Clinical trials of botanical interventions for type 2 diabetes mellitus.
\r\n\tSome studies should be linked to the late-stage tumorigenesis promoting metastasis in cancer. In addition, deregulated cellular processes such as cell proliferation, apoptosis, and differentiation as related to different tumor types should be investigated in this book. Besides tumorigenesis, spontaneous tumor regression and its potential formation mechanisms should be reviewed or researched. In addition, the role of the deregulated immunity in tumorigenesis should be explored. The drug targets and treatment alternatives in various cancer types should be described or investigated in some studies. The studies relating to the laboratory tests used as diagnostic and prognostic in cancer patients should also be presented. Consequently, this book may include but is not limited to these topics.
",isbn:null,printIsbn:null,pdfIsbn:null,doi:null,price:0,priceEur:null,priceUsd:null,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"46d3363b21f482c9a22ba72cca9ec4c0",bookSignature:"Dr. Nevim Aygun",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/6919.jpg",keywords:"Tumorigenesis,clinical significance, biological/genetic features, genomic/chromosomal instability, prognosis, prognostic factors, tumor suppressor genes, promotion of metastasis, spontaneous regression, tumor stages, tumor types/subtypes, signaling pathways, signaling networks, deregulated cellular processes, immunity, diagnosis, laboratory tests, treatment , oncogenes, primary tumor progression",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 26th 2018",dateEndSecondStepPublish:"April 16th 2018",dateEndThirdStepPublish:"June 15th 2018",dateEndFourthStepPublish:"September 3rd 2018",dateEndFifthStepPublish:"November 2nd 2018",remainingDaysToSecondStep:"3 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"195365",title:"Dr.",name:"Nevim",middleName:null,surname:"Aygun",slug:"nevim-aygun",fullName:"Nevim Aygun",profilePictureURL:"https://mts.intechopen.com/storage/users/195365/images/system/195365.jpeg",biography:"Nevim Aygun received her Medical Biology and Genetics Ph.D. in Health Sciences. She is interested in cancer, molecular biology, human genetics, cytogenetics, molecular cytogenetics, genomics, and bioinformatics. She has participated in many research projects on neuroblastoma, human gross gene deletions, non-B DNA-forming sequences, solid tumors, HCV, and leukemia, resulted in six articles, one book chapter, and numerous reports. She performed many molecular biological methods: PCR, real-time PCR, bacterial transformation, plasmid vector transfection, RNA interference, fluorescence in situ hybridization (FISH), cytogenetic, DNA sequencing, and cell culture. She also performed genomics and biostatistics analyses using some bioinformatics tools and SPSS program. She reviewed several manuscripts for some medical, genetics, and genomics journals. 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This requires extensive analysis of developing trends in scientific research in order to offer our readers relevant content. Creating the book catalogue is also based on keeping track of the most read, downloaded and highly cited chapters and books and relaunching similar topics. I am also responsible for consulting with our Scientific Advisors on which book topics to add to our catalogue and sending possible book proposal topics to them for evaluation. Once the catalogue is complete, I contact leading researchers in their respective fields and ask them to become possible Academic Editors for each book project. Once an editor is appointed, I prepare all necessary information required for them to begin their work, as well as guide them through the editorship process. I also assist editors in inviting suitable authors to contribute to a specific book project and each year, I identify and invite exceptional editors to join IntechOpen as Scientific Advisors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"22098",title:"A Review of Clinical Trials in Emerging Botanical Interventions for Type 2 Diabetes Mellitus",doi:"10.5772/20693",slug:"a-review-of-clinical-trials-in-emerging-botanical-interventions-for-type-2-diabetes-mellitus",body:'\n\t\tAlthough type 2 diabetes mellitus (T2DM) is pandemic globally, Asia-Pacific has the largest diabetes burden in the world (International Diabetes Federation, 2009). This region is home to more than half of the world\'s population with some of the richest and most developed countries alongside many developing as well as a significant number of poorest and least developed ones. Despite existing knowledge and recent progress in therapy, the majority of diabetic patients do not achieve an optimal blood glucose control. With a predisposition to disproportionate effect on the lower socioeconomic groups, the combination with the resulting poor health consequences, disability, and dependency is of concern (L.E. Egede, 2004). Taken together with the confluence of the recent upsurge of obesity and an ageing population, this will have far-reaching implications in terms of income security, social welfare and medical services (J.C. Chan et al., 2009; C.Pan et al., 2010). The consequent enormous health, social and economic burden will overwhelm the social and health care systems, particularly of the low and middle-income developing countries in the Asia-Pacific (D.O. Abegunde et al., 2007).
