Pub Date : 2011-11-30DOI: 10.3109/10601333.2011.619540
S. Dey, Kirti Kandhwal, Shabana Nazarudheen, Onkar Singh, S. Mukherjee, Sanjeev Mishra, S. Reyar, A. Khuroo, T. Monif
A rapid, simple, and sensitive liquid chromatography tandem mass spectrometric (LC–MS/MS) method for the determination of clopidogrel in human plasma was developed and validated using clopidogrel-d4 as the internal standard (IS). The analyte and the IS were extracted from 500 µl aliquots of human plasma via solid phase extraction. The precursor to product ion transitions monitored for clopidogrel and IS were m/z 322.2 → 212.0 and 326.2 → 216.0, respectively. The method was fully validated for sensitivity, accuracy and precision, linearity, recovery, matrix effect, dilution integrity, and stability. The Linearity range was 20.4–10,772.6 pg/mL with mean correlation coefficient (r) ≥ 0.9977. The back conversion was also evaluated during method validation as per EMA recommendation. Results proved that clopidogrel was accurately and reliably estimated by the method without any evidence of back conversion of clopidogrel acid. The method was successfully applied to a bioequivalence study of 75 mg clopidogrel bisulfate tablet formulation in 32 healthy male volunteers under fasting conditions. The ratios of least-squares means (with 90% confidence intervals) for the pharmacokinetic parameters Cmax, AUC0–t and AUC0–α were 107.98% (94.52–123.35%), 100.25% (91.28–110.09%), and 100.49% (91.37–110.51%), respectively.
{"title":"Regulatory recommendations for clopidogrel: Focus on validation of a reliable bioanalytical method and its application to a bioequivalence study","authors":"S. Dey, Kirti Kandhwal, Shabana Nazarudheen, Onkar Singh, S. Mukherjee, Sanjeev Mishra, S. Reyar, A. Khuroo, T. Monif","doi":"10.3109/10601333.2011.619540","DOIUrl":"https://doi.org/10.3109/10601333.2011.619540","url":null,"abstract":"A rapid, simple, and sensitive liquid chromatography tandem mass spectrometric (LC–MS/MS) method for the determination of clopidogrel in human plasma was developed and validated using clopidogrel-d4 as the internal standard (IS). The analyte and the IS were extracted from 500 µl aliquots of human plasma via solid phase extraction. The precursor to product ion transitions monitored for clopidogrel and IS were m/z 322.2 → 212.0 and 326.2 → 216.0, respectively. The method was fully validated for sensitivity, accuracy and precision, linearity, recovery, matrix effect, dilution integrity, and stability. The Linearity range was 20.4–10,772.6 pg/mL with mean correlation coefficient (r) ≥ 0.9977. The back conversion was also evaluated during method validation as per EMA recommendation. Results proved that clopidogrel was accurately and reliably estimated by the method without any evidence of back conversion of clopidogrel acid. The method was successfully applied to a bioequivalence study of 75 mg clopidogrel bisulfate tablet formulation in 32 healthy male volunteers under fasting conditions. The ratios of least-squares means (with 90% confidence intervals) for the pharmacokinetic parameters Cmax, AUC0–t and AUC0–α were 107.98% (94.52–123.35%), 100.25% (91.28–110.09%), and 100.49% (91.37–110.51%), respectively.","PeriodicalId":10446,"journal":{"name":"Clinical Research and Regulatory Affairs","volume":"41 1","pages":"87 - 95"},"PeriodicalIF":0.0,"publicationDate":"2011-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86250582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2011-11-30DOI: 10.3109/10601333.2011.631547
A. Fuglsang
Recent publications have introduced sequential (two-stage) designs for investigation of bioequivalence in cross-over trials and the occurrence of type I errors have been investigated using trial simulations. They have so far focused on Test:Reference ratio of 0.95 and 0.9 and it has been observed that type I errors above 0.05 may occur. In this paper the behavior of two-stage designs for investigations of bioequivalence is being further investigated, and it is concluded that the existing methods do not universally control type I errors to an acceptable level, and they have the disadvantage of not using the observed Test:Reference from stage 1 in the dimensioning of stage 2. It is observed that type I errors and the alpha at the second stage follow an approximately linear relation in the region of type I errors of 0.05. This principle is used to propose a method that uses both the CV and Test:Reference ratio and which targets specifically a type I error level of 0.05. This is done by using simulation after stage 1 to identify an optimal value for the second alpha. An example is given which illustrates how the method may be associated with both an ethical and economical advantage.
