. Aliquots (100 ml each) were withdrawn at preset times (1, 2, 3, 4, 5, and 30 min), and then the amount of BDP released estimated using an HPLC system (Shimadzu Co., Ltd., Kyoto, Japan) equipped with a UV detector (wavelengthϭ254 nm). To maintain a constant volume and sink conditions in the experiment, the removed solution was replaced each time with 100 ml of 0.1 M PB prewarmed to 37°C. The cumulative amount of drug release per 1 cm 2 of BDP film was then calculated. Each experiment was perf...

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Section: Discussionmentioning

confidence: 99%

Oral Candidiasis Deteriorated by Local Application of a Glucocorticoid-Containing Film in a Mouse Model

Yanagi

Hisajima

Ishibashi

et al. 2008

Biological & Pharmaceutical Bulletin

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“…Relative to its parent molecule, the fluorinations enhance the corticosteroid potency of difluprednate, the butyric acid augments anti-inflammatory activity, and the acetic acid increases penetration. 15 Difluprednate 0.05% has been shown to be effective at reducing inflammation and pain in patients undergoing ocular surgery. 16,17 This study aimed to test the hypothesis that difluprednate 0.05% dosed four times daily is noninferior to prednisolone acetate 1% dosed eight times daily in patients with endogenous AU.…”

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confidence: 99%

Difluprednate 0.05% Versus Prednisolone Acetate 1% for Endogenous Anterior Uveitis: A Phase III, Multicenter, Randomized Study

Sheppard

Toyos

Kempen

et al. 2014

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Endogenous anterior uveitis (AU), when untreated, may lead to vision loss. This study compared the safety and efficacy of difluprednate versus prednisolone acetate for the treatment of this condition.METHODS. This phase III, double-masked, noninferiority study randomized patients with mild to moderate endogenous AU to receive difluprednate 0.05% (n ¼ 56) four times daily, alternating with vehicle four times daily, or prednisolone acetate 1% (n ¼ 54) eight times daily. The 14-day treatment period was followed by a 14-day dose-tapering period and a 14-day observation period. The primary efficacy end point was change in anterior chamber cell grade (range, 0 for 1 cell to 4 for >50 cells) from baseline to day 14.RESULTS. At day 14, the mean change in anterior chamber cell grade with difluprednate was noninferior to that with prednisolone acetate (À2.2 vs. À2.0, P ¼ 0.16). The proportions of difluprednate-treated patients versus prednisolone acetate-treated patients demonstrating complete clearing of anterior chamber cells at day 3 were 13.0% vs. 2.1% (P ¼ 0.046) and at day 21 were 73.9% vs. 63.8% (P ¼ 0.013). A significant between-group difference in the mean IOP increase was seen at day 3 (2.5 mm Hg for difluprednate-treated patients and 0.1 mm Hg for prednisolone acetate-treated patients, P ¼ 0.0013) but not at other time points. The mean IOP values in both groups remained less than 21 mm Hg throughout the study.CONCLUSIONS. Difluprednate 0.05% four times daily is well tolerated and is noninferior to prednisolone acetate 1% eight times daily for the treatment of endogenous AU. (ClinicalTrials.gov number, NCT01201798.)

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“…At suitable time intervals (0, 0.5, 1, 2, 3,5,8,12, and 24 h), 20 µl of the solution were withdrawn, filtered, and analyzed by HPLC. The rates of disappearance of the dihydroisoquinoline derivative and the appearance of the corresponding quaternaries were determined.…”

Section: Chemical Oxidation and In Vitro Studiesmentioning

confidence: 99%

“…Bodor et al developed a novel redox chemical delivery system (dihydropyridine ↔ pyridinum salt) which delivers drugs specifically to the brain [8].This system was applied successfully for the delivery of many essential drugs to the brain [9]. However, two major problems hindered their pharmaceutical application, short shelf life stability due to hydration of the 5,6-double bond and oxidation and isomerization during reduction of the quaternary salt [10].…”

Section: Introductionmentioning

confidence: 99%

1, 2-Dihydroisoquinoline-N-acetic Acid Derivatives as New Carriers for Brain-specific Delivery II: Delivery of Phenethylamine as Model Drug

Mahmoud¹,

Sheha²,

Aboul‐Fadl³

et al. 2003

Arch. Pharm. Pharm. Med. Chem.

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N-alkyloxycarbonylmethyl-1, 2-dihydroisoquinolin-4-carboxylic acid derivatives 7a-c synthesized as new carriers for brain specific delivery. The design of the carrier systems are based on sequential hydrolysis at the acetic acid ester group linked to dihydroisoquinoline nitrogen followed by ring oxidation and formation of quaternary isoquinolinium derivatives which are then hydrolyzed to release the drug. Once the carrier system is administered, a sequential enzymatic process will take place resulting in significant increase in its rate of oxidation, the key factor in brain specific delivery. The chemical stability of the synthesized carrier system was investigated in aqueous buffer solutions and ferricyanide reagent and proofed to be quite stable against hydration and oxidation during formulation and storage. Furthermore, enzymatic stability was also investigated in 80 % human plasma and 20 % rabbit brain homogenate. Both oxidation and hydrolysis were found to take place; however, hydrolysis was the major route. In vivo distribution of the ethyl ester derivative 7b studied in rats and showed that the concentration of the quaternary product is increasing in the brain and cleared from blood with time.

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Structure-activity relationships in the antiinflammatory steroids: a pattern-recognition approach

Cited by 34 publications

References 7 publications

Oral Candidiasis Deteriorated by Local Application of a Glucocorticoid-Containing Film in a Mouse Model

Oral Candidiasis Deteriorated by Local Application of a Glucocorticoid-Containing Film in a Mouse Model

Difluprednate 0.05% Versus Prednisolone Acetate 1% for Endogenous Anterior Uveitis: A Phase III, Multicenter, Randomized Study

1, 2-Dihydroisoquinoline-N-acetic Acid Derivatives as New Carriers for Brain-specific Delivery II: Delivery of Phenethylamine as Model Drug

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