Comparative Chemical Profiling and Monacolins Quantification in Red Yeast Rice Dietary Supplements by 1H-NMR and UHPLC-DAD-MS.

Red yeast rice dietary supplements (RYR DS) are largely sold in Western countries for their cholesterol-lowering/regulating effect due to monacolins, mainly monacolin K (MK), which is, in fact, lovastatin, the first statin drug on the market. 1H-NMR was used as an easy, rapid and accurate method to establish the chemical profiles of 31 RYR DS and to quantify their monacolin contents. Among all the 1H resonances of the monacolins found in RYR, only those of the ethylenic protons of the hexahydronaphthalenic ring at 5.84 and 5.56 ppm are suitable for quantification because they show no overlap with the matrix signals. The total content in monacolins per capsule or tablet determined in 28 DS (the content in 3 DS being below the limit of quantification of the method, ≈ 0.25 mg per unit dose) was close to that measured by UHPLC, as shown by the good linear correlation between the two sets of values (slope 1.00, y-intercept 0.113, r2 0.986). Thirteen of the 31 RYR DS analyzed (i.e., 42%) did not provide label information on the concentration of monacolins and only nine of the 18 formulations with an indication (i.e., 50%) actually contained the declared amount of monacolins.

Evaluation of a benchtop cryogen-free low-field ¹H NMR spectrometer for the analysis of sexual enhancement and weight loss dietary supplements adulterated with pharmaceutical substances.

Nuclear magnetic resonance (NMR) spectroscopy is a unique tool for detection, structural characterization, and quantification of compounds in complex mixtures. However, due to cost constraints, NMR is rarely used in routine quality control (QC) analysis. The recent release of benchtop cryogen-free low-field NMR spectrometers represents a technological break in the NMR field. In this paper, we evaluated the potential of a benchtop cryogen-free 60 MHz spectrometer for uncovering adulteration of "100% natural" sexual enhancement and weight loss dietary supplements. We demonstrated that the adulterant(s) can readily be detected in ≈20 min of recording after a very simple and rapid sample preparation. We also showed that the quantification by the internal standard method can be done on the low-field NMR spectrometer and leads to results similar to those obtained with high-field NMR. Considering the cost and space efficiency of these spectrometers, we anticipate their introduction in QC laboratories as well as in governmental agencies, especially in the field of fraud detection.

Six-Item Modified Frailty Index independently predicts complications following total shoulder arthroplasty.

Background: In the realm of orthopedic surgery, frailty has been associated with higher rates of complications following total hip and total knee arthroplasties. Among various measures of frailty, the Six-Item Modified Frailty Index (MF-6) has recently gained popularity as a predictor for postoperative complications. The purpose of this study was to investigate MF-6 as a predictor for early postoperative complications in the elderly patient population following total shoulder arthroplasty (TSA). Methods: The authors queried the American College of Surgeons National Surgical Quality Improvement Program database for all patients who underwent TSA between 2015 and 2020. Patient demographics and comorbidities were compared between cohorts using bivariate logistic regression analysis. Multivariate logistic regression, adjusted for all significantly associated patient demographics and comorbidities, was used to identify associations between the MF-6 score and postoperative complications. Results: Of total, 9228 patients were included in this study: 8764 (95.0%) had MF-6 <3, and 464 (5.0%) patients had MF-6 ≥3. Multivariate analysis found MF-6 ≥3 to be independently associated with higher rates of urinary tract infection (odds ratio [OR]: 2.79, 95% confidence interval [CI]: 1.49-5.23; P = .001), blood transfusion (OR: 1.53, 95% CI: 1.01-2.32; P = .045), readmission (OR: 1.58, 95% CI: 1.06-2.35; P = .024), and non-home discharge (OR: 2.60, 95% CI: 2.08-3.25; P < .001). Conclusion: A high MF-6 score (≥3) in patients aged 65 and older is independently associated with higher rates of urinary tract infection, blood transfusion, readmission, and non-home discharge following TSA. The MF-6 score can be easily calculated preoperatively and may allow for better preoperative risk stratification.

The POWER saga from 2007 to 2022: An example of a sexual enhancement dietary supplement tainted by different adulterants and still on the market.

