Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524129EnglishN-0001November30HealthcareSTUDY ON THE USE OF STATISTICAL TOOLS IN PHYSIOTHERAPY AND NURSING RESEARCHES - A
CROSS SECTIONAL SURVEY
English0312Jagatheesan Alagesan Anandbabu RamadassEnglishObjective: There is widespread evidence of the extensive use of statistical methods in medical research. Just the same, standards are generally low and a growing body of literature points to statistical errors in most medical researches. However, there is no comprehensive study contrasting the medical researches for recent practice in their use of statistics. This study is aimed to analyze the usage of statistical tools in post graduate physiotherapy and nursing researches.
Method & Result:
All ongoing post graduate physiotherapy and nursing dissertations from Dakshina Kannada district were screened for their statistical content. Types, frequencies, and complexity of applied statistical methods were systematically recorded and analyzed. There was inappropriate statistical tool selection in 44.6% of the dissertations out of the 148 screened researches and Statistical analysis was done manually in 65.6% of the researches.
Conclusion: As statistical errors seem to remain common in medical researches, closer attention to statistical methodology should be seriously considered to raise standards.
EnglishPhysiotherapy, Nursing, Postgraduate Dissertation, Statistical ToolsINTRODUCTION
Medical research requires usage of biostatistical, epidemiological and logical ways of thinking. Over the past decades, a great increase in the use of statistical methods has been documented for a wide range of medical journals.1,2,3 Favored by the availability of multifaceted statistical software packages, a trend toward the usage of more sophisticated techniques can be observed. Nevertheless there is also strong evidence that, in particular, simple methods such as t tests or chisquare tests remain in common usage.4,5,6,7,8,9 The use of statistics in medical journals has been subjected to considerable debate in recent years and there is wide consensus that standards are generally low, as a high proportion of published medical research contains statistical errors.10,11,12,13,14,15,16,17,18 The misuse of statistics in medical research has therefore been widely discussed, and it has been pointed out that it is both unethical and can have serious clinical consequences.19,20 As a result, there was respectable effort from many medical journals to enhance quality of statistics by adopting statistical guidelines and recommendations for authors or by sharpening the statistical review of incoming manuscripts.21,22,23,24,25,26 Nonetheless also very recent studies, although generally focused on specific statistical details, has statistical problems.17,18,27 Although the statistical content of several medical journals has been reviewed over the past decades.1,2,3,5,6,19,27 There is no comprehensive evaluation of statistical methods used in medical researches which are carried out as part of curriculum fulfillment like post graduate Physiotherapy and Nursing researches. Questions regarding statistical tools and their recent use therefore remain largely unanswered.
Background of the Study
Physiotherapy and nursing are booming medical fields for past two decades. Evidence based medicine which is described at length by Rosenberg and Donald28 as ?attempts to fill the chasm by helping doctors find the information that will ensure they can provide optimum management for their patients?. The practice of evidence based medicine seems to be able to halt the progressive deterioration in clinical performance that is otherwise routine and which continuing medical education cannot stop. In earlier eras, limitations in our understanding of human biology and the absence of powerful clinical research methods meant that major advances were far less commonly than now.
In India, Medical research is carried out by all post graduate students and most of the entry levels too to fulfill the curriculum requirement, but most of the universities focus mainly on the research methodology and adequate attention is not paid to bio-statistics. Hence this study focuses on the awareness of correct/ optimal usage of statistical tools by Physiotherapy and nursing post graduate students for their research work.
Purpose of the Study
The first aim of the study was to investigate and to compare the statistical methods used in post graduate Physiotherapy and Nursing research studies and to assess complexity of statistical analyses. The second was to evaluate the quantity and character of statistical use or misuse and statistical errors if any.
Scope of the study Result of the study will be helpful to understand the statistical knowledge of the medical students and it may be helpful to re-design the curriculum for the same. The results of the study will also allow for the ongoing monitoring of possible trends in statistics usage as well as for an up-to-date in-depth comparison between Physiotherapy and Nursing researches which are closely linked to modern statistics and basic medical researches.
METHODOLOGY
Research Design: Cross Sectional Survey
Source of Data: Postgraduate Physiotherapy and Nursing Colleges in Dakshina Kannada District
Inclusion Criteria All postgraduate dissertations of Physiotherapy and Nursing Students, studying in Dakshina Kannada district, Karnataka, done as part of their curriculum.
Exclusion Criteria Dissertations of Students who were not willing to consent for the study. Dissertations of Students without any statistical procedures in their study.
Sampling Technique & Sample Size All post graduate research studies that fulfills the inclusion criteria were selected for the study which counts to a total of 148 researches.
Data Collection Method Personal interview method by using questionnaire (vide Appendix-I) designed for this study and validated by post graduate physiotherapy and nursing research guides.
Analysis of Data The collected data were analyzed by using percentage values for the accuracy and correctness of tool selection and usage of software packages.
Ethical Committee Clearance Not applied for ethical clearance to any ethical committee since this survey does not involve any intervention on human or animals.
Collection of Data
The Primary data required for the present study, related to Physiotherapy and Nursing Researches like topic, nature of outcome measure and statistical tools used were collected by conducting personal interviews by using questionnaire (vide appendix-I) from post graduate physiotherapy and nursing students who are studying in Dakshina Kannada district and willing to provide their dissertation for the study by signing an informed consent form (vide appendix-II). There are ten post graduate physiotherapy and eleven post graduate nursing colleges in Dakshina Kannada District, Karnataka, India and all were included in the study. All ongoing post graduate physiotherapy and nursing researches during March 2009 and fulfilling the inclusion criteria from the above mentioned colleges were included in the study which counts to one hundred and forty eight out of which eighty one belongs to physiotherapy and sixty seven belongs to nursing.
DATA ANALYSIS
The total colleges included in the study were twenty one out of which ten were physiotherapy and the remaining eleven were nursing colleges. There were 97 on going physiotherapy researches out of which only 81 were selected for the study and 16 were excluded since no statistical tools were used. Out of 123 nursing researches only 67were included in the study and 56 were not included because 17 nursing post graduate students were not interested to participate in the study and remaining 39 were excluded since no statistical tools were used.
Comparison and Findings The data were analyzed from the physiotherapy and nursing researches in terms of usage of statistical packages and manual estimation, various levels of measurement tools and different statistical techniques used. The physiotherapy researches analyzed in the study includes 81 among which forty nine (60.49%) used manual calculations and remaining thirty two (39.51%) used statistical packages. The nursing researches are 67 among which forty eight (71.64%) used manual calculations and remaining nineteen (28.36%) used statistical packages. Table-1 shows the usage of statistical software packages and its percentage in Physiotherapy and Nursing researches. The level of measurement under Nominal, Ordinal, Interval and Ratio (NOIR) grading was analyzed between the physiotherapy and nursing researches. From the analysis, it is found that the ordinal scales were commonly used, the interval and ratio scales were least used in nursing researches. In behavioural sciences ordinal scales are most commonly used than any other levels, most of the nursing researches in this study were related to behaviour and 94% of the researches were using ordinal scales and it is 72.8% in physiotherapy researches. Table-2 shows the frequencies of level of measurement in Physiotherapy and Nursing researches with their percentages. The present study shows usage of nine different statistical tools for the analysis of data in physiotherapy researches and six different tools in nursing researches. The t-Test was most commonly used by both physiotherapy and nursing researches that is 58% and 55.2% respectively. Next are the Wilcoxon Signed Rank Test and Mann Whitney U Test with around 15% to 19% by both the Physiotherapy and Nursing researches. Correlational analysis and multi group researches were usually not preferred in nursing. The frequencies of usage of various statistical tools in physiotherapy and nursing researches were shown in table-3. The statistical tools used by all 148 researches were checked for the correctness of usage of appropriate statistical tools based on Siegel S29 and Reema Al-amoudi30 suggestions. It was found (Table-4) that in physiotherapy researches 35.8% of the tool selection was inappropriate and 55.2% of the tool selection was inappropriate in nursing researches. The commonly noticed error in all the researches was usage of t-test and Karl Pearson Correlation Coefficient analyses in ordinal and nominal level of measurements.
Findings
In the present study it was found that most of the physiotherapy and nursing researches were using t-test manually irrespective of level of scales, may be because it is ease to use. In the present study it was fount that 65.54% of the researches were done by manual statistical analysis and those using statistical software packages preferred only SPSS which might be due to its easy availability.
