A Validated Stability Indicating RP-HPLC Method for Valganciclovir, Identification and Characterization of Forced Degradation Products of Valganciclovir Using LC-MS/MS

  • Smt. Kashibai Navale College of Pharmacy Kondhwa Pune
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The objective of the present study was to report the stability of novel antiviral drug, valganciclovir based on the information obtained from forced degradation studies. Valganciclovir was subjected to forced hydrolytic (acidic, alkaline and neutral), oxidative, photolytic and thermal stress in accordance with the ICH guideline Q1A (R2). The drug showed labiality under only acidic and photoacidic conditions while it was stable to other stress conditions. Resolution of the drug and degradation products was achieved on a Hypersil Gold C-18 column (4.6 × 250 mm, 5 μm) utilizing acetonitrile (A) and potassium dihydrogen ortho phosphate buffer (pH 5.0; 0.01M) in the ratio of 5:95 (v/v) at a flow rate of 0.6 ml/min and at the detection wavelength 252 nm. The major acidic stress degradation product was characterized by LC-MS/MS and its fragmentation pathway was proposed. Validation of the LC-DAD method was carried out in accordance with ICH guideline. The method met all required criteria and was applied for analysis of commercially available tablets.

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... The various methods have been used for the quantitative determination of antiviral drugs such as UV, capillary electrophoresis, and Different chromatographic methods likes GC and HPLC, LC-MS, GC-MS. In this review, authors concentrate on stability, suggesting HPLC /RP-HPLC methods for the accurately and effective development and validation of selected antiviral drugs such as, Atazanavir sulfate [35][36], Abacavir [37][38], Acyclovir [39], Adefovir Dipivoxil [41], Boceprevir [42], Baloxavir marboxil [43],Cobicistat [44], Darunavir ethanolate [45][46], Dolutegravir sodium [47][48], Didanosin [49], Efavirenz [50][51][52], Emtricitabine [53], Etravirine [54][55], Famciclovir [56][57][58], Foscarnet [59], Ganciclovir [60], Imiquimod [61], Lamivudine [62], Oseltamivir [63], Ribavirin [64][65], Simeprevir [66][67], Tenofovir [68], Valganciclovir [69][70][71][72], Zanamivir [73] and Zidovudine [74].The selective stability indicating RP-HPLC/ HPLC approaches for different antiviral drugs is summaries in Table.2 ...
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Force degradation studies of drug substance give perceptive knowledge about the intrinsic stability of the molecule as well as possible degradants which formed during the shelf life of drug and thus, aid within the successive development of its stable formulation. A number of analytical methods with hyphenated techniques are required for the identification, determination and characterization of degraded product and impurities produce during different conditions of stress studies; Chromatographic methodology play a vital role in the field of impurity and degradation profiling .This review summarizes the current regulatory requirements guidelines for the laboratory performance of forced degradation and its application for the development of stability indicating method. There are number of strategies have been implemented for the quantitative assessment of antiviral drugs. This study will provide detailed literature on stability- indicating HPLC/ RP-HPLC approaches for the development and validation of various antiviral drugs.
... Due to its therapeutic effectiveness use, VLGH has been determined in pharmaceuticals using several techniques. Few methods are found in the literature for the determination of VLGH in bulk drug and dosage forms and include visible spectrophotometry [4], UVspectrophotometry [5][6][7][8][9], capillary electrophoresis [10], high performance liquid chromatography (HPLC) [10][11][12][13][14][15], high performance thin-layer chromatographic (HPTLC) [16], ultra performance liquid chromatography (UPLC) [17] and voltammetry [18][19][20]. However, some of the previously reported methods for the determination of VLGH require sophisticated and expensive instrumentation that are not always available in all laboratories. ...