{"title":"Controlling type I errors for two-stage bioequivalence study designs","authors":"A. Fuglsang","doi":"10.3109/10601333.2011.631547","DOIUrl":"https://doi.org/10.3109/10601333.2011.631547","url":null,"abstract":"Recent publications have introduced sequential (two-stage) designs for investigation of bioequivalence in cross-over trials and the occurrence of type I errors have been investigated using trial simulations. They have so far focused on Test:Reference ratio of 0.95 and 0.9 and it has been observed that type I errors above 0.05 may occur. In this paper the behavior of two-stage designs for investigations of bioequivalence is being further investigated, and it is concluded that the existing methods do not universally control type I errors to an acceptable level, and they have the disadvantage of not using the observed Test:Reference from stage 1 in the dimensioning of stage 2. It is observed that type I errors and the alpha at the second stage follow an approximately linear relation in the region of type I errors of 0.05. This principle is used to propose a method that uses both the CV and Test:Reference ratio and which targets specifically a type I error level of 0.05. This is done by using simulation after stage 1 to identify an optimal value for the second alpha. An example is given which illustrates how the method may be associated with both an ethical and economical advantage.","PeriodicalId":10446,"journal":{"name":"Clinical Research and Regulatory Affairs","volume":"207 1","pages":"100 - 105"},"PeriodicalIF":0.0,"publicationDate":"2011-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76087345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2011-08-25DOI: 10.3109/10601333.2011.594443
Pratik Thakkar, V. Balamuralidhara, T. Pramod Kumar, Ravi Valluru, M. Venkatesh
Electronic source data and documentation from clinical investigations should be attributable, legible, contemporaneous, original and accurate. 21 Code of Federal Regulations (CFR) Part 11 provides acceptance criteria for electronic records, signatures, and handwritten signatures executed to electronic records. All study protocols should identify each step at which a computerized system will be used to create, modify, maintain, archive, retrieve, or transmit source data. Standard operating procedures and controls should be established when using computerized systems to create, modify, maintain, or transmit electronic records, and when collecting source data at clinical trial sites. Access must be limited to authorized individuals. Computer generated, time-stamped electronic audits trails should be undertaken to track changes to electronic source documentation. Controls should be established to ensure that the system’s date and time are correct. Procedures and controls should be put in place to prevent the altering, browsing, querying, or reporting of data via external software applications that do not enter through the protective system software. Prompts, flags, or other help features should be incorporated in a computerized system to encourage consistent use of clinical terminology. Individuals should have training necessary to perform their assigned tasks.