Suggestions from this study
The use of statistics in health science research may affect whether individuals live or die, whether their health is protected or jeopardized, and whether a health science advances or gets sidetracked. Therefore, all researchers, regardless of their training and occupation have a social and moral obligation to perform their work in a professional and ethical manner. The awareness about usage of statistical software packages are less with postgraduate medical students, which can be improved by modifying their curriculum. Knowledge about appropriate use of parametric and non-parametric statistical tools are less with post graduate medical students, which also needs modification of curriculum that focus on bio-statistics also. Research Guides should concentrate and help their students in selecting appropriate statistical tools.
Suggestions for future studies In future, studies can be conducted with inclusion of more health related thesis/
research from more colleges and/or universities, so that better comparisons and conclusions can be drawn.
CONCLUSION
The current practices regarding use of statistical tools in physiotherapy and nursing researches were reported in this study, the awareness about appropriate use of bio-statistical tools and usage of statistical packages are less with postgraduate physiotherapy and nursing students. As statistical errors seem to remain common in medical researches, closer attention to statistical methodology should be seriously considered to raise standards.
ACKNOWLEDGEMENTS
Authors express their thanks to the Principals of all Post graduate Physiotherapy and Nursing colleges in DK District for providing permission to conduct the survey and all the post graduate Physiotherapy and Nursing students for participating in the survey.
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Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524129EnglishN-0001November30HealthcareCHARACTERIZATION OF CYTOTHERAPEUTIC POTENTIAL OF SUBPOPULATION VERSUS
STEMCELLS FROM BONE MARROW
English1322Dhanasekaran MarappagoundarEnglish Indumathi SomasundaramEnglish Sowndarya sampathEnglish Baskaran MayakesavanEnglish Rajkumar SankaranEnglish Sudarsanam DorairajEnglishResearch on adult stem cells has been a great deal of excitement. The candidate stem
cells present in the adult tissues are the hematopoietic and mesenchymal stem cells.
However, there exist other heterogenous cell such as side population (SP) and
endothelial progenitors (EP) that has the properties of repair and regeneration. Much
work pertaining to these subpopulations is at its infancy and more research in clinical
practice is of utmost important. Thus, the objective of this work is to find out whether
subpopulations exist in bone marrow in higher percentage and play a vital role in tissue
repair and regeneration. To test this hypothesis, we characterized stem cell populations
versus subpopulations including EP cells and SP cells from Bone Marrow samples (n =
5). Surprisingly, we found that the mean of Endoglin CD105+ CD34-, CD105+ CD90 -
for EP cells was found to be 41.68% and 35.88% respectively. The mean of ABCG2+
and CD117+ SP cells was found to be 3.58% and 4.34%. These results confirm the
hypothesis and emphasize on the fact that migration at the site of injury in vivo and
recovery not only depends on the candidate stem cells but also require the heterogenous
subpopulation cells to regulate the candidate stem cells because of the wide plasticity
and common precursor called hemangioblast. Thus, we conclude that the
subpopulations of especially ABCG2 + and CD105+ found to be a potent source of
repair mechanism and hence need to be more focused on research.
EnglishHematopoietic Stem cells, Mesenchymal stem cells, ABCG2+ Side population cells, Endoglin, Fluorescent Activated Cell Sorter.INTRODUCTION
The therapy through cell transplant has been developed based on the adult multipotent stem cell that is becoming, consequently, an important scientific subject.1 It has already been proved that most promising stem cell source in clinical practice is represented by bone marrow with more focus on candidate stem cells especially HSC and MSC.1 However, recent development in stem cell biology has demonstrated the presence of sub population cells,
especially side population (SP) cells and endothelial progenitor (EP) cells along with stem cells which is said to possess the properties of repair and regeneration.2, 3, 4 Side population cells were first identified as a subpopulation of very primitive CD 34- negative hematopoietic stem cells (HSCs) with long term hematopoietic repopulation activity, which was characterized by their capacity to efflux Hoechst 33342 and was acquired by the expression of the ATP-binding cassette transporters such as Bcrp 1 / ABCG2.3, 5 This has been identified to produce a characteristic SP profile on basis of FACS analysis, regardless of tissue origin. Isolation of SP cells by the Hodye and FACS technique has been reported in Muscular tissue6 , Liver7 , Lung8 , Skin9 , uterus10, Testis11 , Cornea12 and Bone marrow13 . Apart from the side population cells, important subpopulation cells found to possess repair mechanism and neovascularization is Endothelial Progenitor cells that circulate in adult tissues.14 According to the initial discoveries, EPC are defined as cell positive for both hematopoietic stem cell marker such as CD34+ and an endothelial marker protein VEGFR2 as this endothelial progenitor cells have consequently been considered to device from a common precursors putatively termed a hemangioblast.15 Asahara and colleagues published that purified CD 34+ hematopoietic progenitor cells from adults can differentiate ex vivo to an endothelial phenotype.16 Much work does not exist on cell surface characterization and importance of EP cells and SP cell in Bone Marrow. Moreover, focus on homogenous candidate stem cells by sorting of CD 34+ HSC by FACS17, lineage depletion by MACS18, 19 and expansion of MSC in culture20 gained importance in cell therapy.
Hence, we speculated that heterogenous subpopulation cells play a vital role in repair mechanism and faster engraftment by regulating stem cell population of Bone marrow and not homogenous stem cells like HSC and MSC alone possess cytotherapeutic potential. To test this speculated hypothesis we analyzed the percentage of subpopulation cells especially CD 105+ Endothelial cells and CD117+ABCG2+ side population from Bone marrow ( n= 5) mononuclear cells in comparison with CD34+ HSC and CD90+ MSC using FACS. The results demonstrated in this study provide evidence for our speculation. However, further research is required to address our speculations to make bone marrow mononuclear cell therapy successful.
MATERIALS AND METHODS
Reagents used: The following antibodies conjugated with corresponding flurochromes (CD34-PE; Cat No: 348057, CD117- PE-Cy7; Cat No: 339195, CD-90-PERCP-Cy5; Cat No: 555597, Cell viability dye 7-AAD; Cat No: 555816) were purchased from BD Biosciences, (http://www.bd.com/). CD105-APC; Cat No: 17-1057 and ABCG2-PE; Cat No: 12-8888 were purchased from eBioscience, (www.ebioscience.com).
Ficoll Paque Plus; Cat No: 07917 were purchased from stem cell technologies, (www.stemcell.com). Phosphate Buffer Saline (PBS); Cat No: TL1032 were purchased from Himedia.
Bone marrow collection:
Human Bone marrow samples were obtained from the iliac crest of 5 patients with spinal cord injury – paraplegia who was aged between 25 – 40 years and who had applied for a stem cell transplantation procedure after the approval of Institutional ethics committee. Formal written consent from the donors was obtained before collection. About 10 ml of BM aspirate were collected in a syringe containing heparin to prevent coagulation.
Isolation procedure:
The bone marrow sample was diluted 1:2 with 1 X Phosphate Buffer Saline (PBS) and carefully layered on to Ficoll Paque (1.077g/mL) slowly along the sides of the tube at 45° angle to isolate Bone marrow Mononuclear cells (MNCs). The MNCs were isolated by density gradient centrifugation (400g, 30 minutes, room temperature). Further, cells were washed twice with PBS (450g, 10 minutes, room temperature) to remove residual Ficoll and other contaminants. The pellet was resuspended with RBC lysis buffer solution for 10 minutes and immediately treated with 0.9% cold NaCl to stop the lysis reaction and centrifuged (300g, 5 minutes, 4º C). Cell viability was determined using the Trypan blue dye exclusion method using hemocytometry. The mononuclear cells were characterized for various hematopoietic, mesenchymal and subpopulation cells with its surface markers using flowcytometry.