Two non-aqueous titrimetric and one visible spectrophotometric methods were developed and validated for the determination of valganciclovir hydrochloride (VLGH) in pure drug and tablets. The titrimetric methods were carried out by titrating the VLGH solution in glacial acetic acid with acetous perchloric acid (HClO4) in the presence of mercuric acetate and the end point of this titration was being located either visually (method A) or potentiometrically (method B). The spectrophotometric method (method C) was based on the addition of p-dimethylaminobenzaldehyde (DMAB) solution to VLGH solution and the formed yellow condensation product was measured at 420 nm. In titrimetric procedures, both the methods A and B were applicable over the range of 4–20 mg VLGH, and the calculations were based on a 1:1 reaction stoichiometry (VLGH: HClO4). In a spectrophotometric method, Beer’s law was valid in a concentration range of 5–50 μg/mL VLGH with the corresponding value of molar absorptivity of 4.43×10³ L/( for method C. The limits of detection (LOD) and quantification (LOQ) for method C were 0.3 and 0.92 µg/mL, respectively. The developed methods were successfully applied to the determination of VLGH in tablets, and the results were statistically compared with those of a reference method by applying Student’s t-test and F-test. Further, the validity of the developed methods was confirmed by recovery studies via standard addition technique.
... Chromatography tandem mass spectrometric (LC-MS/MS) developed and validated method was found suitable for estimation of Ondansetron HCl in dog plasma using as internal standard [21]. ...
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Ondansetron HCl (OSH) is a 5-HT3 receptor antagonist indicated for the prevention of nausea and vomiting associated with radiotherapy (adults: 8 mg, t.i.d) and/or chemotherapy (adults: 8 mg, b.i.d to t.i.d) and prevention of postoperative nausea and/or vomiting (adults: 8 mg, b.i.d). In elderly subjects, bioavailability may be somewhat higher (65%) and lower clearance, presumably due to reduced hepatic first-pass metabolism. OSH is extensively distributed in the body; about 70 to 75% of the drug in plasma is protein bound and terminal elimination half-life is about 3 hours after oral administration. The study was aimed to develop Push-pull Osmotic Pump (PPOP) bi-layered tablets for Ondansetron HCl ER tablets. The granulation was carried out using non-aqeous solvents followed by compression, seal coating, semi permeable coating, laser drilling (0.6mm) and drug film coating with loading dose. The drug release was controlled by swelleable osmotic polymers of pull layer and push layer and orifice on the surface of tablet. The formulations were optimized for its core composition, extended release coating (Semipermeable membrane) polymer as to plasticizer ratio and orifice diameter. Optimized formulations were evaluated for micromeritic properties and in-vitro drug release. The analytical methods were developed and validated to estimate In-vitro drug potency, drug release and In-vivo pharmacokinetic parameters. Stability studies were done as per the ICH guidelines. The results of In-vivo study concludes that the once OSH ER dose consistently maintains plasma concentration of drug within the therapeutic window over a period of 24 hours.
... VLGH in blood serum has been assayed using high performance liquid chromatography technique (HPLC) (Dagon-Topal, Ozkan, Uslu, 2007b) and liquid chromarography-tandem mass spectrometry (Singh et al., 2011;Heinig et al. 2011;Xu et al., 2006;Xu et al., 2007). Very few methods for the determination of the drug in bulk and dosage forms are found in the open literature, and include UV-spectrophotometry (Konidala et al., 2014), HPLC (Sanll, Sanll, Lunte, 2017;Sawant, Barge, 2014;Lakshmi, Kumara, 2013;Mathrusri, Lakshmi, Sirichandra, 2013), HPTLC (Barge et al., 2011), capillary electrophoresis (Sanll, Sanll, Lunte, 2017) and voltammetry (Prashanth et al. 2014;Dogan-Topal et al. 2013;Gholivand, Torkashvand, 2016). ...
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Two simple, selective and sensitive spectrophotometric methods were developed and validated for the determination of valganciclovir hydrochloride (VLGH) in pure drug and tablets. The first method was based on the reduction of iron(III) to iron(II) by VLGH and subsequent formation of iron(III)-ferricyanide complex (Prussian blue) in acid medium which was measured at 730 nm (method A). In the second method (method B), permanganate was reduced by VLGH to bluish green manganate in alkaline medium and the absorbance was measured at 610 nm. The absorbance measured in each case was related to VLGH concentration. The experimental conditions were carefully studied and optimized. Beer’s law was obeyed over the concentration ranges of 2.5-20.0 and 2.0-40.0 µg mL-1 for method A and method B, respectively, with corresponding molar absorptivity values of 1.28×104 and 6.88×103 L mol-1 cm-1. The limits of detection (LOD) and quantification (LOQ) were 0.11 and 0.33 µg mL-1 (method A) and 0.21 and 0.64 µg mL-1 (method B). Within-day and between-day relative standard deviations (%RSD) at three different concentrations levels were < 2.4%, and the respective relative errors (%RE) were ≤ 3%. The proposed methods were successfully applied to the determination of VLGH in tablets, and the results confirmed that the proposed methods were equally precise and accurate as the official method.