{"title":"Use of computerized systems in clinical research: A regulatory perspective","authors":"Pratik Thakkar, V. Balamuralidhara, T. Pramod Kumar, Ravi Valluru, M. Venkatesh","doi":"10.3109/10601333.2011.594443","DOIUrl":"https://doi.org/10.3109/10601333.2011.594443","url":null,"abstract":"Electronic source data and documentation from clinical investigations should be attributable, legible, contemporaneous, original and accurate. 21 Code of Federal Regulations (CFR) Part 11 provides acceptance criteria for electronic records, signatures, and handwritten signatures executed to electronic records. All study protocols should identify each step at which a computerized system will be used to create, modify, maintain, archive, retrieve, or transmit source data. Standard operating procedures and controls should be established when using computerized systems to create, modify, maintain, or transmit electronic records, and when collecting source data at clinical trial sites. Access must be limited to authorized individuals. Computer generated, time-stamped electronic audits trails should be undertaken to track changes to electronic source documentation. Controls should be established to ensure that the system’s date and time are correct. Procedures and controls should be put in place to prevent the altering, browsing, querying, or reporting of data via external software applications that do not enter through the protective system software. Prompts, flags, or other help features should be incorporated in a computerized system to encourage consistent use of clinical terminology. Individuals should have training necessary to perform their assigned tasks.","PeriodicalId":10446,"journal":{"name":"Clinical Research and Regulatory Affairs","volume":"1 1","pages":"55 - 62"},"PeriodicalIF":0.0,"publicationDate":"2011-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82335887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2011-08-25DOI: 10.3109/10601333.2011.597762
N. Thudi, V. Shrivastav, T. Monif, A. Khuroo, S. Gurule, P. Partani, M. Tandon, R. Mathur
Tretinoin belongs to the class of retinoids indicated in induction of remission in acute promyelocytic leukemia (APL-FAB classification AML-M3). It is an endogenous metabolite of Vitamin A and is normally present in human plasma. The objective of the present study was to evaluate the bioequivalence between the Tretinoin 10 mg capsules of Ranbaxy Laboratories Limited and VESANOID® 10 mg capsules of Roche Pharmaceuticals Inc. It was a 2-way cross-over single dose study in 60 adult Indian male volunteers under fasting conditions. Since tretinoin is endogenously present in the human body, for baseline adjustment four pre-dose samples were collected. Plasma samples were analyzed for tretinoin by using validated liquid chromatographic mass spectrometry (LC-MS/MS) method. This method has separated both isomeric metabolites (i.e. isotretinoin and 9-oxo retinoic acid) from tretinoin to accurately measure the tretinoin concentrations in plasma for this study. The Mean ± SD of pharmacokinetic parameters Tmax, Cmax, and AUC0−t for tretinoin were 2.55 ± 0.84 and 2.40 ± 0.86 h, 34.29 ± 10.45 and 32.77 ± 9.16 ng/ml, 87.28 ± 30.99 and 80.81 ± 24.68 ng.h/ml, respectively, for test and reference. The ratios of least square means and its 90% confidence interval for Cmax, AUC0−t and AUC0–∞ on both baseline corrected and uncorrected data were found to be within 80–125%.
{"title":"Pharmacokinetic and bioequivalence study of endogenous compound tretinoin 10 mg capsules in healthy volunteers by base line correction approach","authors":"N. Thudi, V. Shrivastav, T. Monif, A. Khuroo, S. Gurule, P. Partani, M. Tandon, R. Mathur","doi":"10.3109/10601333.2011.597762","DOIUrl":"https://doi.org/10.3109/10601333.2011.597762","url":null,"abstract":"Tretinoin belongs to the class of retinoids indicated in induction of remission in acute promyelocytic leukemia (APL-FAB classification AML-M3). It is an endogenous metabolite of Vitamin A and is normally present in human plasma. The objective of the present study was to evaluate the bioequivalence between the Tretinoin 10 mg capsules of Ranbaxy Laboratories Limited and VESANOID® 10 mg capsules of Roche Pharmaceuticals Inc. It was a 2-way cross-over single dose study in 60 adult Indian male volunteers under fasting conditions. Since tretinoin is endogenously present in the human body, for baseline adjustment four pre-dose samples were collected. Plasma samples were analyzed for tretinoin by using validated liquid chromatographic mass spectrometry (LC-MS/MS) method. This method has separated both isomeric metabolites (i.e. isotretinoin and 9-oxo retinoic acid) from tretinoin to accurately measure the tretinoin concentrations in plasma for this study. The Mean ± SD of pharmacokinetic parameters Tmax, Cmax, and AUC0−t for tretinoin were 2.55 ± 0.84 and 2.40 ± 0.86 h, 34.29 ± 10.45 and 32.77 ± 9.16 ng/ml, 87.28 ± 30.99 and 80.81 ± 24.68 ng.h/ml, respectively, for test and reference. The ratios of least square means and its 90% confidence interval for Cmax, AUC0−t and AUC0–∞ on both baseline corrected and uncorrected data were found to be within 80–125%.","PeriodicalId":10446,"journal":{"name":"Clinical Research and Regulatory Affairs","volume":"23 9","pages":"68 - 73"},"PeriodicalIF":0.0,"publicationDate":"2011-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91426673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2011-08-25DOI: 10.3109/10601333.2011.597761