Flowcytometric protocol for
characterization:
Flow cytometry was performed on a Becton, Dickinson FACS Aria (http://www.bd.com/) using a 488-nm argon-ion LASER and 632nm red LASER for excitation; fluorescence emission was collected using its corresponding detectors. 1X106 cells were stained with appropriate amount of conjugated antibodies in each of 12X75 mm falcon polystyrene FACS tube, BD Bioscience; Cat No: 352054. The quantity of each antibody conjugated with fluorochromes added to the cells in each tube were 20μl of CD34-PE, 5μl of CD90- PER CP CY5, 20μl of CD 105-APC, 5μl of CD117-PE CY7, 20μl of ABCG2-PE, 20μl of 7- AAD (BD Via probe), respectively. All tubes were incubated for 20 minutes in dark. After incubation, cells were washed in phosphate buffer saline to remove the unbound antibodies. The pellet was further resuspended to 500μl. Data analysis and acquisition was then performed using DIVA Software, Becton Dickinson. Flow cytometer instruments were set using unstained cells. Cells were gated by forward versus side scatter to eliminate debris. The number of cells staining positive for a given marker was determined by the percentage of cells present within a gate established. A minimum of 10 000 events was characterized and recorde
DISCUSSION
It has already been proved that Bone marrow is the promising source of stem cell therapy with presence of HSC and MSC2 . The Efficiency of the processed mononuclear cell from Bone marrow is of utmost importance before cellular characterization or cellular transplant. Thus in our study to confirm whether processed Bone marrow MNC (n=5) are devoid of contaminants and is highly efficient for further research and therapy, we performed a differential count analysis before and after MNC processing (Figure 1, Table 1). Though granulocytes live only ~10hrs in circulation, there exist many complications of granulocyte interface with MNC. It might even disrupt the stem cells from further engraftment. Hence, we emphasize on the fact that this must be an essential step for any researcher working on MNC isolation for cell transplant or research to yield better and efficient result. Recently, focus on homogenous candidate stem cells by sorting of CD 34+ HSC by FACS17, 18 , lineage depletion by MACS19 and expansion of MSC in culture20, 21 has gained importance in research for cellular transplant than mononuclear cell (MNC) therapy. However, homogenous HSC population or MSC from Bone marrow has a vast disadvantage. MSC decreases as age increases22 and phenotypic variations exist in each MSC population from various sources.23 Likewise, pure HSC population exhibit less percentage and are not plastic as well compared to heterogenous MNC.24 Moreover, by isolating or sorting pure HSC/MSC population for transplant, faster engraftment and recovery might not be fully satisfied. Existing evidence suggests that EP cells of CD34+CD133+Flk+ possess efficient repair mechanism of neovascularization in Ischemia.4, 14, 15 Much work on EP cell plasticity is not widely studied and CD 105+ Endoglin which is said to be putative EP cell population is also not much focused in research. Likewise, Presence of side population cells has been shown in many adult tissues and the SP phenotype might be represented as a common molecular regulatory feature for a wide variety of stem cells.5 However, importance of CD117+ABCG2+ SP cell research exists much only on tumor cell not in bone marrow cells.25, 26 Thus we speculated that Bone marrow, being heterogenous, not only contain HSC/MSC but also subpopulation especially EP & SP cells which serves to be an effective repair mechanism. To confirm our speculated hypothesis, in our experiment, we analyzed the percentage of subpopulation cells especially CD 105+ EP cells and CD117+ABCG2+ SP cells from Bone marrow ( n= 5) mononuclear cells in comparison with CD34+ HSC and CD90+ MSC using FACS. The results demonstrated in this study provide evidence for our speculation. We found that Bone marrow MNC contain more percentage of CD 105+ EP cells compared to CD105+ cells obtained from other research works of Takayuki Asahara et al16. We also found that CD105+ EP cell percentage is found to be much higher compared to CD34+CD133+ EP cells obtained from Carmen Urbich et al, 2006 and Mihali Hristov et al, 20034, 14. Similarly, several researchers have demonstrated that the percentage of SP cells from bone marrow ranges between 0.01- 3.0 %.3,5 In contrast to the existing data, the percentage of ABCG2+CD117+ SP cells in our results from all 5 samples was found to be much higher (Figure 3& Bar diagram 2). Moreover, the percentage of CD105+ and CD117+ABCG2+ from bone marrow is found to be higher than the percentage obtained from stromal vascular fraction of subcutaneous and omentum fat tissue from our previous research work.27 This confirms that the Subpopulation cells are exhibited in higher percentage in bone marrow compared to adipose tissue. Finally it is evident from our research work that the migration at the site of injury and recovery in vivo not only depends on the candidate stem cells ( HSC and MSC) but also require the heterogenous subpopulation (EP and SP) cells to regulate the candidate stem cells. Thus, we emphasize that Bone marrow mononuclear cells are the best source of clinical transplants unlike homogenous HSC and MSC population because of the vast heterogeneity and plasticity. However, further research on these subpopulation cells will bring this work closer to clinical applications.
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27. Dhanasekaran Marappagoundar, Indumathi Somasundaram et al. Characterization of Hematopoietic stem cells, mesenchymal stem cells and side population cells from adipose tissue. International Journal of Biology 2010; 2(1): 71-78.
Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524129EnglishN-0001November30HealthcareDEVELOPMENT OF ULTRAVIOLET SPECTROPHOTOMETRIC METHOD FOR DETERMINATION OF DICLOFENAC SODIUM IN STRATUM CORNEUM BY TAPE STRIPPING METHOD
English2328V. A. ArsulEnglish R. MayeeEnglish S. A. BhaleEnglishThe release of Diclofenac sodium from transdermal gels was studied using the skin stripping method. The tape stripping method in its standardized form is well-suited to determine the dermatopharmacokinetics of topically applied substances. The tape strips contain the amount of corneocytes and the corresponding amount of the penetrated Diclofenac sodium formulation, which was determined by UV spectroscopic method. Simple, rapid, sensitive and accurate UV- Spectrophotometric methods have been developed for estimation of Diclofenac Sodium in stratum corneum. Diclofenac sodium exhibited distinct λmax in methanol at 285nm. Linearity was observed in the concentration range 2-24 μg/ml. (r2 =0.9845). Amounts of drug estimated from gel formulation applied on skin and recovered through tape stripping method were in good agreement with label claim. The UV spectroscopic method was validated statistically and by recovery studies. The proposed methods are economical and sensitive for the estimation of Diclofenac sodium present in stratum corneum, when applied topically.
EnglishDiclofenac sodium, Method validation, Recovery study, Tape strippingINTRODUCTION
Diclofenac Sodium is chemically Sodium 2-[(2,6-dichlorophenyl)- amino]phenylacetate. It is Non-steroidal anti-inflammatory drug (NSAID) taken to reduce inflammation and as an analgesic reducing pain in conditions such as arthritis or acute injury1 .
nbutylammonium hydroxide (Cakirer et al., 1999), Spectrofluorimetry using europium (III) as a fluorescent probe (Carreria et al, 1995), Gas and Liquid chromatography in biological fluids (De-Jong et al, 1989). Literature survey revealed the availability of method of estimation of drugs by skin stripping method2 . But a quantitative determination method of diclofenac sodium for studying the bioequivalence of transdermal gel preparations of this drug was not validated. The aim of present investigation is to develop simple, rapid and cost effective analytical method for diclofenac sodium containing gel formulation and its validation.
MATERIALS AND METHOD
Instruments
A Shimadzu UV-Visible Spectrophotometer (UV-1700) with a matched pair of 10 mm quartz cells were used for this experiment.
Materials
Diclofenac sodium was procured as gift sample from Torrent Research Centre, Ahmadabad. The obtained Diclofenac sodium was dissolved in methanol for experimental purpose. The commercially available marketed gel formulation containing Diclofenac sodium, 2% w/w in gel was used for estimation.
Preparation of Standard Stock Solution
The standard stock solution was prepared by dissolving 0.2gm Diclofenac sodium in 200ml methanol to make final concentration of 100μg/ml. Different aliquots were taken from stock solution and diluted with methanol separately to prepare series of concentrations from 2-24 μg/ml. The λ max for Diclofenac sodium in methanol was found to be 285 nm. The calibration curve was prepared by plotting absorbance versus concentration of Diclofenac sodium3 .
Method
The proposed procedure was adopted for determination of Diclofenac sodium in following manner. The Diclofenac diethylamine gel containing 2% diclofenac sodium was applied on the skin. The release of Diclofenac sodium from transdermal gels was studied using the skin stripping method. Tape stripping is a simple and efficient method for the assessment of quality and efficacy of cosmetical and dermatological formulations. The tape stripping method in its standardized form is well-suited to determine the dermatopharmacokinetics of topically applied substances. After topical application and penetration of Diclofenac sodium formulations, the cell layers of the stratum corneum are successively removed from the same skin area using adhesive films4 . The tape strips contain the amount of corneocytes and the corresponding amount of the penetrated Diclofenac sodium formulation, which can be determined by UV spectroscopic method. Shake these tape strips with 60 ml of methanol in a 200-ml volumetric flask and dilute to volume with methanol. From this solution, suitable aliquots were prepared, then these dilutions were scanned in UV region and absorbances were noted at 285 nm and concentration was determined by linear regression equation5 .