Cytomegalovirus (CMV) is a common virus which infects people of all ages. It causes serious illness like mononucleosis or hepatitis in immunocompromised patients. Ganciclovir had been the first drug of choice to treat cytomegalovirus infection. At present, Valganciclovir, the prodrug, is more predominantly used because of its higher oral bioavailability. Both the drugs act by inhibiting the replication of viral DNA. Commercially, ganciclovir is available in the form of capsules, suspensions, injections, nanoparticles and microspheres while valganciclovir is available as tablets and injections. This review provides an overview of physicochemical, pharmacokinetic and pharmacodynamic properties of ganciclovir and valganciclovir and a detailed investigation on different analytical techniques used for detection and quantification of these drugs on various matrices. Various techniques like spectroscopy, chromatography, electrochemical methods and hyphenated techniques were reported to determine ganciclovir and valganciclovir, either alone or in combination with other drugs, in different kinds of matrices like in bulk, existing dosage forms and also biological samples like plasma, serum, urine and myocardial tissue. Among various techniques used, HPLC, LC-MS systems are more commonly used because of their high sensitivity. This article summarizes the research works carried out since 1985 and intents to act as a handbook for future researchers.
A new reverse phase and shorter run time (3.0 min) liquid chromatography–quadrupole time of flight‐tandem mass spectrometry method was developed and validated for identification and ultra‐trace level quantification (0.83 ppm) of genotoxic impurity 1,3‐diacetoxy‐2‐(acetoxymethoxy) propane in valganciclovir hydrochloride active pharmaceutical ingredient. The method is cost effective, time saving and proficient to confirm the parent and fragment ion masses through mass spectrometry and tandem mass spectrometry further fragmentation. An isocratic program and acquity bridged ethylene hybrid C18 reverse phase column (100 mm × 4.6 mm × 1.7 μm) was used to accomplish optimum separation between valganciclovir and 1,3‐diacetoxy‐2‐(acetoxymethoxy) propane impurity. Mobile phase‐A used was 0.1% formic acid in milli Q water and mobile phase‐B used was acetonitrile in the ration of 50:50 v/v. Diluent used was water and methanol in the ratio of 30:70 v/v. Chromatographic conditions are selected as injection volume: 3 μL, flow rate: 0.2 mL/min, oven temperature: ambient, auto sampler: 5°C and run time: 3.0 min. The retention time of 1,3‐diacetoxy‐2‐(acetoxymethoxy) propane impurity was found at 1.830 min. The detection and quantification levels found at 0.027 and 0.083 ppm. The 1,3‐diacetoxy‐2‐(acetoxymethoxy) propane impurity is linear from 0.082 to 1.236 ppm levels with regression coefficient 0.9972. The recoveries were from 93.3 to 110.0%.
In this study, a rapid, selective and sensitive method was developed for the determination of valganciclovir (VLG). The electrochemical oxidation of VLG was studied at the designed sensor based on magnetic nanoparticles (Fe3O4), graphene and Nafion via cyclic and square wave voltammetry in a wide pH range. The oxidation signal of the drug was significantly improved, and its peak potential shifted to a negative value; this indicated the catalytic activity of the used electrode modifier. Moreover, optimization of the useful parameters, including the accumulation potential and time, was carried out. The calibration curve was composed of two linear portions in the concentration ranges of 0.005–1.8 μM and 1.8–6 μM with the detection limit of 2.9 nM. Based on the obtained results, it can be concluded that the fabricated sensor has desirable stability and reproducibility. The selective and sensitive analysis of VLG in blood plasma and commercial tablets as real samples was energetically feasible.