Navneeta Bansal
Technological advancements have made diagnostic assays very powerful and valuable tools for disease diagnosis. Diagnostic assays are used for a wide range of applications: diagnosis and prognosis of disease, identification of increased risk of developing certain disorders, and monitoring response to therapy. New diagnostic techniques allow us to format personalized medicine with pharmacogenetic assays such as drug metabolism assays to avoid adverse drug effects, companion diagnostics to identify patients who will respond to a specific drug, forensic assays, and histocompatibility assays. The molecular diagnostics market has become a significant segment of the in vitro diagnostics (IVD) industry. Worldwide sales of $2.5–2.8 billion in recent years for molecular diagnostic products to clinical laboratories, plus clinical laboratory testing service revenues of ~ $3.2 billion in the US alone in 2007, make molecular diagnostics a major market. The market for molecular diagnostics is growing rapidly (1). Moreover these diagnostic assays have made detection of many diseases faster and easier, which would otherwise take a long time for detection due to slow growth or difficulty in growing cultures (2). Such assays are often created by a clinical laboratory because commercial assays for the analyte(s) of interest may not be available or the analyte may be rare; the market for such products would be too small to be profitable. Since rapid and accurate analysis of a patient’s condition is an imperative part of clinical management, these laboratory diagnostic assays become the vital part of this process. All laboratories in the US that perform clinical testing on humans—excluding clinical trials and basic science research—are regulated by the Clinical Laboratory Improvement Amendments (CLIA) of 1988, which were extensively revised in 2003 (3, 4). The 2003 final rules require that laboratories do studies for Food and Drug Administration (FDA)-approved non-waived assays to verify performance specifications established by the manufacturer. The performance characteristics that must be verified include accuracy, precision, reportable range, and reference interval. Nonetheless, laboratory developed diagnostic assays require more extensive studies: accuracy, precision, reportable range, reference interval, analytical sensitivity and specificity, validation, verification of the assays at the time of assay development (5). While most FDA-waived assays are reviewed by CLIA, CLIA regulations stipulate that it is the responsibility of clinical laboratory directors to establish performance characteristics for laboratorydeveloped diagnostic assays used in their laboratories. The fact is, laboratories face many challenges in trying to accomplish this. Although laboratories determine the type of experiments that are required, including the acceptable number and type of specimens, and choose the statistical methods to evaluate the data for the performance of tests, the techn
{"title":"Regulation of laboratory-developed diagnostic assays: Where we are","authors":"Navneeta Bansal","doi":"10.3109/10601333.2011.597761","DOIUrl":"https://doi.org/10.3109/10601333.2011.597761","url":null,"abstract":"Technological advancements have made diagnostic assays very powerful and valuable tools for disease diagnosis. Diagnostic assays are used for a wide range of applications: diagnosis and prognosis of disease, identification of increased risk of developing certain disorders, and monitoring response to therapy. New diagnostic techniques allow us to format personalized medicine with pharmacogenetic assays such as drug metabolism assays to avoid adverse drug effects, companion diagnostics to identify patients who will respond to a specific drug, forensic assays, and histocompatibility assays. The molecular diagnostics market has become a significant segment of the in vitro diagnostics (IVD) industry. Worldwide sales of $2.5–2.8 billion in recent years for molecular diagnostic products to clinical laboratories, plus clinical laboratory testing service revenues of ~ $3.2 billion in the US alone