\n\t\t\tControlling this disease is important for reducing complications, improving quality of life, and reducing the economic burden associated with disability and dependency (UKPDS 37, 1999). Strategies for the effective treatment of this devastating disease are of great interest to the general public, government organisations, and the healthcare industry. Besides nutritional intervention as an essential component of diabetes management, botanicals and associated products are also remedies for T2DM in traditional medicine practices. In the past decade, enhanced global research into botanicals has identified more than 600 plants as potential contributors to the management of T2DM (M.Modak et al., 2007; L.W. Qi et al., 2010).
\n\t\t\tUse of plant-based complementary and alternative medicine is common in many communities (H.Y. Chang et al., 2007; A. Metcalfe et al., 2010; H.T. Nguyen et al., 2010). In the past, the traditional ‘observation’ as remedies in complimentary alternative medicines, preliminary preclinical studies, and anecdotal evidence, have endorsed the use of these plants. However, their safety and efficacy in humans are of concern. Adding to the complexity of such issues are the challenges in the management of T2DM. Specifically, these are the use of pluralistic medical practices and the relevant roles of these botanicals in the management of T2DM in mainstream medicine (C.C. Shih et al., 2010). In addition, there are also issues of adequate regulatory standards and patients’ disclosures to their mainstream medical practitioners (S. Tyreman, 2010). Thus, rigorous research in translating these botanicals to the clinical arena is warranted (M. Kantor, 2009).
\n\t\t\tThere has been no evaluation of the clinical trials for the use of these emerging botanicals for type 2 diabetes mellitus. The aim of this review is to assess the effects of botanicals on type 2 diabetes mellitus. Existing opportunity for these botanicals in the management of diabetes and the state of the evidence for their anti-diabetic usefulness will be discussed. This includes issues pertaining to these clinical trials, the quality of antihyperglycemic efficacy data and related complementary metabolic effects. The adverse effects of interventions, a critical aspect of diabetic care, will also be emphasised. Finally, important limitations, which may affect the interpretation of data from these clinical studies and the implications for future research; in the context of T2DM in developing Asia-Pacific countries, will also be addressed.
\n\t\tSearch was carried out in the following databases: MEDLINE, CINHAL, Proquest Health & Medical Complete, ProQuest Dissertations & Theses, CAM-PubMed, and the Cochrane Library Database from April 2006 to March 2011 using the MeSH terms CAM, alternative therapies, hypoglycemic plants or botanicals, anti-diabetic plants or botanicals and individual botanicals and supplement names from popular sources, each crossed with the term diabetes mellitus. Databases of ongoing trials (http://www.controlled-trials.com/ with links to several databases and https://www.clinicaltrialsregister.eu/) were also searched.
\n\t\t\t\tOnly emerging botanical derived products or drugs not in the established armamentarium of modalities used in the current management of T2DM were included. Supplements in which animal products were major components were excluded. We also did not include soluble or dietary fibre supplements that were already established in conventional diabetes nutrition advice.
\n\t\t\t\tSpecific filters for retrieving controlled clinical trial, double-blind, placebo-controlled, phase II, or III randomised controlled trials of any duration; published systematic reviews and meta-analyses of randomised controlled trials; and randomised controlled trials (RCT) in human adults (aged ≥18), were incorporated. Hand searching was not performed, but reference lists of identified systematic reviews, meta-analyses, and pooled analyses were reviewed to identify further studies. Unpublished studies were also not sought. References in any articles that met the inclusion criteria were included. There were no language restrictions.
\n\t\t\t\tThe results of the search from the various databases were entered in a bibliographic manager software, Endnote X4 (Thomson Reuters). Duplicates were automatically discarded. We screened the identified articles to ensure they met pre-determined inclusion criteria. To ensure uniformity of appraisal for each study a checklist of specified inclusion criteria was used. The initial review for all identified citations included titles or abstracts, or both. Following, a second review stage of full text publications for citations remaining after the first pass was carried out. We used a positive exclusion method to exclude only those publications that did not meet one or more of the inclusion criteria. In ambiguous cases, inclusion of studies was based on expert opinion.
\n\t\t\t\tA structured table was developed for data extraction to ensure uniformity of appraisal for each study as well as capturing all relevant data. Extracted data consisted of study characteristics (such as treatments and doses, status of T2DM and associated conditions, duration, and study location) and relevant outcomes (glycaemic control, adverse effects, morbidity, blood lipids level, body weight or body mass index).
\n\t\t\t\tThere were two primary outcomes: glycaemic control and adverse effects. These were considered as measures of efficacy and measures of tolerability respectively. Secondary outcomes were included when present. These included serum insulin, body weight or body mass index, blood lipids level and morbidity. Morbidity included both type 2 diabetes mellitus as well as cardiovascular-related comorbidity and all cause morbidity. The above data were only extracted and analysed when reported.