Introduction: Hydrolytic degradation is the most common cause of formation of impurities or degradation products in drugs during different stages of drug product development and/or shelf life of the drug/product. Degradation products formed by hydrolysis of ester, amide, urethane, sulfonamide, sulfonate and ether linkages, and of nitrile, hydroxyl and amino groups in drugs can be conveniently predicted and identified. Many drugs are known to degrade to such expected conventional hydrolytic degradation products, and the mechanisms of such degradations are also well known and reported. However, many drugs are reported to degrade under hydrolytic conditions to products, which cannot be justified by the conventional hydrolytic reactions. Objectives: Though structures of such unconventional hydrolytic products can be characterized through different spectral techniques, but there is a need to understand the mechanisms of such unconventional hydrolytic reactions in order to help in establishing intrinsic stability characteristics of a drug. Methodology: In the present review, we have studied and critically analysed all possible reports on hydrolytic degradation of various dugs to provide a thorough insight into unconventional routes of hydrolytic degradations of drugs. The various unconventional hydrolytic reactions found responsible for degradation of drugs are classified as oxidation, dehydrogenation, coupling/condensation, N-alkylation, C-C bond cleavage, C-N bond cleavage, dehalogenation, cyclization, decarboxylation and hydroxylation. Discussion: Varied types of reactions under hydrolytic conditions are triggered/controlled by the nature of substituent (s) across or around the susceptible bonds/groups. The mechanisms for such unconventional hydrolytic reactions have been discussed or proposed with support from the standard literature. The contents are expected to enable an analyst and a drug formulator to predict various possible as well as seemingly improbable hydrolytic degradation products of a drug well ahead of systematic forced degradation studies. © Indian Journal of Pharmaceutical Education and Research. All rights reserved.
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A simple, sensitive and economical UV spectrophotometric method has been developed for the determination of Valganciclovir in bulk and tablet dosage form. Valganciclovir is a prodrug of ganciclovir that is used for the treatment of cytomegalovirus retinitis in patients with AIDS. Valganciclovir shows maximum absorbance at 254 nm in methanol. Beer’s law was obeyed within the concentration range of 5-30 mcg/ml with the correlation coefficient of 0.9999. The standard plot was clearly showed a straight line passing through the origin. The results of analysis were validated statistically and by recovery studies and found to be satisfactory. The proposed method was extended to pharmaceutical formulations and there was no interference of additives and excipients.
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Valganciclovir is an orally administered prodrug that is rapidly hydrolyzed to ganciclovir. We compared the effects of oral valganciclovir with those of intravenous ganciclovir as induction therapy for newly diagnosed cytomegalovirus retinitis in 160 patients with the acquired immunodeficiency syndrome (AIDS). The primary end point was photographically determined progression of cytomegalovirus retinitis within four weeks after the initiation of treatment. Secondary end points included the achievement of a prospectively defined satisfactory response to induction therapy and the time to progression of cytomegalovirus retinitis. After four weeks, all patients received valganciclovir as maintenance therapy. Eighty patients were randomly assigned to each treatment group. Of the patients who could be evaluated, 7 of 70 assigned to intravenous ganciclovir (10.0 percent) and 7 of 71 assigned to oral valganciclovir (9.9 percent) had progression of cytomegalovirus retinitis during the first four weeks (difference in proportions, 0.1 percentage point; 95 percent confidence interval, -9.7 to 10.0). Forty-seven of 61 patients (77.0 percent) assigned to intravenous ganciclovir and 46 of 64 (71.9 percent) assigned to valganciclovir had a satisfactory response to induction therapy (difference in proportions, 5.2 percentage points; 95 percent confidence interval, -20.4 to 10.1). The median times to progression of retinitis were 125 days in the group assigned to intravenous ganciclovir and 160 days in the group assigned to oral valganciclovir. The mean values for the area under the curve for the ganciclovir dosage interval were similar at both induction doses and maintenance doses. The frequency and severity of adverse events were similar in the two treatment groups. Orally administered valganciclovir appears to be as effective as intravenous ganciclovir for induction treatment and is convenient and effective for the long-term management of cytomegalovirus retinitis in patients with AIDS.
