Simple and Convenient Synthesis of 21‐Thioalkylether Derivatives of Methyl 16‐Prednisolone Carboxylates

The antedrug approach for corticosteroids has been described as a fundamentally sound approach for the development of safer anti‐inflammatory and anti‐asthmatic therapy. However, the derivatization of prednisolone and its congeners have been considered to be major pitfalls, because their syntheses are complicated by the presence of numerous carboxylate esters and hydroxyl functions in the steroid nucleus. A simple and direct synthesis of 21‐thioalkylether derivatives of methyl 16‐prednisolonecarboxylates is described. The 21‐mesylate of the methyl 16‐prednisolonecarboxylate and 9‐fluoro‐17‐dehydro methyl 16‐prednisolonecarboxylate were reacted with Na‐thioalkoxides to furnish the desired thioethers in good yields. A previously published method for the methanolysis of 16‐cyanoprednisolone to methylcarboxylate has been reexamined, and the conditions are explained clearly. The reaction conditions for all these reactions were critical.     

醋酸泼尼松龙的荧光分析法研究

肾上腺皮质激素类药物醋酸泼尼松龙被浓H2 SO4氧化 ,生成有荧光的反应产物 ,据此建立了一种测量醋酸泼尼松龙的荧光光度分析新方法 ,考察了醇、表面活性剂和 β 环糊精对产物荧光性质的影响 ,提出了醋酸泼尼松龙被氧化及荧光增强的作用机理 ,检出限为 4 .96× 10 -7mol·L-1,荧光强度与醋酸泼尼松龙在 0～ 1.2 4× 10 -5mol·L-1浓度范围内呈良好线性关系     

Stepwise optimization and sensitivity improvement of green micellar electrokinetic chromatography method to simultaneously determine some fluoroquinolones and glucocorticoids present in various binary ophthalmic formulations

A sensitive micellar electrokinetic chromatography method is presented to simultaneously quantify ofloxacin, gatifloxacin, dexamethasone sodium phosphate and prednisolone acetate. The method has the advantages of being rapid, accurate, reproducible, ecologically acceptable and sensitive. The electrophoretic separation utilized 20 mm borate buffer as background electrolyte with pH 10.0 ± 0.1 and 50 mm sodium dodecyl sulfate as a micelle forming molecule. A capillary tube (50 μm i.d., 33 cm) of fused silica was used and on-column diode array detection at 243 nm for dexamethasone sodium phosphate and prednisolone acetate, and 290 nm for ofloxacin and gatifloxacin. Various factors were optimized such as the background electrolyte (type, concentration and pH), addition of sodium dodecyl sulfate and its concentration, detection wavelength, applied voltage and injection parameters. The studied drugs were efficiently separated in 6.2 min, at 20 kV with high resolution. The greenness of the method was estimated using an eco-scale tool and the presented method was found to have excellent green characteristics. The method was validated in conformance with International Conference on Harmonization guidelines, with acceptable accuracy, precision and selectivity. The suggested method can be employed for the economic analysis of the four drugs in dissimilar binary combinations of eye drops saving solvents and chemicals.     

Tetrahydrophthalic esters of prednisolone

The two biologically active isomers of prednisolone tetrahydrophthalate have been studied by X-ray diffraction methods. The compounds crystallize in the orthorhombic system in the space groupP2₁2₁2₁, with similar lattice parameters. The isomers differ both in configuration [(1′S),(6′R) isomerA and (1′R),(6′S) isomerB] and conformation of the thetetrahydrophthalic part of the molecules. Cell parameters of isomerA:a=9.595(2),b=14.465(2),c=18.988(3) Å andB:a=9.114(2),b=14.283(6),c=20.398(5) Å. The O(3) carbonyl oxygen atom interactsvia hydrogen bonds with three neighboring molecules accepting hydrogen bonds from two hydroxyl groups and one carboxylic group. Additional short intermolecular C?H…O type contacts occur in the structure of theB isomer, which has a somewhat larger unit cell and significantly higher melting point.     

Determination of unbound prednisolone, prednisone and cortisol in human serum and saliva by on-line solid-phase extraction liquid chromatography tandem mass spectrometry and potential implications for drug monitoring of prednisolone and prednisone in saliva

Prednisolone (PLN) and prednisone (PN) are widely used glucocorticoids. Drug monitoring of PLN and PN is not routinely done owing to the need for multiple blood sampling and challenging measurement of unbound PLN and PN in blood. Here we present a robust method for quantification of cortisol, PLN and PN in serum, ultrafiltrate and saliva by on‐line solid‐phase extraction LC‐MS/MS. The method is linear for the three analytes over the range of 6–1400 nmol/L for serum and 2–450 nmol/L for ultrafiltrate and saliva. Within‐run precision of all three analytes was <10% and total precision was <15%. This method was applied to create time–concentration profiles of cortisol, PLN and PN after an oral dose of prednisolone in a healthy volunteer. Salivary levels of PLN correlated well with ultrafiltrate levels (p < 0.01), while this correlation was only marginal for PN (p = 0.052). The PN/PLN ratio was significantly higher in saliva than in ultrafiltrate and serum (p < 0.01). Addition sums of both metabolites in saliva showed excellent correlation with those of ultrafiltrate (p < 0.01). These findings have not been presented before and may have important implications for future studies concerning drug monitoring of PLN and PN in saliva. Copyright © 2011 John Wiley & Sons, Ltd.     