RESULTS AND DISCUSSION
The method was validated by studying the following parameters as International Conference on Harmonization guide lines (ICH guide lines 1995) for method validation6.
Linearity
The linearity of the response of the drug was verified at 2 to 100 μg/ml concentrations, but linearity was found to be between 2-24 μg/ml concentrations. The calibration graphs were obtained by plotting the absorbance versus the concentration data and were treated by linear regression analysis. The equation of the calibration curve for Diclofenac sodium obtained y = 0.0048x - 0.0006, the calibration curve was found to be linear in the aforementioned concentrations. The correlation coefficient (r2 ) of determination was R² = 0.9845(Table 1, 2)
Precision
Assay of method precision (intraday precision) was evaluated by carrying out six independent assays of test samples of Diclofenac sodium. The intermediate precision (interday precision) of the method was also evaluated using two different analysts, systems and different days in the same laboratory. The relative standard deviation (RSD) and assay values obtained by two analysts were 0.36, 99.50 and 0.31, 99.60 respectively. (Table 3)
Accuracy (Recovery test)
Accuracy of the method was studied by recovery experiments. The recovery experiments were performed by adding known amounts of the drug in the placebo. The recovery was performed at two levels, 50 and 100% of Diclofenac sodium standard concentration. The recovery samples were prepared in before mentioned procedure. Three samples were prepared for each recovery level. The solutions were then analyzed, and the percentage recoveries were calculated from the calibration curve. The recovery values for Diclofenac sodium ranged from 99.7 to 101.5%. The result of analysis for the recovery studies were as presented in Tables 4 and 5. The percentage recovery value indicates that there was no interference from the excipients present in the formulation. The developed method is found to be sensitive, accurate, precise and most reproducible.
CONCLUSION
A method for the determination of Diclofenac sodium in the gel formulation which is obtained by tape stripping method has been developed. A good linear relationship (r2 =0.9845) was observed between the concentration ranges of 2-24 μg/mL. The assay of Diclofenac sodium was found to be 99.50%. The high percentage recovery indicates the high accuracy of the method. This demonstrates that the developed spectroscopic method is simple, accurate and reproducible. Thus the developed method can be easily used for the routine quality control of Diclofenac sodium in stratum corneum by tape stripping method.
ACKNOWLEDGEMENTS
The authors’ thanks to Torrent Research Centre, Ahmadabad for providing the diclofenac sodium standard and gel formulation. The authors would like to acknowledge Principal, Dr. Vedprakash patil Pharmacy College, Aurangabad, India for providing facilities for conducting this research.
Englishhttp://ijcrr.com/abstract.php?article_id=2218http://ijcrr.com/article_html.php?did=22181. United States Pharmacopoeia, USP 24/NF 19, US Pharmacopoeial Convention Inc2000, USA, pp.2149- 2152.
2. U.V.Sera, M.V.Ramana, In vitro skin absorption and drug release – a comparison of four commercial hydrophilic gel preparations for topical use. The Indian Pharmacist, 2006, 73, 356-360
3. Agrawal YK and Shivramchandra K, Spectrophotometric determination of diclofenac sodium in tablets. J. Pharm. Biomed. Anal. 1991, 9: 97- 100.
4. Knudsen, EA. Isolation of dermatophytes from foot wear with adhesive tape strips. J, of Medical and veterinary Mycology 1986, 25; 59-61
5. Flynn, G.L., Shah, V.P., Tenjarla, S.N., et al., Assessment of value and applications of in vitro testing of topical dermatological drug products. Pharm. Res. 1999, 16, 1325–1330.
6. ICH-Q2R1, Validation of Analytical Procedures: Methodology International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use 1996, Geneva, Switzerland.
Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524129EnglishN-0001November30HealthcarePHYSIOTHERAPY MANAGEMENT OF PAINFUL DIABETIC PERIPHERAL NEUROPATHY: A CRITICAL REVIEW OF TREATMENT METHODS FOR CLINICAL DECISION MAKING IN PRACTICE AND RESEARCH
English2939Senthil P KumarEnglish Prabha AdhikariEnglish PS JeganathanEnglishSydney C D'SouzaEnglishObjective: Diabetes is a global epidemic and one of the most leading complications of
diabetes is peripheral neuropathy. Recent research and clinical practice focus is on
symptomatic or painful diabetic peripheral neuropathy (PDPN). The objective of this
paper was to review the physiotherapy management methods for symptomatic
management in PDPN patients.
Methods:
The therapeutic modalities reported in MEDLINE, EMBASE, SCOPUS,
Ovid, CINAHL and Google Scholar were searched independently and 29 suitable trials
were identified and reviewed. The selected studies were grouped under each treatment
method and were described under exercise therapy, electrotherapy, actinotherapy and
manual therapy in the review.
Results: The physiotherapy management of PDPN patients includes transcutaneous
electrical nerve stimulation, pulsed electromagnetic energy, frequency-modulated
electromagnetic neural stimulation, electrical stimulation, photon stimulation,
monochromatic near-infrared (anodyne) light therapy, static magnetic fields, and
acupuncture. One study studied combined efficacy of electrotherapy with
pharmacotherapy in PDPN patients.
Conclusion: The review findings would facilitate clinicians, researchers and
stakeholders to understand the established physiotherapy treatment options for
symptomatic management of patients with painful diabetic peripheral neuropathy, and
also rehabilitation clinicians and therapists to develop better treatment methods in the
future.
Englishphysiotherapy, diabetic neuropathy, neuropathic pain, rehabilitation.INTRODUCTION
Diabetic peripheral neuropathy (DPN) is a common complication estimated to affect 30% to 50% of individuals with diabetes. Chronic sensorimotor distal symmetric polyneuropathy is the most common form of DPN. The prevalence of neuropathy in type 2 diabetes ranges from 27% to 63% and from 14% to 70% in diabetes mellitus in general.4 The first description of ?diabetic neuropathy as a presence of pain and paresthesiae in lower limbs? was done by Rollo in 1798.7 The consensus of opinion at the San Antonio conference on diabetic neuropathy was that diabetic neuropathy was "a descriptive term meaning a demonstrable disorder, either clinically evident or subclinical that occurs in a setting of diabetes mellitus without other causes of neuropathy. The neuropathic disorder includes manifestations in both somatic and/or autonomic parts of the nervous system.? Diabetic peripheral neuropathic pain (DPNP) affects approximately 11% of patients with diabetic peripheral neuropathy (DPN). The most common type of neuropathy in DM is DPN, with up to 50% of patients experiencing some degree of painful symptoms and 10% to 20% having symptoms severe enough to warrant treatment. World Confederation for Physical Therapy (WCPT) defines Physical Therapy as; ?… providing services to people and populations to develop, maintain and restore maximum movement and functional ability throughout the lifespan. Physiotherapy includes the provision of services in circumstances where movement and function are threatened by the process of ageing or that of injury or disease. Full and functional movement are at the heart of what it means to be healthy …Physiotherapy is concerned with identifying and maximising movement potential, within the spheres of promotion, prevention, treatment and rehabilitation. Physiotherapy involves the interaction between physiotherapist, patients or clients, families and care givers, in a process of assessing movement potential and in establishing agreed upon goals and objectives using knowledge and skills unique to physiotherapists.? (Kumar, 2010).9 Physiotherapy for neuropathic pain in symptomatic patients with painful diabetic peripheral neuropathy (PDPN) include: modalities for pain relief like electrotherapy, actinotherapy, exercise therapy and manual therapy (Kumar and Jim, 2010).10 While electrotherapy includes electrical and thermal modalities, actinotherapy includes radiation modalities.11 The aim of this systematic review was to identify and summarize the existing evidence on physiotherapy management in patients with PDPN through published studies to establish an evidence-informed clinical decisionmaking for clinical practice and research.
MATERIALS AND METHODS
Independent search was carried out by testers using a well-defined search strategy as follows; we searched the MEDLINE, EMBASE, SCOPUS, Ovid, CINAHL and Google Scholar databases using the key terms- pain AND diabetic AND neuropathy; management OR treatment OR physiotherapy OR rehabilitation; IN title OR abstract. A total of 242 studies were potentially identified by the authors. Studies published in English language on effectiveness, efficacy, effects of physiotherapy treatment methods was included in our review; and studies on pharmacotherapy (118 studies); comparison of drugs (36 studies) or combined drug therapy (28 studies) with other treatments (32 studies) were excluded. A total of 29 studies were finally identified that were published from 1954 to 2010 and then considered for review. To avoid search bias, the testers performed independent searches and then disagreements were solved by consensus at various stages of the study.