Ten POWER dietary supplements, chronologically called tabs, pills then caps, and advertised as 100% natural aphrodisiacs, were analyzed by 1H NMR from 2007 to 2022. They were all tainted by PDE-5 inhibitors. Eight different adulterants were identified (sildenafil (1), sildenafil analogues (6), and vardenafil analogue (1)). Their amounts ranged from 15 to 145 mg/capsule. Four supplements contained at least 100 mg/capsule of PDE-5 inhibitor or analogue, the maximal recommended dose of sildenafil. The nature of the adulterant has changed over time, probably to evade its detection by regulatory agencies routine screening tests. Despite several warnings and/or seizures from several European food and/or health authorities, the dietary supplement POWER is still on sale on the Internet, thus demonstrating the impossibility of controlling this market. Faced with this situation, the consumer should be better informed by establishing at the European level a public database of tainted dietary supplements on the model of that of the US Food and Drug Administration. It should indicate the product name, its photo, the adulterant name, and be easily accessible to everyone.

Quality evaluation of berberine food supplements with high-field and compact 1H NMR spectrometers.

Due to their health benefits, including regulating blood sugar and lowering cholesterol, berberine food supplements (FS) are widely used by consumers. This study aims to evaluate the quality of such products by proposing a new analytical methodology based on low-field NMR. Eighteen berberine FS were analyzed with both conventional (500 MHz) and benchtop (60 MHz) NMR spectrometers. Three quantitative 60 MHz 1H NMR methodologies were performed to determine berberine contents that were compared to those obtained at 500 MHz considered as reference measurements. To make the recording time of the spectra acquired at low field compatible with the requirements of a routine control, the quantification was carried out using a calibration curve established under conditions of incomplete relaxation of BrB protons. This methodology, applied to a test sample of 15 mg of FS, allowed to accurately measure a minimum quantity of berberine of ≈ 10 mg/capsule or tablet in 15 min. Regarding the FS, their labels are often unclear and/or incomplete for the consumer. Moreover, only 56 % of the FS analyzed actually contain the claimed quantity of berberine. The amounts of active they supply per day are extremely variable with only 39 % of the FS delivering a sufficient dose to achieve a hypoglycemic or hypolipidemic effect (1000-1500 mg/day based on literature data). These results show that health authorities should institute much stricter control and regulation over the production, labeling and marketing of berberine-based FS.

Quality assessment of Curcuma dietary supplements: Complementary data from LC-MS and 1H NMR.

Due to the numerous potential health benefits of Curcuma, turmeric dietary supplements (DS) are among the top selling products. To assess the quality of these formulations, thirty Curcuma DS along with five standard Curcuma rhizomes were analyzed with UHPLC-MS and 1H NMR. The chemometric treatment of the UHPLC-MS spectra showed a significant variability of their chemical composition that was confirmed by 1H NMR which allowed the absolute quantification of the Curcuma major bioactive components, i.e. curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin), and turmerones (aryl-, α- and ß-) as well as piperine, a commonly associated curcumin bioavailability enhancer: respectively 3.5-556, 0-8.6, 0.18-8.1 mg/capsule or tablet. The comparison of the actual and claimed quantities of curcuminoids and piperine showed that 58% of the DS contained the expected amounts of actives.

Novel lipophilic 7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid derivatives as potential antitumor agents: improved synthesis and in vitro evaluation.

A convenient route for the synthesis of some acyloxymethyl esters and carboxamides of levofloxacin (LV) with modulated lipophilicity is described. The synthesized compounds were evaluated in vitro for their growth inhibitory effect in five human cancer cell lines. The most efficient LV derivatives (ester 2e and amide 4d) displayed IC(50) values in the 0.2-2.2 µM range, while IC(50) values for parent LV ranged between 70 and 622 µM depending on the cell line. The esters displayed no in vivo toxicity up to 80 mg/kg when administered intraperitoneally. This study thus shows that LV analogs displayed antitumor efficacy, at least in vitro, a feature that appeared to be independent from the lipophilicity of the grafted substituent.

Isolation and identification of ten new sildenafil derivatives in an alleged herbal supplement for sexual enhancement.