γ-环糊精和波尼松龙的相互作用分子动力学模拟和自由能计算

运用分子动力学（Molecular dynamics,MD）和MM—PBSA（molecular mechanics／Poisson Boltzmann surfaeearea）相结合的方法预测了γ-环糊精（γ-cyclodextrin,γ-CD）和波尼松龙的包结模式．在MD模拟过程中,波尼松龙分别采用A环和D环两种取向从γ-CD大口端进入其空腔．在MD轨迹采样基础上,采用高效MM—PBSA方法计算了两种取向的包结自由能．结果表明,计算包结自由能值和实验包结自由能值非常吻合．进一步分析各个能量项,发现范德华相互作用能为包结的主要驱动力．通过比较两种取向的包结自由能大小,预测D环取向为优势包结模式．     

Acoustic Measures of Phonatory Improvement Secondary to Treatment by Oral Corticosteroids in a Professional Singer: A Case Report

Short-term administration of corticosteriods is sometimes indicated for professional voice users experiencing laryngeal edema and/or inflammation. Unfortunately, no data are available to document the effectiveness of these medications to improve phonatory parameters. We present a case report of a 32-year-old male professional singer with vocal fold edema experiencing imminent vocal demands who was prescribed a 6-day course (dose-pack) of oral methyl prednisolone. Endoscopic and stroboscopic evaluations were completed premedication and postmedication, and acoustic measures of phonatory function were obtained premedication, 3 days during the dose cycle, 5 days during the dose cycle, and 1 day postmedication. Postmedication results revealed an increase in fundamental frequency (F0) and large decreases in jitter, shimmer, long-term frequency, and amplitude variability. These corresponded with patient and evaluator perceptual measures of improved voice, and with endoscopic observations of reduced edema. The benefits and risks of corticosteroid therapy are discussed, specific to their use in the professional voice population.     

GC-MS Derivatization Studies: The Formation of Dexamethasone MO-TMS

Abstract

The 16α-methyl group in dexamethasone increases drastically the steric hindrance to reaction of both the 20-ketone and 17α-hydroxyl groups, as shown by kinetic studies with GC-MS techniques. A procedure is described for the preparation of the MO derivative (reaction et 60[ddot]C for 3 hr) and complete conversion of all hydroxyl groups to TMS ether groups (reaction at 100[ddot]C for 6 hr). The resulting MO-TMS derivative is thermostable and suitable for use in GC-MS methods. The procedures usually employed in urinary steroid studies are satisfactory for prednisone and prednisolone.     

Ag（III）-鲁米诺化学发光体系对泼尼松龙的测定研究

建立了应用Ag(Ⅲ)配合物-鲁米诺化学发光体系检测泼尼松龙的方法。在碱性介质中,泼尼松龙可以改变Ag(Ⅲ)配合物-鲁米诺化学发光体系的光信号,一定范围内,其浓度与光信号的减弱程度呈线性关系。于最优条件下,该方法的线性范围是2．0×10-9~1．0×10-7 mol·L-1和2．0×10-7~1．0×10-6 mol·L-1,检出限为5．0×10-10mol·L-1。对2．0×10-8mol·L-1与6．0×10-7mol·L-1的泼尼松龙进行平行测定11次,其相对标准偏差分别为1．1%与1．5%。该方法用于醋酸泼尼松龙注射液的测定,回收率为98．0%~101%。本方法具有快速、简便、准确的特点,适用于泼尼松龙新剂型药代动力学的研究,也可应用于泼尼松龙其他剂型的检测。     

Photochemical Induced Fluorescence for the Determination of Prednisolone and Triamcinolone

Abstract

In the present work, a photochemical derivatization procedure to induce fluorescence from two synthetic glucocorticoids (triamcinolone acetonide and prednisolone) was developed. The procedure consisted of the exposure of analyte acidic solutions to ultraviolet (UV) radiation (254 and 300 nm) in a photochemical reactor at 65°C. Experimental parameters such as type and concentration of the acid, composition of the solvent system, and sample treatment time in the reactor were found to be critical, and, therefore, they were carefully optimized. The intensity of the fluorescence (240/350 nm) and the stability of the signal were, appropriated for analytical purposes. Limits of detection (LD) of 5 and 6 µg L^?1, respectively, for triamcinolone acetonide and prednisolone were achieved. Linear dynamic range for both analytes extended up to 20 mg L^?1. The spectrofluorimetric determination of prednisolone and triamcinolone acetonide was tested by the analysis of different anti‐inflammatory pharmaceutical formulations (tablets, ointment, and veterinary parenteral suspensions). The recoveries achieved were between 95% and 107%. A study to evaluate the effect of potential interferents (polimixine B and benzocaine) on the fluorescence signal of the analytes also has been done.