in 2007, make molecular diagnostics a major market. The market for molecular diagnostics is growing rapidly (1). Moreover these diagnostic assays have made detection of many diseases faster and easier, which would otherwise take a long time for detection due to slow growth or difficulty in growing cultures (2). Such assays are often created by a clinical laboratory because commercial assays for the analyte(s) of interest may not be available or the analyte may be rare; the market for such products would be too small to be profitable. Since rapid and accurate analysis of a patient’s condition is an imperative part of clinical management, these laboratory diagnostic assays become the vital part of this process. All laboratories in the US that perform clinical testing on humans—excluding clinical trials and basic science research—are regulated by the Clinical Laboratory Improvement Amendments (CLIA) of 1988, which were extensively revised in 2003 (3, 4). The 2003 final rules require that laboratories do studies for Food and Drug Administration (FDA)-approved non-waived assays to verify performance specifications established by the manufacturer. The performance characteristics that must be verified include accuracy, precision, reportable range, and reference interval. Nonetheless, laboratory developed diagnostic assays require more extensive studies: accuracy, precision, reportable range, reference interval, analytical sensitivity and specificity, validation, verification of the assays at the time of assay development (5). While most FDA-waived assays are reviewed by CLIA, CLIA regulations stipulate that it is the responsibility of clinical laboratory directors to establish performance characteristics for laboratorydeveloped diagnostic assays used in their laboratories. The fact is, laboratories face many challenges in trying to accomplish this. Although laboratories determine the type of experiments that are required, including the acceptable number and type of specimens, and choose the statistical methods to evaluate the data for the performance of tests, the techn","PeriodicalId":10446,"journal":{"name":"Clinical Research and Regulatory Affairs","volume":"73 1","pages":"63 - 67"},"PeriodicalIF":0.0,"publicationDate":"2011-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86150876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2011-08-25DOI: 10.3109/10601333.2011.605368
Jean-Marc C. Haeusler
Post-approval research can provide critical information for clinical practice. However, quantitative evidence of its value is lacking. This study aimed to assess the impact of publications of post-approval studies on drug utilization. This was a retrospective analysis of US sales data of drugs approved in 2002/2003, compared with the timing of publications in Pubmed within 5 years of marketing. The primary outcome, dSAMP, was a surrogate measure for the impact on utilization, defined as the difference between the sums of SAMP (Sales Actuals Minus Predicted by linear regression) in the three quarters up to the publication and the three following quarters. Seven hundred and sixty-four publications of 15 products were included. Average dSAMP was US$ 14M (95% CI 7.3–20.7; p = 0.00005), with an increase in SAMP mainly in the second and third quarter after publication. dSAMP was negative for publications in years 0–2, neutral in years 2–4, and positive thereafter. Methodological rigor, geographic distribution, and positive or negative outcome only had limited impact on dSAMP. In conclusion, this was the first study demonstrating an impact of post-approval research on utilization of medicines. One published study led to a relative increase in average sales of US$ 14M. Further research is necessary to elucidate the link between utilization and societal value.
批准后的研究可以为临床实践提供关键信息。然而，缺乏量化证据来证明其价值。本研究旨在评估批准后研究发表对药物使用的影响。这是对2002/2003年批准的美国药品销售数据的回顾性分析，并与上市后5年内在Pubmed上发表的时间进行比较。主要结果dSAMP是对利用率影响的替代度量，定义为发布前三个季度和随后三个季度的SAMP(实际销售减去线性回归预测)总和之间的差异。共收录15种产品764种出版物。平均dSAMP为1400万美元(95% CI 7.3-20.7;p = 0.00005)， SAMP主要在发表后的第二和第三季度上升。dSAMP在0-2年为负，2-4年为中性，此后为正。方法的严谨性、地理分布和阳性或阴性结果对dSAMP的影响有限。总之，这是第一项证明批准后研究对药物利用影响的研究。一项已发表的研究导致平均销售额相对增加了1400万美元。有必要进一步研究以阐明利用与社会价值之间的联系。