Prodrugs are substances administered in an inactive form that is then metabolized in the body in vivo into the active compound. The rationale behind administering prodrugs is to optimize absorption, distribution, metabolism, and excretion of these drugs. Since first described in the 1950s, prodrugs continue to be a fertile area of research. There are a number of small pharmaceutical/biotech companies dedicated to using prodrugs for the delivery of older but problematic drugs as well as to developing broad-based prodrug technologies for application to new and future drugs. These volumes represent a comprehensive guide to prodrugs and will guide the reader through the current status of the prodrug concept and its many applications and to highlight its many successes in overcoming formulation and delivery of problematic drugs.
The photolability of the anti-inflammatory drug Nabumetone (4-(6-methoxy-2-naphthyl)-butan-2-one) was studied in water. The photoproducts were followed by UV-Vis absorption, fluorescence and FTIR spectroscopies as well as gas chromatography–mass spectrometry (GC–MS).The photodegradation process in water followed first-order kinetics, with an half-life, t1/2=9.7min whereas leading to different products.In this medium, the side chain is photoxidised to 6-methoxy-2-naphthalene aldehyde, as major product, probably via a Nabumetone radical cation formation and the addition of singlet oxygen generated in the drug photolysis. In addition the (4-(6-methoxy-2-naphthyl)-3-buten-2-one) was detected. The most likely origin of the unsaturated compound is the dehydratation of an alcoholic derivative in alpha position of the naphthalene ring, produced via the same radical cation.
Recent applications of LC-MS in the analysis of drug degradation products in pharmaceutical formulations are reviewed. Drug degradation products are categorized according to their formation mechanism: oxidation, hydrolysis, dimerization and adduct formation with excipients and packaging materials. The oxidative ring opening and dimerization of an indole derivative are discussed in detail. The examples used in this review clearly demonstrate that LC-MS is a very powerful technique for the analysis of low-level degradates in formulations without the time-consuming isolation process. At the same time, limitations and precaution of using LC-MS techniques for unknown identification are also addressed. In some cases, the LC-MS data could become misleading if the ionization process and gas-phase behavior of the analytes are not well understood. Copyright © 2000 John Wiley & Sons, Ltd.Abbreviations used:APCIatmospheric pressure chemical ionizationCIDcollision-induced dissociationESIelectrospray ionizationXICextracted ion chromatogram.
The photolability of the anti-inflammatory drug Nabumetone was studied in n-butanol. The photoproducts were followed by UV-Vis absorption, fluorescence and FTIR spectroscopies as well as gas chromatography–mass spectrometry (GC/MS).The photodegradation process in this organic medium followed first-order kinetics. In contrast with what was expected on the basis of the changes in the electronic spectra observed, the process seems to be more efficient than in water, with a Φ=0.47 and a half-life, t1/2=3.0 min, leading to different products.In this medium, the side chain is photo-oxidised to 6-methoxy-2-naphthaldehyde, as a major product. In addition the (4-(6-methoxy-2-naphthyl)-3-buten-2-one) was detected.The kinetic behaviour suggests that the photoproducts are formed from the singlet excited state () of the drug. Therefore the increase in the rate constant of the degradation of the Nabumetone, may be thought to be due to an increase in the concentration of this excited species via hydrogen bond formation with the solvent.
A rapid, sensitive, and specific reverse phase high performance liquid chromatography with diode array detection procedure for the simultaneous determination of abacavir, efavirenz and valganciclovir in spiked human serum is described. Separation was performed on a 5μm Waters Spherisorb column (250×4.6mm ID) with acetonitrile: methanol:KH2PO4 (at pH 5.00) (40:20:40 v/v/v) isocratic elution at a flow rate of 1.0mLmin−1. Calibration curves were constructed in the range of 50–30,000ngmL−1 for abacavir and efavirenz, and 10–30,000ngmL−1 for valganciclovir in serum samples. The limit of detection and limit of quantification concentrations of the HPLC method were 3.80 and 12.68ngmL−1 for abacavir, 2.61 and 8.69ngmL−1 for efavirenz, 1.30 and 4.32ngmL−1 for valganciclovir. The method has been applied, without any interference from excipients or endogenous substances, for the simultaneous determination of these three compounds in human serum.