\n\t\t\t\t\tData for glycaemic control, FBG and 2HPBG, was collected for trials of at least 6 weeks and over. For HbAic, trials over three months were considered. Data of all other outcomes will be collected from studies of any duration.
\n\t\t\t\tAnalyses were performed on data that were explicitly reported in the individual papers, with no imputations for data that were not reported. When available, we analysed the intention-to-treat population; when this was not possible, we used data from the last observation carried forward. The analyses were conducted using RevMan 5.0 meta-analytic software (The Cochrane Collaboration, 2008).
\n\t\t\t\tThe search returned a total of 45 publications and abstracts (Figure 1). After review of titles and abstracts, we identified and included 22 relevant papers. All were clinical trials (1 clinical trial, 1 controlled clinical trial, and 20 randomised controlled trials) (Table 1). Six were excluded because duration of these studies were less than 6 weeks. Another was excluded because the primary outcome was not glycaemic control or adverse effects. Of the 15 remaining studies, all were randomised controlled trials. All the trials consisted of different plant-based interventions.
\n\t\t\t\tThere were fifteen studies that met all the inclusion criteria. Table 1 shows the characteristics of the trials. The study participants for each trial range from 24 to 109. All studies included both genders. The participants were middle-age and older adults. Study length ranged from 12 weeks to 4 months.
\n\t\t\t\t\tFour papers provided information on different forms of cinnamon extracts (S.M. Blevins et al., 2007; P.Crawford, 2009; B. Mang et al., 2006; S. Suppapitiporn& N. Kanpaksi, 2006). Two papers provided information on different forms of Silybum marianum preparations (H.F. Huseini et al., 2006; S.A. Hussain, 2007) and another two papers provided findings of
\n\t\t\t\t\tModified PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses ) flow-chart of study selection (D.Moher et al., 2009)
catechin-containing tea preparations (T.Mackenzie et al., 2007; T. Nagao et al., 2009). The rest of the seven papers were focussed on 7 diffent plant-based preparations for T2DM (A.M. Dans et al., 2007; H.F. Huseini et al., 2009; V.T. Huyen et al., 2010; R.Kuriyan et al., 2008; F.R. Lu et al., 2008; V. Vuksan et al., 2008; S.Zibadi et al., 2008).
\n\t\t\t\tRisk of bias assessments included assessments of minimisation of selection, performance, attrition, reporting biases as well as other sources of biases (A.R. Jadad et al., 1996; L.L. Kjaergard et al., 2001; K.F. Schulz et al., 1995).
\n\t\t\t\t\tOne trial was a crossover randomised trial (V.Vuksan et al., 2008), while the rest was parallel-group design. Recruitment of patients was limited to the centres of the studies. Of the 15 included randomised trials, five trials described the methods of randomisation (P. Crawford, 2009; A.M. Dans et al., 2007; H.F. Huseini et al., 2006; T. Mackenzie et al., 2007; V.Vuksan et al., 2008). Among them, three used simple randomisation methods (random number generator, table and computer generated sequence) (A.M. Dans et al., 2007; T. Mackenzie et al., 2007; V. Vuksan et al., 2008), one used block randomisation technique (P.Crawford, 2009) and another used a balanced randomisation technique (H.F. Huseini et al., 2006). Only three trials reported generation of allocation concealment (P.Crawford, 2009; A.M. Dans et al., 2007; H.F. Huseini et al., 2006). The rest of the trials did not document adequate methods of randomisation.