{"title":"Retrospective analysis of the impact of post-approval drug research on utilization of new medicines in the US","authors":"Jean-Marc C. Haeusler","doi":"10.3109/10601333.2011.605368","DOIUrl":"https://doi.org/10.3109/10601333.2011.605368","url":null,"abstract":"Post-approval research can provide critical information for clinical practice. However, quantitative evidence of its value is lacking. This study aimed to assess the impact of publications of post-approval studies on drug utilization. This was a retrospective analysis of US sales data of drugs approved in 2002/2003, compared with the timing of publications in Pubmed within 5 years of marketing. The primary outcome, dSAMP, was a surrogate measure for the impact on utilization, defined as the difference between the sums of SAMP (Sales Actuals Minus Predicted by linear regression) in the three quarters up to the publication and the three following quarters. Seven hundred and sixty-four publications of 15 products were included. Average dSAMP was US$ 14M (95% CI 7.3–20.7; p = 0.00005), with an increase in SAMP mainly in the second and third quarter after publication. dSAMP was negative for publications in years 0–2, neutral in years 2–4, and positive thereafter. Methodological rigor, geographic distribution, and positive or negative outcome only had limited impact on dSAMP. In conclusion, this was the first study demonstrating an impact of post-approval research on utilization of medicines. One published study led to a relative increase in average sales of US$ 14M. Further research is necessary to elucidate the link between utilization and societal value.","PeriodicalId":10446,"journal":{"name":"Clinical Research and Regulatory Affairs","volume":"25 1","pages":"74 - 80"},"PeriodicalIF":0.0,"publicationDate":"2011-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74979658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2011-05-23DOI: 10.3109/10601333.2011.560154
Shiva Naga Vara Prasad Bathula, Vijayshekar Dustakar
Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disorder manifested by cognitive and memory deterioration, progressive impairment of activities of daily living, and a variety of neuropsychiatric symptoms and behavioral disturbances. This article discusses worldwide prevalence patterns, history, and summarizes hypotheses about the causes of AD. Currently available diagnostic methods, their effectiveness of, and problems with, different methods and recent advances are thoroughly discussed. Finally, current treatment strategies are discussed in light of the benefits and drawbacks of different therapeutic approaches along with ongoing drugs under development.
{"title":"Alzheimer’s disease: Recent advances in diagnosis and overview of clinical research in newer treatments","authors":"Shiva Naga Vara Prasad Bathula, Vijayshekar Dustakar","doi":"10.3109/10601333.2011.560154","DOIUrl":"https://doi.org/10.3109/10601333.2011.560154","url":null,"abstract":"Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disorder manifested by cognitive and memory deterioration, progressive impairment of activities of daily living, and a variety of neuropsychiatric symptoms and behavioral disturbances. This article discusses worldwide prevalence patterns, history, and summarizes hypotheses about the causes of AD. Currently available diagnostic methods, their effectiveness of, and problems with, different methods and recent advances are thoroughly discussed. Finally, current treatment strategies are discussed in light of the benefits and drawbacks of different therapeutic approaches along with ongoing drugs under development.","PeriodicalId":10446,"journal":{"name":"Clinical Research and Regulatory Affairs","volume":"20 1","pages":"34 - 37"},"PeriodicalIF":0.0,"publicationDate":"2011-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87425730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2011-05-23DOI: 10.3109/10601333.2010.551403
Vedavathi Thavva, V. Jayanti, Joseph Weinberg
Generic drugs play a very important role in health care. A study was undertaken to ascertain the equality or inequality between generics and branded generics. NSAIDs are the most commonly used drugs. So these drugs were chosen for the study. Selected branded generic and generic products of ibuprofen, nimesulide, and diclofenac sodium were tested by oral administration of their suspensions to different groups of rats. Freshly prepared drug suspensions equivalent to doses of 40, 10, and 5 mg/kg of ibuprofen, nimesulide, and diclofenac sodium, respectively, were administered orally to the rats and anti-inflammatory activity was measured by the carrageenan-induced rat paw edema model employing Zeitlin’s apparatus to measure the paw thickness. Statistical analysis by t-test, of the activity at the point of maximum difference indicated that with respect to anti-inflammatory activity generic ibuprofen and generic diclofenac sodium are better than branded generic ibuprofen and branded generic diclofenac sodium, respectively, and generic nimesulide is similar to branded generic nimesulide. All the products studied meet the Pharmacopoeial requirements. Hence it may be concluded that branded generic and generic NSAIDs, tested in this study, are of the same efficacy and inter-changeability among branded generics, and switching between branded generics and generics would not result in any difference in efficacy.