Main findings of the review
The 29 included studies were grouped under nine treatment methods studied for their effectiveness in PDPN patient population which are descriptively reported below using a qualitative approach;
Electrotherapy
Pieber et al12 in their MEDLINE search, reviewed 15 studies where the beneficial effects of prolonged use of transcutaneous electrical nerve stimulation was consistently shown in four studies. The effects of other modalities studied were insufficient enough to draw conclusions and/or recommendations.
Transcutaneous Electrical Nerve Stimulation- TENS:
One systematic review by Dubinsky and Miyasaki13 and one meta-analysis by Jin et al14 both concluded TENS therapy might be an effective and safe strategy in treatment of symptomatic DPN.
Two controlled clinical trials by Forst et al15 and Kumar and Marshall16 suggested TENS as a novel treatment modality for reducing pain and discomfort in patients with PDPN. One quasi-experimental study by Moharic and Burger17 inferred that TENS did not alter C, A-delta nor Abeta fibre-mediated perception thresholds. One case report by Somers and Somers18 presented a PDPN patient who was treated successfully by application of TENS to the low back region.
High frequency external muscle stimulation
Reichstein et al19 performed a pilot randomized controlled trial to compare the effects of high-frequency external muscle stimulation (HFEMS) with those of TENS in patients with symptomatic PDPN and found that HFEMS was more effective than TENS in relieving the symptoms of nonpainful neuropathy and painful neuropathy.
Pulsed electrical stimulation
Oyibo et al20 assessed the efficacy of pulsed-dose electrical stimulation (through stocking electrodes) in the treatment of 30 patients with painful diabetic neuropathy versus the control group and the authors found no evidence from their results that this treatment is more effective than control in the treatment of painful diabetic neuropathy.
Weight-bearing (walking) exercise intervention
LeMaster et al21 studied 79 patients with DM + PN who were randomly assigned to receive intervention components included leg strengthening and balance exercises; a graduated, selfmonitored walking program (part 1); and motivational telephone calls every 2 weeks (part 2). Both groups received diabetic foot care education, regular foot care, and 8 sessions with a physical therapist. The authors found that promoting weight-bearing activity did not lead to significant increases in foot ulcers and they suggested that weightbearing activity could be considered following adequate assessment and counseling of patients with DM + PN.
Vibrating insoles
Hijmans et al22 investigated the effects on standing balance of random vibrations applied to the plantar side of the feet by vibrating insoles in subjects with neuropathy and nondisabled subjects. In subjects with neuropathy, an interaction effect was found between vibration and an ADT for balance. No effects of vibration on balance were found in nondisabled subjects. The authors also found that vibrating insoles improved standing balance in subjects with neuropathy only when attention was distracted.
Plantar orthoses
Mohamed et al23 determined the effect of Plastazote® and Aliplast®/Plastazote® orthoses in decreasing plantar pressures. One group wore custom Plastazote orthoses, the other, custom Aliplast/Plastazote orthoses, for 3 months. The authors found that wearing custom-made orthoses reduced plantar pressures by increasing contact area. Plastazote alone and Aliplast/Plastazote were equally effective in decreasing pressures at time of fabrication, at 1 month after 9 of 16 pairs of orthoses were adjusted for wear, and after orthoses wear for an additional 2 months.
Frequency-modulated electromagnetic neural stimulation
Bosi et al24 evaluated the efficacy of frequency-modulated electromagnetic neural stimulation (FREMS) on 31 patients with painful neuropathy in a randomised, double-blind, crossover study designed to compare the effects of FREMS with those of placebo. Furthermore, FREMS induced a significant increase in sensory tactile perception, as assessed by monofilament; a decrease in foot vibration perception threshold, as measured by a biothesiometer; and an increase in motor nerve conduction velocity. No significant changes were observed after placebo.
Photon stimulation
Swislocki et al25 evaluated the effects of photon stimulation on pain intensity, pain relief, pain qualities, sensation and quality of life (QOL) in patients with painful diabetic peripheral neuropathy in their randomized, placebo-controlled trial. The authors did not find any differences in favor of the photon stimulation group in immediate posttreatment but significant decreases,
over time, were found in some pain quality scores, and significant improvements in sensation were found in patients who received the photon stimulation compared with placebo.
Monochromatic near Infrared (Anodyne) light therapy
Three controlled clinical trials by Leonard et al26, Lavery et al27 and Clifft et al28 determined the effect of monochromatic infrared energy (MIRE) in subjects with diabetic peripheral neuropathy and all the authors found that MIRE therapy was useful in subjects with diabetic peripheral neuropathy. Li et al29 performed a systematic review in MedLine, CINAHL, Cochrane Databases, and Physical Therapy on the efficacy of the anodyne therapy system (ATS) for treating patients with diabetic peripheral neuropathy. The results indicated efficacy for improving lower extremity sensation, balance, gait and decreasing fall risk, particularly if subjects have a relatively recent diabetic peripheral neuropathy onset (short duration). DeLellis et al30 examined the medical records of 1,047 patients with established peripheral neuropathy and showed that MIRE therapy was associated with significant clinical improvement in foot sensation in patients, with diabetic peripheral neuropathy. Two quasi-experimental studies by Kochman et al31 and Kochman32 examined the effectiveness of MIRE therapy and they prove it to be effective.
Static magnetic field therapy
Weintraub et al33 did a large multicenter trial of 375 PDPN patients in a randomized, placebo-controlled parallel-group study where the patients were given either multipolar static magnetic (450G) shoe insoles or unmagentized placebo insoles for 4 months. The authors reported statistically significant changes in pain scores, and improvements were also noted in nerve conduction studies and quantitative sensory testing measures. Best analgesic benefits were observed at 3rd and 4th month duration in the active group compared to the placebo.
Percutaneous electrical nerve stimulation (PENS)
Hamz et al34 evaluated 50 patients with PDPN who were randomly assigned to receive active PENS (needles with electrical stimulation at an alternating frequency of 15 and 30 Hz) and sham (needles only) treatments for 3 weeks. The authors concluded that PENS was a useful non-pharmacological therapeutic modality for treating diabetic neuropathic pain.
Low-Level Laser Therapy
Zinman et al35 conducted a randomized double-blind sham-controlled clinical trial of low intensity laser therapy (LLLT) in 50 patients. After a 4-weeks intervention, the LLLT group had statistically insignificant changes in self-reported pain and had no effects on Toronto clinical neuropathy score, nerve conduction studies, sympathetic skin response or quantitative sensory testing.
Massage therapy
Finch et al36 reported immediate effects of 80 min of single-session of massage therapy to lower limbs on plantar foot pressure variability, and foot contact time in their one patient with PDPN. The treatment involved myofascial techniques, passive stretching, trigger point treatment and mobilization of the joints of the lower limb distal to the knee. Additionally, preparatory hydrotherapy was also applied. The massage therapy intervention utilized by the authors increased the variability of pressure below the hallux of a participant with diabetic neuropathy, and also affected gait positively in terms of velocity and fluidity.
Acupuncture
Though acupuncture is a part of Chinese Medicine, two trials, one by Abuaisha et al 37 and other by Ahn et al38 both found therapy to be effective.
Pulsed electromagnetic field therapy
Graak et al39 carried out a study to evaluate the effects of low-power, lowfrequency pulsed electromagnetic field (PEMF) of two doses- 600 and 800 Hz on 30 subjects for 30 min for 12 consecutive days versus a control group of standard medical care and they found significant improvements in pain and motor nerve conduction parameters and the authors concluded that PEMF could be used as an adjunct in reducing neuropathic pain as well as retarding the progression of neuropathy in a short span of time.
Combined electrotherapy and drug therapy
Kumar et al40 evaluated the efficacy of combining TENS with amitriptyline in their PDPN patients and they found it to be effective than individual treatment with the drug.