This paper describes the validation of an isocratic high-performance liquid chromatographic method for the assay of valganciclovir in raw materials, tablets and human serum samples. Valganciclovir and fluvastatin (internal standard) were well separated using a reversed phase column and a mobile phase consisting of a mixture of acetonitrile:methanol:KH2PO4 (0.02M) (40:20:40; v/v/v) (at pH 5.0). The mobile phase was pumped at 1.0mLmin−1 flow rate and valganciclovir was detected by diode-array detection at 255nm. The retention times for valganciclovir and fluvastatin were 3.41 and 5.60min, respectively. A linear response (r>0.999) was observed in the range of 10–30,000ngmL−1 in mobile phase and serum. The limit of detection and limit of quantification were found as 2.95 and 9.82ngmL−1 in mobile phase and 1.73 and 5.77ngmL−1 in human serum samples, respectively. Validation parameters as precision, accuracy, selectivity, reproducibility and system suitability tests were also determined. The method can be used for valganciclovir assay of tablets and human serum samples as the method separates valganciclovir from tablet excipients and endogenous substances.
High efficiency and less run time are the basic requirements of high-speed chromatographic separations. To fulfill these requirements, a new separation technique, ultra-performance liquid chromatography (UPLC), has shown promising developments. A rapid, specific, sensitive, and precise reverse-phase UPLC method is developed for the determination of nabumetone in tablet dosage form. In this work, a new isocratic chromatographic method is developed. The newly developed method is applicable for assay determination of the active pharmaceutical ingredient. The chromatographic separation is achieved on a Waters Acquity BEH column (100 mm, i.d., 2.1 mm, 1.7 µm) within a short runtime of 2 min using a mobile phase of 5 mM ammonium acetate–acetonitrile (25:75, v/v), at a flow rate of 0.3 mL/min at an ambient temperature. Quantification is achieved with photodiode array detection at 230 nm, over the concentration range of 0.05–26 µg/mL. Forced degradation studies are also performed for nabumetone bulk drug samples to demonstrate the stability-indicating power of the UPLC method. Comparison of system performance with conventional high-performance liquid chromatography is made with respect to analysis time, efficiency, and sensitivity. The method is validated according to the ICH guidelines and is applied successfully for the determination of nabumetone in tablets.
The aim of this work was to develop a simple, sensitive and selective LC/MS/MS method for the assay of valganciclovir and ganciclovir in human plasma. Sample preparation involved solid phase extraction on mix mode cation exchanger. Separation was performed on Chromolith RP18e column using water, trifluoroacetic acid (1M, pH 4.4) and methanol (29.9:0.1:70, v/v) as mobile phase. Both analytes were detected by electro spray ionization mass spectrometry in positive ion multiple reaction monitoring mode. CCs with good linearties having r≥0.9990 and ≥0.9992 were obtained in the range of 5-800ng/mL and 70-11,200ng/mL for valganciclovir and ganciclovir, respectively. The extraction recoveries were around 85% for both the analytes. The method provided a simple and selective procedure that can be easily used for the evaluation of the pharmacokinetic profile of valganciclovir and ganciclovir in human plasma.
This manuscript describes the determination of Ganciclovir (GCV), active component of the antiviral drug Valcyte®, and its ester prodrug Valganciclovir (VGC) in human and rat plasma, using liquid chromatography coupled to tandem mass spectrometry. Protein precipitation with acetonitrile was followed by hydrophilic interaction liquid chromatography on a silica column with 4 min run time. After electrospray ionization, the compounds were detected in positive ion selected reaction monitoring (SRM) mode. The lower limits of quantification (LLOQ) were 16 ng/mL for GCV and 4 ng/mL for VGC in human and rat plasma. Inter-day and intra-day precisions and inaccuracies were below 15% and between 85 and 115%, respectively. Five-fold deuterated GCV and VGC were used as internal standards and compensated for any matrix effect. The method was successfully applied to samples from a rat pharmacokinetic study. The feasibility of blood analysis as dried blood spots (DBS) was investigated.