A sexual enhancer dietary supplement in pre-commercialization phase was analyzed. It contained the two phosphodiesterase-5 inhibitors (PDE-5i) sildenafil and methisosildenafil as major adulterants. Fourteen more sildenafil derivatives were detected and after isolation, their structures were elucidated thanks to NMR, high resolution and tandem mass spectrometry, and UV spectroscopy. Ten of them were never described. All these compounds are probably by-products of different reaction steps during the synthesis of the two PDE-5i that were not properly eliminated during the purification procedure. The total amount of sildenafil-related compounds was estimated at 68 mg per capsule, sildenafil and methisosildenafil accounting for 20 mg and 38 mg respectively.

Combining two-dimensional diffusion-ordered nuclear magnetic resonance spectroscopy, imaging desorption electrospray ionization mass spectrometry, and direct analysis in real-time mass spectrometry for the integral investigation of counterfeit pharmaceuticals.

During the past decade, there has been a marked increase in the number of reported cases involving counterfeit medicines in developing and developed countries. Particularly, artesunate-based antimalarial drugs have been targeted, because of their high demand and cost. Counterfeit antimalarials can cause death and can contribute to the growing problem of drug resistance, particularly in southeast Asia. In this study, the complementarity of two-dimensional diffusion-ordered (1)H nuclear magnetic resonance spectroscopy (2D DOSY (1)H NMR) with direct analysis in real-time mass spectrometry (DART MS) and desorption electrospray ionization mass spectrometry (DESI MS) was assessed for pharmaceutical forensic purposes. Fourteen different artesunate tablets, representative of what can be purchased from informal sources in southeast Asia, were investigated with these techniques. The expected active pharmaceutical ingredient was detected in only five formulations via both nuclear magnetic resonance (NMR) and mass spectrometry (MS) methods. Common organic excipients such as sucrose, lactose, stearate, dextrin, and starch were also detected. The graphical representation of DOSY (1)H NMR results proved very useful for establishing similarities among groups of samples, enabling counterfeit drug "chemotyping". In addition to bulk- and surface-average analyses, spatially resolved information on the surface composition of counterfeit and genuine antimalarial formulations was obtained using DESI MS that was performed in the imaging mode, which enabled one to visualize the homogeneity of both genuine and counterfeit drug samples. Overall, this study suggests that 2D DOSY (1)H NMR, combined with ambient MS, comprises a powerful suite of instrumental analysis methodologies for the integral characterization of counterfeit antimalarials.

7-((4-Substituted)piperazin-1-yl) derivatives of ciprofloxacin: synthesis and in vitro biological evaluation as potential antitumor agents.

Ciprofloxacin (CP), an antibiotic has been shown to have antiproliferative and apoptotic activities in several cancer cell lines. Moreover, several reports have highlighted the interest of increasing the lipophilicity to improve the antitumor efficacy. These studies have led us to synthesize new CP derivatives of various lipophilicities and to evaluate their activity in five human cancer cell lines. With an easy and cost-efficient procedure, 31 7-((4-substituted)piperazin-1-yl) derivatives of CP were prepared that displayed IC(50) values ranging from microM to mM concentrations and are non-toxic in vivo in healthy mice as shown by their maximal tolerated dose (MTD) indices >80 mg/kg. Several derivatives displayed higher in vitro antitumor activity than parent CP however this was not dependent on the lipophilicity of the substituent. Among all synthesized derivatives, the most potent were 2 and 6h whose IC(50) values were 10 microM in three (derivative 2) or four (derivative 6h) cancer cell lines.

The usefulness of 2D DOSY and 3D DOSY-COSY 1H NMR for mixture analysis: application to genuine and fake formulations of sildenafil (Viagra).

Two-dimensional diffusion ordered spectroscopy (DOSY) (1)H NMR is proposed to analyze drugs that are complex mixtures in order to discriminate genuine from fake formulations. The method was applied to the analysis of 17 formulations of sildenafil, one being genuine Viagra and the others illegally manufactured formulations of this drug coming from India, Syria and China. It enabled (i) distinguishing imitations or counterfeit from the authentic formulation, (ii) detecting the presence of sildenafil or adulterants, (iii) gaining information on the formulation process by detection of various excipients, thus giving a precise and global 'signature' of the manufacturer. Even though some samples are slightly overdosed, the quality of products manufactured in India and Syria was better than that of Chinese formulations which were adulterated with vardenafil and homosildenafil. This study also presents a three-dimensional DOSY-COSY (1)H NMR experiment that provides both virtual separation and structural information.