DISCUSSION
This review was a clinically and scientifically applicable of its kind for use both by clinicians and researchers involved with patients of painful diabetic peripheral neuropathy. Some of the potential limitations of this review were the lack of meta-analysis and quality scoring of the included studies. We included studies of all designs leading to heterogeneity not only in interventions, outcome assessment and follow-up, but also in analysis and effect size. We also reviewed only studies in English and this might have missed some other important studies. Though a large volume of literature on management of PDPN patients is on pharmacotherapy41, future research could be on developing a comprehensive management involving other treatment methods as effective adjuncts like neurodynamic mobilization42 in patients with painful diabetic peripheral neuropathy. The magnitude of tissue changes in chronic painful diabetic peripheral neuropathy shifts to mechanical from neurophysiological.43 Mechanical changes were earlier observed in neural tissues and neurodynamic interventions like nerve sliders and nerve massage were extensively studied for peripheral neuropathic pain symptoms.44 The effectiveness of physical and manual (neurodynamic) treatment methods could also be evaluated using standardized multifaceted clinical assessment scales45 to study the wholistic impact on pain, activity limitation, clinical examination findings and psychosocial issues. Further good quality controlled clinical trials on comparison between the physiotherapy modalities and also with standard care of glycemic control and lifestyle modification are necessary to derive valid conclusions.
CONCLUSION
Physiotherapy treatment methods of electrotherapy for symptomatic relief were studied widely and Monochromatic near infra-red energy and transcutaneous electrical nerve stimulation was shown to be effective in high quality studies. Further research on other treatment methods such as manual therapy and exercise therapy are indicated.
ACKNOWLEDGMENTS
The authors wish to acknowledge the biomedical companies for manufacturing the electrotherapy equipments discussed and the prolific authors for testing physiotherapy treatment methods in their clinical trials on patients with painful diabetic peripheral neuropathy.
Disclosures:
This review was performed as part of review of literature for Doctoral thesis (PhD) of the first author.
Englishhttp://ijcrr.com/abstract.php?article_id=2219http://ijcrr.com/article_html.php?did=22191. World Health Organization (Switzerland). Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications - Part1: Diagnosis and Classification of Diabetes Mellitus. Geneva: Report of a WHO Consultation; 1999.
2. Wild S, Roglic G, Green J, Sicree R, King H. Global prevalence of diabetes- estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27:1047-53.
3. Bell DSH. Current status of diabetes treatment. South Med J 2002;95:24-9.
4. Deshpande AD, Harris-Hayes M, Schootman M. Epidemiology of diabetes and diabetes-related complications. Phys Ther 2008;88:1254-64.
5. Argoff CE, Cole BE, Fishbain DA, Irving GA. Diabetic peripheral neuropathic pain- clinical and quality of life issues. Mayo Clinic Proc 2006;81(4, suppl):s3-s11.
6. Horowitz SH. Diabetic neuropathy. Clin Orthop Rel Res 1993;296:78- 85.
7. Fernando D. Diabetic neuropathy: clinical features and natural history. Int J Diab Dev Ctries 1995;15: 55- 60.
8. Argoff CE, Cole BE, Fishbain DA, Irving GA. Diabetic peripheral neuropathic pain- clinical and quality of life issues. Mayo Clin Proc 2006; 81(4, suppl):s3-s11.
9. Kumar SP. Physical therapy: past, present and future- a paradigm shift. J Phys Ther 2010;1:58-67
10. Kumar SP, Jim A. Physical therapy in palliative care: from symptom control to quality of life- a critical review. Indian J Palliat Care 2010;In press.
11. American Physical Therapy Association. Who Are Physical Therapists, and What Do They Do? (A Guide to Physical Therapist Practice). Phys Ther 2001;81:39.
12. Pieber K, Herceg M, PaternostroSluga T. Electrotherapy for the treatment of painful diabetic peripheral neuropathy: a review. J Rehabil Med 2010;42:289-95.
13. Dubinsky RM, Miyasaki J. Assessment: efficacy of transcutaneous electrical nerve stimulation in the treatment of pain in neurologic disorders (an evidence-based review): report of the therapeutics and technology assessment subcommittee of the American Academy of Neurology. Neurology 2010;74:173-6.
14. Jin DM, Xu Y, Geng DF, Yan TB. Effect of transcutaneous electrical nerve stimulation on symptomatic diabetic peripheral neuropathy: a meta-analysis of randomized controlled trials. Diabetes Res Clin Pract 2010;89:10-5.
15. Forst T, Nguyen M, Forst S, Disselhoff B, Pohlmann T, Pfutzner A. Impact of low frequency transcutaneous electrical nerve stimulation on symptomatic diabetic neuropathy using the new Salutaris device. Diabetes Nutr Metab 2004;17:163-8.
16. Kumar D, Marshall HJ. Diabetic peripheral neuropathy: amelioration of pain with transcutaneous electrostimulation. Diabetes Care 1997;11:1702-5.
17. Moharic M, Burger H. Effect of transcutaneous electrical nerve stimulation on sensation thresholds in patients with painful diabetic neuropathy: an observational study. Int J Rehabil Res 2009;doi:10.1097/MRR.0b013e328 3352151.
18. Somers DL, Somers MF. Treatment of neuropathic pain in a patient with diabetic neuropathy using transcutaneous electrical nerve stimulation applied to the skin of the lumbar region. Phys Ther 1999;79:767-75.
19. Reichstein L, Labrenz S, Ziegler D, Martin S. Effective treatment of symptomatic diabetic polyneuropathy with high frequency external muscle stimulation. Diabetologia 2005; 48: 824-8.
20. Oyibo SO, Breislin K, Boulton AJ. Electrical stimulation therapy through stocking electrodes for painful diabetic neuropathy: a double-blind, controlled crossover study. Diabet Med 2004;21:940-4.
21. LeMaster JW, Mueller MJ, Reiber GE, Mehr DR, Madsen RW, Conn VS. Effect of weight-bearing activity on foot ulcer incidence in people with diabetic peripheral neuropathy: feet first randomized controlled trial. Phys Ther 2008;88:1385-98.
22. Hijmans JM, Geertzen JHB, Zijlstra W, Hof AL, Postema K. Effects of vibrating insoles on standing balance in diabetic neuropathy. J Rehab Res Dev 2008;45:1441-50.
23. Mohamed O, Cerny K, Rojek L, Herbert K, Turner R, Waistell S. The effects of plastazote and aliplast/plastozote orthoses on plantar pressures in elderly persons with diabetic neuropathy. J Prosthet Orthot 2004;16:55-63.
24. Bosi E, Conti M, Vermigli C, Cazzetta G, Peretti E, Cordoni MC et al. Effectiveness of frequencymodulated electromagnetic neural stimulation in the treatment of painful diabetic neuropathy. Diabetologia 2005;48:817-23.
25. Swislocki A, Orth M, Bales M, Weisshaupt J, West C, Edrington J et al. A randomized clinical trial of the effectiveness of photon stimulation on pain, sensation and quality of life in patients with diabetic peripheral neuropathy. J Pain Symptom Manage 2010;39:88- 99.
26. Leonard DR, Farooqi MH, Myers S. Restoration of sensation, reduced pain and improved balance in subjects with diabetic peripheral neuropathy. Diabetes Care 2004; 27:168-72.
27. Lavery LA, Murdoch DP, Williams J, Lavery DC. Does anodyne light therapy improve peripheral neuropathy in diabetes? A doubleblind sham-controlled randomized trial to evaluate monochromatic infrared photoenergy. Diabetes Care 2008; 31: 316-21.
28. Clifft JK, Kasser RJ, Newton TS, Bush AJ. The effect of monochromatic infrared energy on sensation in patients with diabetic peripheral neuropathy: a doubleblind placebo-controlled study. Diabetes Care 2005; 28: 2896-900.
29. Li H, Nyland J, Shelton T. Effectiveness of the anodyne therapy system in treating diabetic peripheral neuropathy: a systematic review. Phys Ther Rev 2008; 13: 395-405.
30. DeLellis SL, Carnegie DH, Burke TJ. Improved Sensitivity in Patients with Peripheral Neuropathy: Effects of Monochromatic Infrared Photo Energy. J Am Podiatr Med Assoc 2005;95:143-7.
31. Kochman AB, Carnegie DH, Burke TJ. Symptomatic reversal of peripheral neuropathy in patients with diabetes. J Amer Podiatr Med Assoc 2002;92:125-30.
32. Kochman AB. Monochromatic infrared photo energy and physical therapy for peripheral neuropathy: Influence on sensation, balance, and falls. J Geriatr Phys Ther 2004;27:16–9.