{"title":"Comparative study of anti-inflammatory activity of some branded generic and generic non-steroidal anti-inflammatory drugs","authors":"Vedavathi Thavva, V. Jayanti, Joseph Weinberg","doi":"10.3109/10601333.2010.551403","DOIUrl":"https://doi.org/10.3109/10601333.2010.551403","url":null,"abstract":"Generic drugs play a very important role in health care. A study was undertaken to ascertain the equality or inequality between generics and branded generics. NSAIDs are the most commonly used drugs. So these drugs were chosen for the study. Selected branded generic and generic products of ibuprofen, nimesulide, and diclofenac sodium were tested by oral administration of their suspensions to different groups of rats. Freshly prepared drug suspensions equivalent to doses of 40, 10, and 5 mg/kg of ibuprofen, nimesulide, and diclofenac sodium, respectively, were administered orally to the rats and anti-inflammatory activity was measured by the carrageenan-induced rat paw edema model employing Zeitlin’s apparatus to measure the paw thickness. Statistical analysis by t-test, of the activity at the point of maximum difference indicated that with respect to anti-inflammatory activity generic ibuprofen and generic diclofenac sodium are better than branded generic ibuprofen and branded generic diclofenac sodium, respectively, and generic nimesulide is similar to branded generic nimesulide. All the products studied meet the Pharmacopoeial requirements. Hence it may be concluded that branded generic and generic NSAIDs, tested in this study, are of the same efficacy and inter-changeability among branded generics, and switching between branded generics and generics would not result in any difference in efficacy.","PeriodicalId":10446,"journal":{"name":"Clinical Research and Regulatory Affairs","volume":"8 1","pages":"27 - 33"},"PeriodicalIF":0.0,"publicationDate":"2011-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74480813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2011-05-23DOI: 10.3109/10601333.2011.578139
M. Tomar, A. Patni, R. Arora, N. Thudi, V. Shrivastav, S. Iyer, A. Khuroo, Sachin Mehra, T. Monif
Ceftazidime is a third generation cephalosporin with a broad range of activity. Clavulanic acid is a β-lactamase inhibitor. A fixed dose combination, with the wide spectrum of action of ceftazidime and clavulanic acid’s high stability to β-lactamases has been developed by Ranbaxy Laboratories Limited (India). The present study was planned to predict any interaction between ceftazidime and clavulanic acid which could affect the safety and efficacy of the fixed dose combination. The study was an open label, balanced, randomized two-treatment, two-period, two-sequence, crossover, single-dose comparative pharmacokinetic study under fed conditions. A single intravenous injection of the test product containing a fixed dose combination of ceftazidime 2000 mg and potassium clavulanate 200 mg and the reference product containing ceftazidime 2000 mg only, was administered during each period. Serial blood samples were collected until 12 h post-dose in each period. Ceftazidime and clavulanic acid concentration in plasma were determined using two separate LC-MS/MS methods and then pharmacokinetic parameters were evaluated. No significant difference was seen in the mean Tmax, Cmax, AUC0–t, and AUC0–∞ when the drug was administered as ceftazidime alone and in combination with clavulanic acid. The Confidence Intervals for the log transformed parameters Cmax, AUC0–t and AUC0–∞ were within limits of 80–125% of ceftazidime for the test and reference products. The lack of significant difference between the pharmacokinetic parameters for ceftazidime alone and in the presence of clavulanic acid ruled out any significant interaction between ceftazidime and clavulanic acid.