The objective of this endoscopic, double-blind study was to evaluate the gastric tolerability of nabumetone, a novel nonsteroidal anti-inflammatory drug, compared with naproxen in patients with rheumatoid arthritis. Patients with definite or classic rheumatoid arthritis as defined by ACR criteria were eligible for entry into the study if an initial endoscopy was normal or showed the presence of only one erosion or one or two submucosal hemorrhages. After a 7-day washout period, the patients were randomized to receive either nabumetone, 1 g, or naproxen, 500 mg, b.i.d. Blinding was achieved by the use of double dummies. Endoscopy was repeated after 4 wk of treatment. The primary efficacy parameters were Ritchie articular index, duration of morning stiffness, and global assessments. Gastric mucosal lesions of different degrees were observed in 9% (2/22) of nabumetone-treated patients and in 40% (12/30) of those who received naproxen (p = 0.01). One duodenal ulcer was found in a patient treated with nabumetone, and this patient had a history of duodenal ulcer. In the naproxen group, six patients were found to have an ulcer. Clinical evaluation of rheumatological symptomatology showed no statistical difference in relieving symptoms between the two drugs in the primary efficacy assessments. However, six nabumetone-treated patients dropped out because of lack of efficacy, compared with one in the naproxen group. Side effects were noted in three patients treated with nabumetone and in 14 treated with naproxen (p = 0.004). This study showed that nabumetone, 1 g daily, results in significantly less deterioration of gastric mucosa than naproxen, 500 mg daily, but the efficacy of naproxen, 1 g, appears to be more than that achieved with nabumetone, 1 g.
This study examined the relative effects of equally-effective anti-inflammatory doses of nabumetone, naproxen, piroxicam and diclofenac on gastric irritancy induced by over-the-counter (OTC) non-steroidal anti-inflammatory drugs (NSAIDs) aspirin and ibuprofen and a variety of necrotizing agents (0.6 N HCl, 0.2 N NaOH and 25% NaCl). Within one hour, aspirin 100 and 200 mg/kg and ibuprofen up to 15 mg/kg produced significant gastric mucosal injury. Aspirin 50 mg/kg produced only minimal damage that was enhanced by 5 x ID25 piroxicam and naproxen, but not by nabumetone or diclofenac. 5 x ID25 naproxen, piroxicam, and diclofenac significantly enhanced mucosal damage produced by ibuprofen 2.5 mg/kg. An equivalent anti-inflammatory dose of nabumetone failed to enhance the gastric irritancy produced by ibuprofen 2.5 mg/kg. Similarly, naproxen, piroxicam, and diclofenac enhanced the susceptibility of the gastric mucosa to the necrotizing actions of 0.6 N HCl, 0.2 N NaOH or 25% NaCl. Naproxen, piroxicam, or diclofenac are more likely than nabumetone to enhance gastric mucosal injury produced by OTC NSAIDs (aspirin and ibuprofen) or other gastric irritants.
Nabumetone is a nonsteroidal anti-inflammatory drug (NSAID) of the 2,6-disubstituted naphthyl-alkanone class. Nabumetone is metabolised to an active metabolite 6-methoxy-2-napthylacetic acid (6-MNA) which is a relatively selective cyclo-oxygenase-2 inhibitor that has anti-inflammatory and analgesic properties. Nabumetone and its metabolites bind extensively to plasma albumin. Nabumetone is eliminated following biotransformation to 6-MNA, which does not undergo enterohepatic circulation and the respective glucoroconjugated metabolites are excreted in urine. Substantial concentrations of 6-MNA are attained in synovial fluid, which is he proposed site of action in chronic inflammatory arthropathies. A smaller area under the plasma concentration-time curve (AUC) is evident at steady state as compared with a single dose; this is possibly due to an increase in the volume of distribution and saturation of protein binding. Relationships between 6-MNA concentrations and the therapeutic and toxicological effects have yet to be elucidated for this NSAID. Renal failure significantly reduces 6-MNA elimination but steady-state concentrations of 6-MNA are not increased, possibly because of nonlinear protein binding. Elderly patients with osteoarthritis demonstrate decreased elimination and increased plasma concentrations of nabumetone as compared with young healthy volunteers. Rheumatic disease activity also influences 6-MNA plasma concentrations, as patients with more active disease and lower serum albumin concentrations demonstrate a lower area under the plasma concentration versus time curve. A reduced bioavailability of 6-MNA in patients with severe hepatic impairment is also evident. Dosage adjustment may be required in the elderly, patients with active rheumatic disease and those with hepatic impairment, but not in patients with mild-to-moderate renal failure.