Quality assessment of fluoxetine and fluvoxamine pharmaceutical formulations purchased in different countries or via the Internet by 19F and 2D DOSY 1H NMR.

A simple and selective (19)F NMR method has been validated for the quantitation of fluoxetine (FLX) and fluvoxamine (FLV) in methanol solutions and in human plasma and urine. The regression equations for FLX and FLV showed a good linearity in the range of 1.4-620 microg mL(-1) (3.3 x 10(-6)-1.8 x 10(-3) mol L(-1)) with a limit of detection of approximately 0.5 microg mL(-1) (1.3 x 10(-6) mol L(-1)) and a limit of quantification of approximately 2 microg mL(-1) (4.6 x 10(-6) mol L(-1)). The precision of the assay depends on the concentrations and is comprised between 1.5 and 9.5% for a range of concentrations between 1.2 x 10(-3) and 3.2 x 10(-6) mol L(-1). The accuracy evaluated through recovery studies ranged from approximately 96 to 103% in methanol solutions and in urine, and from approximately 93 to 104% in plasma, with standard deviations <7.5%. The low sensitivity of the method precludes its use for the assay of these antidepressants in biofluids at least at therapeutic doses as the ranges of FLX and FLV plasma levels are 0.15-0.5 microg mL(-1) and 0.15-0.25 microg mL(-1), respectively. The method was applied successfully to the determination of FLX and FLV contents in pharmaceutical samples (brand-named and generic) purchased in several countries or via the Internet. All the commercial formulations contain the active ingredient in the range 94-103% of stated concentration. A "signature" of the formulations (solid and liquid) was obtained with 2D Diffusion-Ordered SpectroscopY (DOSY) (1)H NMR which allowed the characterisation of the active ingredient and excipients present in the formulations studied. Finally, the DOSY separation of FLX and FLV whose molecular weights are very close was obtained by using beta-cyclodextrin as host-guest complexing agent.

Analysis of illegally manufactured formulations of tadalafil (Cialis) by 1H NMR, 2D DOSY 1H NMR and Raman spectroscopy.

Counterfeit and/or imitation medicines are becoming a major health problem not only in developing countries but also in wealthier countries. The need of new and easy analytical methods for quality control of drugs is essential. We describe the use of Raman spectroscopy, 1H nuclear magnetic resonance (NMR) and 2D diffusion-ordered spectroscopy (DOSY) NMR to analyse genuine Cialis and seven illegally manufactured formulations of this drug purchased via the internet. Seven out of the eight commercial formulations of tadalafil contain the active ingredient, measured by high performance liquid chromatography (HPLC), within 100+/-5% of stated concentration. Vardenafil and homosildenafil instead of tadalafil were found in the Chinese imitation. 2D DOSY NMR spectra clearly showed similarities and differences in the composition of the pharmaceutical formulations of tadalafil, thus giving a precise and global "signature" of the manufacturer. Our data show that the quality of the Cialis imitations manufactured in India and Syria is correct, whereas the Chinese formulation is adulterated with active pharmaceutical ingredients.

Generic ciprofloxacin tablets contain the stated amount of drug and different impurity profiles: A 19F, 1H and DOSY NMR analysis.

The objective of this study was to control the purity of 16 commercial formulations of ciprofloxacin tablets purchased in different countries or via the Internet using 19F and 1H nuclear magnetic resonance (NMR). Twelve out of the sixteen commercial formulations of ciprofloxacin measured by 19F NMR contain the active ingredient within 100+/-5% of stated concentration. Three formulations have a lower ciprofloxacin content between 90 and 95% and one shows a higher concentration superior to 105%. The impurity profile was characterised using 19F and 1H NMR, and is characteristic of the manufacturer. Four to twelve fluorinated impurities among them fluoride ion and two already known compounds were detected and quantified in the sixteen formulations analysed by 19F NMR. Two other non-fluorinated impurities were observed in the seven formulations analysed with 1H NMR. The total content of impurities as well as their individual levels are in agreement with those reported previously in the few studies devoted to ciprofloxacin purity. However, all the formulations do not comply with the limits for impurities given in the ciprofloxacin monograph of the European Pharmacopeia. Finally, a "signature" of the formulations was obtained with Diffusion-Ordered SpectroscopY (DOSY) 1H NMR which allowed the characterisation of some excipients present in the formulations studied.