33. Weintraub MI, Wolfe GI, Barohn RA, Cole SP, Parry GJ, Hayat G et al; Magnetic research group. Static magnetic field therapy for symptomatic diabetic neuropathy: a randomized, double-blind, placebocontrolled trial. Arch Phys Med Rehabil 2003;84:736-46.
34. Hamza MA, White PF, Craig WF, Ghoname ES, Ahmed HE, Proctor TJ. Percutaneous electrical nerve stimulation: a novel analgesic therapy for diabetic neuropathic pain. Diabetes Care 2000;23:365- 70.
35. Zinman LH, Ngo M, Ng ET, New KT, Gogov S, Bril V. Low-intensity laser therapy for painful symptomatic diabetic sensorimotor polyneuropathy: a controlled trial. Diabetes Care 2004;27:921-4.
36. Finch P; Baskwill A; Marincola F; Becker P; Changes in pedal plantar pressure variability and contact time following massage therapy: a case study of a client with diabetic neuropathy. J Bodywork Mov Ther 2007;11:295-301.
37. Abuaisha BB, Costanzi JB, Boulton AJ. Acupuncture for the treatment of chronic painful peripheral neuropathy: a long-term study. Diabetes Res Clin Pract 1998;39:115-21.
38. Ahn AC, Bennani T, Freeman R, Hamdy O, Kaptchuk TJ. Two styles of acupuncture for treating painful diabetic neuropathy- a pilot randomised control trial. Acupunct Med 2007;25:11-7.
39. Graak V, Chaudhary S, Bal BS, Sandhu JS. Evaluation of the efficacy of pulsed electromagnetic field in the management of patients with diabetic polyneuropathy. Int J Diab Dev Ctries 2009;29:56-61.
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42. Nee RJ, Butler DS. Management of peripheral neuropathic pain: integrating neurobiology, neurodynamics and clinical evidence. Phys Ther Sport 2006;7:36-49.
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44. Ellis RF, Hing WA. Neural Mobilization: A Systematic Review of Randomized Controlled Trials with an Analysis of Therapeutic Efficacy. J Manual Manipulative Ther 2008;16:8-22.
45. Kumar SP, Adhikari P, D’Souza SC, Jeganathan PS. Painful diabetic peripheral neuropathy: a current concepts review of clinical assessment scales for use in research and practice. International Journal of Current Research and Review. 2010;2(5):3-13.
Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524129EnglishN-0001November30HealthcareA REVIEW OF FLOATING DRUG DELIVERY SYSTEM
English4047Jawale S. K.English Bairagi A. S. EnglishJaybhai S. English Deshmukh V.K.EnglishFloating drug delivery systems (FDDS) have a bulk density less than gastric fluids and so remain buoyant in stomach without affecting the gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents, drug is released slowly at a desired rate from the system. After release of drug, the residual system is emptied from the stomach. This results in an increased Gastric Residence Time (GRT) and a better control of fluctuations in plasma drug concentration. The system must have sufficient structure to form a cohesive gel barrier to maintain an overall specific gravity lower than that of gastric contents and to dissolve slowly enough to serve as a drug reservoir. Based on the mechanism of buoyancy, two distinctly different technologies, i.e. noneffervescent and effervescent systems, have been utilized in the development of FDDS.
EnglishINTRODUCTION
Oral administration of a drug is perhaps the least predictable route of drug administration, yet it is the route that is used most frequently. Oral medications such as tablets, capsules are relatively cheap to manufacture, offer convenient form of drug administration and reduce the possibility of errors in total dose if the patient is self administering the dosage form. Classically, oral medications are administered as immediate release dosage forms. The major disadvantage of such immediate release preparations is the repeated frequency of drug administration and fluctuations in plasma drug levels. So, controlled release preparations were introduced. Oral controlled drug delivery systems (CDDS) have been developed for the past three decades due to their advantages. The design of oral CDDS is primarily aimed at achieving more predictable and increased bioavailability of drugs, hence, improving the efficiency of treatment. They help in reducing the frequency of administration, and single doses at periodic intervals of time are sufficient, resulting in improved patient compliance. However, the developmental process is precluded by several physiological difficulties, such as inability to restrain and locate the CDDS within desired regions of gastrointestinal (GI) tract due to variable gastric emptying and motility.
Floating drug delivery systems
Floating drug delivery systems (FDDS) have a bulk density less than gastric fluids and so remain buoyant in stomach without affecting the gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents, drug is released slowly at a desired rate from the system.
Advantages 1. This type of drug delivery system is especially very useful in the treatment of the disorders related to the stomach, as the prime objective of such systems is to produce a gastro retentive product or a product which has an enhanced retention time in the stomach.
2. All those molecules with considerably short half life can be administered in this manner to get an appreciable therapeutic activity.
3. This is a primary manner in which the bioavailability of a therapeutic agent can be enhanced. Especially all those drugs which get metabolized in the upper GIT.
4. They also have an advantage over the conventional system as it can be used to over come the adversities of gastric retention time as well as the gastric emptying time. As these systems are expected to remain buoyant on the gastric fluid without affecting the intrinsic rate of emptying because their bulk density is lower than that of the gastric fluids.
5. The duration of treatment through a single dose, which releases the active ingredient over an extended period of time.
Practical approaches in the development of FDDS
The concept of FDDS was described in the literature as early as 1968, when Davis disclosed a method for overcoming the difficulty experienced by some persons of gagging and choking while swallowing medicinal pills. The following approaches have been used for the design of floating dosage forms of single- and multipleunit systems:
Single Unit Dosage Forms
It was suggested that most of the floating systems suggested in literature are single unit systems. In low density approach, globular shells having lower density than that of gastric fluid can be used as a drug carrier for its controlled release. In fluid filled systems, gas filled floatation chamber is incorporated into a microporous component that also has drug reservoir incorporated within it.
Multiple-Unit Dosage Forms
The purpose of designing multiple-unit dosage form is to develop a reliable formulation that has all the advantages of a single-unit form and also is devoid of any of the above mentioned disadvantages of single-unit formulations. In pursuit of this endeavor many multiple-unit floatable dosage forms have been designed. In Carbon dioxide–generating multipleunit oral formulations several devices with features that extend, unfold, or are inflated by carbon dioxide generated in the devices after administration have been described in the recent patent literature. These dosage forms are excluded from the passage of the pyloric sphincter if a diameter of ~12 to 18 mm in their expanded state is exceeded. The major advantage of multiple unit dosage forms over single unit dosage forms is that they distribute uniformly within the gastric content and are gradually emptied from the stomach, possibly resulting in long lasting effects and reduced variability in absorption with lower probability of dose dumping.
Classification of FDDS Based on the mechanism of buoyancy, two distinctly different technologies, i.e. effervescent and non-effervescent have been used in the development of FDDS. FDDS are classified as follows:
1) Non-effervescent floating dosage forms:
a) Colloidal gel barrier system
b) Microporous compartment system
c) Alginate beads
d) Hollow microspheres
2) Effervescent floating dosage forms:
a) Volatile liquid containing systems
b) Gas generating system
Dosage forms available
The various buoyant preparations include single-unit as well as multipleunit dosage forms including tablets (pills), capsules, powders, microspheres (including microballoons). The most used FDDS are the single unit systems i.e. tablets and capsules, though they have several disadvantages as discussed previously. The major dosage forms have been discussed as follows:
Tablets
Among all the orally administered forms of drug the tablets are most convenient both from the point of view of the patient as well as the manufacturer. The tablets are the unit dosage forms which are mainly spherical in shape but the shape can be round, oval, oblong, etc.
Excipients
The floating tablet formulation uses excipients that are different from the one used in conventional tablet formulation. The excipients used in conventional formulations are:
(i) Diluents: Lactose, Dextrose, Microcrystalline cellulose, hydrolyzed starches, Sucrose, sorbitol, Mannitol
. (ii) Binders and Adhesives: Acacia, tragacanth, Gelatin, starch, polyvinyl pyrrolidone
(iii) Disintegrants: Starch, clays, cellulose, Alginates
. (iv) Lubricants: Stearic acid, talc, stearic acid salts, waxes, surfactants.
(v) Glidants: Silica derivatives, talc, etc.
(vi)Color and Flavor: FD and C and D and C dyes and lakes as color.