To summarize current evidence that three new additions to nonsteroidal anti-inflammatory drugs (NSAIDs) offer comparable efficacy with fewer adverse effects than established NSAIDs. No large randomized controlled trials (RCTs) have compared all important NSAIDs. Several RCTs have shown that H2 antagonists do not protect against NSAID side effects, but some RCTs compared the protective effect of misoprostol (Cytotec) used with other NSAIDs; others have compared etodolac (Ultradol) or nabumetone (Relafen) with placebo and naproxen (eg, Naprosyn). Postmarketing surveys have been used to support claims that the new NSAIDs have few gastric or renal side effects. Using misoprostol in conjunction with traditional NSAIDs reduces gastric and renal adverse effects. Misoprostol can be taken at the same time as NSAIDs or in a combination tablet. Two new NSAIDS, etodolac and nabumetone, do not inhibit cyclooxygenase 1 prostaglandins, which occur in the stomach and kidneys, but more selectively block cyclooxygenase 2 prostaglandins, which cause arthritic inflammation. These two NSAIDs have efficacy profiles comparable to older NSAIDs but have markedly fewer side effects. Safer treatment for arthritis can be achieved by combining misoprostol with traditional NSAIDs or by using one of two new agents, nabumetone or etodolac.
This write-up provides a review on the development of validated stability-indicating assay methods (SIAMs) for drug substances and products. The shortcomings of reported methods with respect to regulatory requirements are highlighted. A systematic approach for the development of stability-indicating methods is discussed. Critical issues related to development of SIAMs, such as separation of all degradation products, establishment of mass balance, stress testing of formulations, development of SIAMs for combination products, etc. are also addressed. The applicability of pharmacopoeial methods for the analysis of stability samples is discussed. The requirements of SIAMs for stability study of biotechnological substances and products are also touched upon.
A protein precipitation, liquid chromatography/tandem mass spectrometry (LC/MS/MS) method has been developed and validated for the simultaneous determination of valganciclovir and its active metabolite ganciclovir in human plasma. The solvent system also served as a protein precipitation reagent. The chromatographic separation was achieved on an Aquasil C18 column (50 mm x 2.1mm, 5 microm). A linear gradient mobile phase between 0.02% formic acid and methanol was used. Detection was by positive ion electrospray tandem mass spectrometry on a Sciex API3000. The standard curves, which ranged from 4 to 512 ng/mL for valganciclovir and from 0.1 to 12.8 microg/mL for ganciclovir, were fitted to a 1/x weighted quadratic regression model. The method was proved to be accurate, specific and sensitive enough and was successfully applied to a pharmacokinetic study.
We compared the efficacy and safety of valganciclovir with those of oral ganciclovir in preventing cytomegalovirus (CMV) disease in high-risk seronegative solid organ transplant (SOT) recipients of organs from seropositive donors (D+/R-). In this randomised, prospective, double-blind, double-dummy study, 364 CMV D+/R- patients received valganciclovir 900 mg once daily or oral ganciclovir 1000 mg three times a day (tid) within 10 days of transplant and continued through 100 days. CMV disease, plasma viremia, acute graft rejection, graft loss and safety were analyzed up to 6 and 12 months post-transplant. Endpoint committee-defined CMV disease developed in 12.1% and 15.2% of valganciclovir and ganciclovir patients, respectively, by 6 months, though with a difference in the relative efficacy of valganciclovir and ganciclovir between organs (i.e. an organ type-treatment interaction). By 12 months, respective incidences were 17.2% and 18.4%, and the incidence of investigator-treated CMV disease events was comparable in the valganciclovir (30.5%) and ganciclovir (28.0%) arms. CMV viremia during prophylaxis was significantly lower with valganciclovir (2.9% vs. 10.4%; p=0.001), but was comparable by 12 months (48.5% valganciclovir vs 48.8% ganciclovir). Time-to-onset of CMV disease and to viremia were delayed with valganciclovir; rates of acute allograft rejection were generally lower with valganciclovir. Except for a higher incidence of neutropenia with valganciclovir (8.2%, vs 3.2% ganciclovir) the safety profile was similar for both drugs. Overall, once-daily oral valganciclovir was as clinically effective and well-tolerated as oral ganciclovir tid for CMV prevention in high-risk SOT recipients.
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