A revisited structure for nitrosoprodenafil from NMR, mass spectrometry, X-ray and hydrolysis data.

The sildenafil analogue adulterant previously identified as a nitroso derivative (nitrosoprodenafil) in a dietary supplement (DS) marketed to increase sexual performance and sold in Europe in the early 2010s is the same as that found in the same type of DS available in Japan whose structure was established as a nitro derivative (mutaprodenafil or nitroprodenafil). Indeed, the compound isolated from the Man Power DS has identical UV, IR, NMR and MS spectroscopic characteristics and hydrolysis behavior than nitrosoprode-nafil. By revisiting its NMR assignments and MS and MS/MS data interpretation, it is demonstrated that the compound is actually a nitrothioimidazole-methisosildenafil hybrid, i.e. nitroprodenafil, whose structure is unequivocally confirmed by X-ray crystallography and synthesis experiments. Because the product is converted to methisosildenafil by hydrolysis, it is named nitropromethisosildenafil.

Fluorine nuclear magnetic resonance spectroscopy of human biofluids in the field of metabolic studies of anticancer and antifungal fluoropyrimidine drugs.

Fluorine-19 nuclear magnetic resonance (19F NMR) spectroscopy provides a highly specific tool for the detection, identification and quantification of fluorine-containing drugs and their metabolites in biofluids. The value and difficulties encountered in investigations on drug metabolism are first discussed. Then the metabolism of three fluoropyrimidines in clinical use, 5-fluorouracil, 5-fluorocytosine and capecitabine are reported. Besides the parent drug and the already known fluorinated metabolites, 12 new metabolites were identified for the first time with 19F NMR in human biofluids. Nine of them can only be observed with this technique: fluoride ion, N-carboxy-alpha-fluoro-beta-alanine, alpha-fluoro-beta-alanine conjugate with deoxycholic acid, 2-fluoro-3-hydroxypropanoic acid, fluoroacetic acid, O2-beta-glucuronide of fluorocytosine, fluoroacetaldehyde hydrate and its adduct with urea, fluoromalonic acid semi-aldehyde adducts with urea. This emphasizes the high analytical potential of 19F NMR for the furtherance in the understanding of fluoropyrimidine catabolic pathways. 19F NMR should also play a role in the therapeutic monitoring of FU and its prodrugs in specific groups of patients, e.g. hemodialyzed patients or patients with deficiency in FU catabolic enzymes.

Proton NMR for detection, identification and quantification of adulterants in 160 herbal food supplements marketed for weight loss.

One hundred and sixty food supplements (FS) marketed for weight loss and mainly purchased on the Internet were analyzed. All the FS were claimed as 100% natural containing only natural compounds, plant extracts and/or vitamins and the presence of an active pharmaceutical ingredient (API) was never mentioned. (1)H NMR spectroscopy was used for detecting the presence of adulterants and for their identification and quantification. Mass spectrometry was used as a complementary method for supporting their identification. Among the 164 samples considered because capsules from 5 different blisters of the same FS were analyzed, 56% were tainted with six API. Forty three contained sibutramine as single adulterant (26%), 9 phenolphthalein (6%) and 23 a mixture of these API (14%) that were both withdrawn from the market several years ago because of toxicity concerns. Sildenafil was found in 12 samples, either as a single adulterant (n=5) or in combination with sibutramine (n=3), phenolphthalein (n=3) and both sibutramine and phenolphthalein (n=1). Fluoxetine was present in 4 formulations, alone (n=3) or in combination with sibutramine and orlistat (n=1). At last, lorcaserine was detected in one FS. The content of sibutramine per dosage unit was comprised between 0.1 and 22 mg and that of phenolphthalein between 0.05 and 56 mg. The study also highlights poor manufacturing practices as evidenced for instance by the variability of API in capsules from different blisters of the same box. This paper demonstrates the need for more effective quality control of weight loss FS and the efficiency of (1)H NMR spectroscopy for the detection of tainted FS.

Fluorine-19 or phosphorus-31 NMR spectroscopy: a suitable analytical technique for quantitative in vitro metabolic studies of fluorinated or phosphorylated drugs.