Excipients used in floating tablets are
(i) Hydrophilic Polymers: Hydroxy propylmethylcellulose (HPMC)
(ii) Carrier matrix: Gelucire
(iii) Gel forming hydrocolloids / Matrix Formers: Polycarbonate, Polyacrylate, Polymethacrylate and polystyrene
(iv) Swellable polymers used in Effervescent Systems: Chitosan and sodium bicarbonate and citric acid or tartaric acid
(v) Matrix forming polymers: HPMC, Polyarcylates, cargeenan gum guar, gum arabic
(vi) Fillers: Lactose, microcrystaline cellulose.
(vii) Lubricant: Magnesium stearate, purified talc
(viii) Buoyancy Agents: Cellulose, gums, polysaccharides, starch, gelatin.
(ix) Diluents: Lactose, mannitol, glucose, microcrystalline cellulose, starch, di-calcium phosphate.
(x) Porosity Agents: Lactose.
Excipients used in FDDS
The major excipients other than the conventional ones used are the bioadhesive polymers and their properties are explained as follows:
1. Hydroxypropyl methylcellulose (HPMC)
HPMC is a hydrocolloid used in the HBS. The HBS would contain or be covered by a capsule of HPMC, which upon dissolution on contact with gastric fluid would form a soft gelatinous mass on the surface by hydration as discussed previously. The hydrated layer slowly dissolves releasing the medicament.
Synonyms:
Cellulose, 2- Hydroxypropylmethyl Ether; Hypromellose
Definition;
Hydroxypropylmethylcellulose is a cellulose having some of the hydroxyl groups in the form of the methyl ether and some in the form of the 2- hydroxypropyl ether. The various grades commercially available are distinguished by a number indicative of the apparent viscosity in millipascal seconds of a 2% w/v solution measured at 20o .
Category: Treatment of tear deficiency; pharmaceutical aid (tablet excipient; suspending agent).
Description: White or yellowish white, fibrous or granular powder; almost odourless; hygroscopic after drying.
Solubility: Practically insoluble in hot water, in acetone, in ethanol, in ether and in toluene. It swells in water forming an opalescent, viscous colloidal solution.
2. Gelucire Gelucires are a family of vehicles derived from mixtures of mono-,di-, and triglycerides with polyethylene glycol (PEG) esters of fatty acids. Gelucires are available with a range of properties depending on their Hydrophilic Lipophilic Balance (HLB 1-18) and melting point (33°C-65°C) range. The various types available in the market manufactured by Gattefossé (St Priest, Cedex, France) are:
a) Gelucire 33/01 Glycerol esters of sat. C8-C18 fatty acids; used as excipient, carrier, vehicle, antioxidant
b) Gelucire 37/02 Saturated polyglycolized glycerides; used as excipient
c) Gelucire 39/01 Glycerol esters of sat. C12-C18 fatty acids; used as excipient, vehicle, consistency agent, fatting agent, antioxidant
3. Chitosan
They are biodegradable high weight cationic polysaccharides used widely in pharmaceutical industry.
4. Poly(ethylene oxide)
Poylethyleneglycol (PEG) and PEO are terms for materials containing repeated connected units of structure [-CH2CH2- O-]. PEG is the subspecies of PEO that contains hydroxyl group on each end of chain i.e. HO[-CH2CH2-O-]nH. depending upon the molecular weight, PEO is a liquid, a waxy solid or a solid. Solid PEO has a very regular backbone structure, free of side chains.
5. Polymethacrylates
Polymethacrylates are metacrylic acidethyl ethacrylate copolymers (1:1) as copolymer of methacrylic acid and ethyl ethacrylate.
Synonyms: Eudragit, polymeric methacrylates.
Evaluation of FDDS The various parameters that need to be evaluated for their effects on GRT of FDDS which are common to all dosage forms are described as follows:
A. In vitro evaluation
1. Floating time: The test for buoyancy and in vitro drug release studies are usually carried out in simulated gastric and intestinal fluids maintained at 37°C. In practice, floating time is determined by using the USP dissolution apparatus containing 900ml of 0.1N HCl as a testing medium maintained at 37°C. The time required to float the dosage form is noted as floating or floatation time.
2. Dissolution tests: Dissolution tests are performed using the USP dissolution apparatus to see the in vitro drug release. It is performed using USP Apparatus 1 (Paddle) or Apparatus 2 (basket) or Apparatus 3 (modified disintegration testing apparatus) or Apparatus 4 (flow through cell) using 900 mL of 0.1N HCl at rotation of 50 or 100 rpm at 37°C ± 0.5°C. The samples are withdrawn at predetermined time intervals for a period of time and replenished with the same volume of fresh medium each time, and then analyzed for their drug contents after an appropriate dilution.
3. Specific gravity test: The specific gravity of FDDS can be determined by the displacement method using analytical grade benzene as a displacing medium.
4. Resultant weight test: An in vitro measuring apparatus has been conceived to determine the real floating capabilities of buoyant dosage forms as a function of time. It operates by measuring the force equivalent to the force F required to keep the object totally submerged in the fluid. This force determines the resultant weight of the object when immersed and may be used to quantify its floating or nonfloating capabilities. The magnitude and direction of the force and the resultant weight corresponds to the vectorial sum of buoyancy ( F bouy ) and gravity ( F grav ) forces acting on the object as shown in the equation
F = F buoy – F grav F = d f gV – d s gV = (d f - d s ) gV F = (df – M / V) gV
in which F or RW is the total vertical force (resultant weight of the object), g is acceleration due to gravity, d f is the fluid density, d s is the object density, M is the object mass, and V is the volume of the object .By convention, a positive resultant weight signifies that the force F is exerted upward and that the object is able to float, whereas a negative resultant weight means that the force F or RW acts downward and that the object sinks.
B. In vivo evaluation
The in vivo gastric retentivity of a floating dosage form is usually determined by gamma scintigraphy or roentgenography. The dosage forms are labeled by a radiopharmaceutical and are monitored. In case the dosage form contains different layers, then each layer is labeled using a different radiopharmaceutical each time. Studies are done both under fasted and fed conditions using F and NF (control) dosage forms. It is also important that both dosage forms are non disintegrating units, and human subjects are young and healthy.
Applications and scope
Floating drug delivery offers several applications for drugs having poor bioavailability because of the narrow absorption window in the upper part of the gastrointestinal tract.
Sustained Drug Delivery
HBS systems can remain in the stomach for long periods and hence can release the drug over a prolonged period of time. The problem of short gastric residence time encountered with an oral CR formulation hence can be overcome with these systems. These systems have a bulk density of less than 1 as a result of which they can float on the gastric contents. These systems are relatively large in size and passing from the pyloric opening is prohibited.
Site-Specific Drug Delivery
These systems are particularly advantageous for drugs that are specifically absorbed from stomach or the proximal part of the small intestine,
e.g., riboflavin and furosemide. Furosemide is primarily absorbed from the stomach followed by the duodenum. It has been reported that a monolithic floating dosage form with prolonged gastric residence time was developed and the bioavailability was increased. AUC obtained with the floating tablets was approximately 1.8 times those of conventional furosemide tablets.
Absorption Enhancement
Drugs that have poor bioavailability because of site-specific absorption from the upper part of the gastrointestinal tract are potential candidates to be formulated as floating drug delivery systems, thereby maximizing their absorption. A significant increase in the bioavailability of floating dosage forms (42.9%) could be achieved as compared with commercially available LASIX tablets (33.4%) and enteric coated LASIX-long product (29.5%). FDDS of bromocriptine, might lead to better treatment of Parkinson’s disease. Furthermore, the codelivery of bromicriptine and metoclopramide based on dual delivery concept similar to that of Madopar HBS might further improve the therapeutic efficacy of HBS dosage form. The use of metoclopramide, a standard antiemetic agent is justifiable because it can prevent the side-effects caused especially by high doses of bromocriptine. Seeing the various advantages of FDDS over the conventional systems and the vast amount of research work being performed in this area, there is an immense amount of scope for it to be more
popular and useful. The day-byday increasing popularity of FDDS shows more promise for a bright future.
CONCLUSION
Dosage forms with a prolonged GRT will bring about new and important therapeutic options. They will significantly extend the period of time over which drugs may be released and thus prolong dosing intervals and increase patient compliance beyond the compliance level of existing CRDFs. Many of the ?Once-a-day? formulations will be replaced by products with release and absorption phases of approximately 24 hrs. Also, FDDS will greatly improve the pharmacotherapy of the stomach itself through local drug release leading to high drug concentrations at gastric mucosa which are sustained over a large period. Finally, FDDS will be used as carriers of drugs with the ?absorption window?.
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