{"title":"A pharmacokinetic drug interaction study of ceftazidime with clavulanic acid in healthy male Indian subjects","authors":"M. Tomar, A. Patni, R. Arora, N. Thudi, V. Shrivastav, S. Iyer, A. Khuroo, Sachin Mehra, T. Monif","doi":"10.3109/10601333.2011.578139","DOIUrl":"https://doi.org/10.3109/10601333.2011.578139","url":null,"abstract":"Ceftazidime is a third generation cephalosporin with a broad range of activity. Clavulanic acid is a β-lactamase inhibitor. A fixed dose combination, with the wide spectrum of action of ceftazidime and clavulanic acid’s high stability to β-lactamases has been developed by Ranbaxy Laboratories Limited (India). The present study was planned to predict any interaction between ceftazidime and clavulanic acid which could affect the safety and efficacy of the fixed dose combination. The study was an open label, balanced, randomized two-treatment, two-period, two-sequence, crossover, single-dose comparative pharmacokinetic study under fed conditions. A single intravenous injection of the test product containing a fixed dose combination of ceftazidime 2000 mg and potassium clavulanate 200 mg and the reference product containing ceftazidime 2000 mg only, was administered during each period. Serial blood samples were collected until 12 h post-dose in each period. Ceftazidime and clavulanic acid concentration in plasma were determined using two separate LC-MS/MS methods and then pharmacokinetic parameters were evaluated. No significant difference was seen in the mean Tmax, Cmax, AUC0–t, and AUC0–∞ when the drug was administered as ceftazidime alone and in combination with clavulanic acid. The Confidence Intervals for the log transformed parameters Cmax, AUC0–t and AUC0–∞ were within limits of 80–125% of ceftazidime for the test and reference products. The lack of significant difference between the pharmacokinetic parameters for ceftazidime alone and in the presence of clavulanic acid ruled out any significant interaction between ceftazidime and clavulanic acid.","PeriodicalId":10446,"journal":{"name":"Clinical Research and Regulatory Affairs","volume":"22 1","pages":"49 - 53"},"PeriodicalIF":0.0,"publicationDate":"2011-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88308991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2011-05-23DOI: 10.3109/10601333.2011.568492
E. B. Asafu-Adjaye, A. Carlin, E. Jefferson, A. Bryant, B. Rothman, M. A. Khan, P. Faustino
The stability of a 40 mg furosemide tablet drug product repackaged in a unit-dose USP class A blister pack and the identical product in its original container made of HDPE material was studied under ICH long-term conditions of 25°C and relative humidity (RH) of 60% and accelerated stressed conditions of 40°C and 75% RH. Samples from original and repackaged drug products were periodically removed from storage conditions and subjected to pharmaceutical and spectroscopic analysis. Results indicate the potency 91.5 ± 0.9% of the tablet strength for the original packaging drug product vs 91.6 ± 4.0% for the repackaged product are statistically similar for long-term and accelerated stress conditions. Tablet hardness (6.0 ± 0.3 KP) and loss on drying (3.2%) was the same for original and repackaged drug products under both stressed conditions indicating similar moisture sorption behavior. Non-invasive spectroscopic techniques did not show any differences in moisture content. Dissolution and TGA results were similar for all study samples. In conclusion, contrary to a previous FDA repackaging study for tablets with hygroscopic excipients, the product quality attributes of furosemide tablets formulated with low sorption excipients were not affected by repackaging, under the specific stress conditions of this study.
{"title":"Comparative stability study of unit-dose repackaged furosemide tablets","authors":"E. B. Asafu-Adjaye, A. Carlin, E. Jefferson, A. Bryant, B. Rothman, M. A. Khan, P. Faustino","doi":"10.3109/10601333.2011.568492","DOIUrl":"https://doi.org/10.3109/10601333.2011.568492","url":null,"abstract":"The stability of a 40 mg furosemide tablet drug product repackaged in a unit-dose USP class A blister pack and the identical product in its original container made of HDPE material was studied under ICH long-term conditions of 25°C and relative humidity (RH) of 60% and accelerated stressed conditions of 40°C and 75% RH. Samples from original and repackaged drug products were periodically removed from storage conditions and subjected to pharmaceutical and spectroscopic analysis. Results indicate the potency 91.5 ± 0.9% of the tablet strength for the original packaging drug product vs 91.6 ± 4.0% for the repackaged product are statistically similar for long-term and accelerated stress conditions. Tablet hardness (6.0 ± 0.3 KP) and loss on drying (3.2%) was the same for original and repackaged drug products under both stressed conditions indicating similar moisture sorption behavior. Non-invasive spectroscopic techniques did not show any differences in moisture content. Dissolution and TGA results were similar for all study samples. In conclusion, contrary to a previous FDA repackaging study for tablets with hygroscopic excipients, the product quality attributes of furosemide tablets formulated with low sorption excipients were not affected by repackaging, under the specific stress conditions of this study.","PeriodicalId":10446,"journal":{"name":"Clinical Research and Regulatory Affairs","volume":"24 1","pages":"38 - 48"},"PeriodicalIF":0.0,"publicationDate":"2011-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89752940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：