Fluorine-19 or phosphorus-31 NMR (19F NMR or 31P NMR) spectroscopy provides a highly specific tool for identification of fluorine- or phosphorus-containing drugs and their metabolites in biological media as well as a suitable analytical technique for their absolute quantification. This article focuses on the application of in vitro 19F or 31P NMR to the quantitative metabolic studies of some fluoropyrimidine or oxazaphosphorine drugs in clinical use. The first part presents an overview of the advantages (non-destructive and non-selective direct quantitative study of the biological matrices) and limitations (expensive cost of the spectrometers, limited mass or concentration sensitivity) of NMR spectroscopy. The second part deals with the criteria to be considered for successful quantification by NMR (uniform excitation over the entire spectral width of the spectrum, resonance signals properly characterised by taking into account T1 values and avoiding NOE enhancements, optimisation of the data processing, choice of a suitable standard reference). The third and fourth parts report some examples of quantification of 5-fluorouracil, its prodrug capecitabine, 5-fluorocytosine and their metabolites in bulk solutions (biofluids, tissue extracts, perfusates and culture media) and heterogeneous media (excised tissues and packed intact cells) as well as cyclophosphamide and ifosfamide in biofluids. These two parts emphasise the high potential of in vitro 19F or 31P NMR for absolute quantification, in a single run, of all the fluorine- or phosphorus-containing species in the matrices analysed. The limit of quantification in bulk solutions is 1-3 microM for 19F NMR and approximately 10 microM for 31P NMR. In heterogeneous media analysed with 19F NMR, it is 2-5 nmol in excised tissues and cell pellets.

Detection, identification and quantification by 1H NMR of adulterants in 150 herbal dietary supplements marketed for improving sexual performance.

One hundred and fifty dietary supplements (DS) marketed to increase sexual performance were analyzed. All these formulations were claimed to contain only natural compounds, plant extracts and/or vitamins. (1)H NMR spectroscopy was used for detecting the presence of adulterants and for their identification and quantification. Mass spectrometry was used as a complementary method for confirming the chemical structures. 61% of DS were adulterated with phosphodiesterase-5 inhibitors (PDE-5i) (27% with the PDE-5i medicines sildenafil, tadalafil and vardenafil, and 34% with their structurally modified analogues). Among them, 64% contained only one PDE-5i and 36% mixtures of two, three and even four. The amounts of PDE-5i medicines were higher than the maximum recommended dose in 25% of DS tainted with these drugs. Additional 5.5% DS included other drugs for the treatment of sexual dysfunction (yohimbine, flibanserin, phentolamine, dehydroepiandrosterone or testosterone). Some DS (2.5%) contained products (osthole, icariin) extracted from plants known to improve sexual performance. Only 31% of the samples could be considered as true herbal/natural products. A follow-up over time of several DS revealed that manufacturers make changes in the chemical composition of the formulations. Lack of quality or consistent manufacture (contamination possibly due to inadequate cleaning of the manufacturing chain, presence of impurities or degradation products, various compositions of a given DS with the same batch number, inadequate labelling) indicated poor manufacturing practices. In conclusion, this paper demonstrates the power of (1)H NMR spectroscopy as a first-line method for the detection of adulterated herbal/natural DS and the need for more effective quality control of purported herbal DS.

Isolation of an unknown metabolite of capecitabine, an oral 5-fluorouracil prodrug, and its identification by nuclear magnetic resonance and liquid chromatography-tandem mass spectrometry as a glucuroconjugate of 5'-deoxy-5-fluorocytidine, namely 2'-(beta-D-glucuronic acid)-5'-deoxy-5-fluorocytidine.

A new metabolite of capecitabine, a prodrug of 5-fluorouracil, was detected by (19)F NMR in bile and liver of rats treated with this anticancer drug. Crude bile and perchloric acid extract of liver was subjected to liquid-liquid separation followed by a pre-purification step on a preparative octadecyl silane column (C(18)). The compound was purified by HPLC optimised to allow the detection of the unknown metabolite and its assumed precursor 5'-deoxy-5-fluorocytidine (5'-DFCR). Treatment with beta-glucuronidase from three sources showed that it was a glucuroconjugate of 5'-DFCR. HPLC-TIS-MS-MS and (1)H NMR allowed identification of the unknown metabolite as 2'-(beta-D-glucuronic acid)-5'-deoxy-5-fluorocytidine.