\n\t\t\t\t\tRef | \n\t\t\t\t\t\t\t\tStudy design | \n\t\t\t\t\t\t\t\tSubjects | \n\t\t\t\t\t\t\t\tIntervention | \n\t\t\t\t\t\t\t\tControl | \n\t\t\t\t\t\t\t
(S.M. Blevins et al., 2007) | \n\t\t\t\t\t\t\t\tDBRPCT | \n\t\t\t\t\t\t\t\t58 with T2DM | \n\t\t\t\t\t\t\t\tCinnamon powder capsule (C. cassia) | \n\t\t\t\t\t\t\t\tWheat flour placebo capsule | \n\t\t\t\t\t\t\t
(B. Mang et al., 2006) | \n\t\t\t\t\t\t\t\tDBRPCT | \n\t\t\t\t\t\t\t\t65 with T2DM | \n\t\t\t\t\t\t\t\tAqueous cinnamon extract (C. cassia) capsule | \n\t\t\t\t\t\t\t\tMicrocrystalline cellulose placebo capsule | \n\t\t\t\t\t\t\t
(S. Suppapitiporn& N. Kanpaksi, 2006) | \n\t\t\t\t\t\t\t\tSBRPCT | \n\t\t\t\t\t\t\t\t60 with T2DM | \n\t\t\t\t\t\t\t\tCinnamon powder capsule (C. Cassia) | \n\t\t\t\t\t\t\t\tPlacebo | \n\t\t\t\t\t\t\t
(P. Crawford, 2009) | \n\t\t\t\t\t\t\t\tRCT | \n\t\t\t\t\t\t\t\t109 with T2DM | \n\t\t\t\t\t\t\t\tCinnamon capsule (C. Cassia) | \n\t\t\t\t\t\t\t\tNo placebo intervention | \n\t\t\t\t\t\t\t
(A.M. Dans et al., 2007) | \n\t\t\t\t\t\t\t\tDBRPCT | \n\t\t\t\t\t\t\t\t40 with T2DM \n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\tMomordica charantia leaf capsules | \n\t\t\t\t\t\t\t\tPlacebo | \n\t\t\t\t\t\t\t
(H.F. Huseini et al., 2009) | \n\t\t\t\t\t\t\t\tDBRPCT | \n\t\t\t\t\t\t\t\t50 with T2DM | \n\t\t\t\t\t\t\t\tCitrullus. colocynthis dried fruit powder capsules | \n\t\t\t\t\t\t\t\tPlacebo | \n\t\t\t\t\t\t\t
(H.F. Huseini et al., 2006) | \n\t\t\t\t\t\t\t\tDBRPCT | \n\t\t\t\t\t\t\t\t51 with T2DM | \n\t\t\t\t\t\t\t\tSilybum marianum seed extract tablets | \n\t\t\t\t\t\t\t\tPlacebo | \n\t\t\t\t\t\t\t
(S.A. Hussain, 2007) | \n\t\t\t\t\t\t\t\tDBRPCT | \n\t\t\t\t\t\t\t\t59 with T2DM | \n\t\t\t\t\t\t\t\tSilybum marianum extract tablets | \n\t\t\t\t\t\t\t\tPlacebo | \n\t\t\t\t\t\t\t
(V.T. Huyen et al., 2010) | \n\t\t\t\t\t\t\t\tDBRPCT | \n\t\t\t\t\t\t\t\t24 with T2DM | \n\t\t\t\t\t\t\t\tGynostemma pentaphyllum tea | \n\t\t\t\t\t\t\t\tPlacebo tea | \n\t\t\t\t\t\t\t
(R. Kuriyan et al., 2008) | \n\t\t\t\t\t\t\t\tDBRPCT | \n\t\t\t\t\t\t\t\t60 with T2DM | \n\t\t\t\t\t\t\t\tCoccinia cordifolia leaves and fruit extract capsules | \n\t\t\t\t\t\t\t\tMaltosedextrin capsule placebo | \n\t\t\t\t\t\t\t
(F.R. Lu et al., 2008) | \n\t\t\t\t\t\t\t\tRCT | \n\t\t\t\t\t\t\t\t69 with T2DM | \n\t\t\t\t\t\t\t\tTrigonella foenum-graecum powder capsules | \n\t\t\t\t\t\t\t\tChinese yam powder placebo | \n\t\t\t\t\t\t\t
(T. Mackenzie et al., 2007) | \n\t\t\t\t\t\t\t\tDBRPCT | \n\t\t\t\t\t\t\t\t49 with T2DM | \n\t\t\t\t\t\t\t\tGreen and black tea extract capsules | \n\t\t\t\t\t\t\t\tCellulose capsule placebo | \n\t\t\t\t\t\t\t
(T. Nagao et al., 2009) | \n\t\t\t\t\t\t\t\tRCT | \n\t\t\t\t\t\t\t\t43 with T2DM | \n\t\t\t\t\t\t\t\tGreen tea extract (catechin-rich 528 mg) beverage | \n\t\t\t\t\t\t\t\tLow dose catechin (96.3 mg) placebo tea | \n\t\t\t\t\t\t\t
(V. Vuksan et al., 2008) | \n\t\t\t\t\t\t\t\tDBRPCT, crossover | \n\t\t\t\t\t\t\t\t19 with T2DM | \n\t\t\t\t\t\t\t\tPanax ginseng extract capsules | \n\t\t\t\t\t\t\t\tVanilla flavoured cornstarch capsule placebo | \n\t\t\t\t\t\t\t
(S. Zibadi et al., 2008) | \n\t\t\t\t\t\t\t\tRCT | \n\t\t\t\t\t\t\t\t48 with T2DM | \n\t\t\t\t\t\t\t\tPinus maritima bark extract pill | \n\t\t\t\t\t\t\t\tPlacebo | \n\t\t\t\t\t\t\t
Clinical trials of botanical interventions for type 2 diabetes mellitus.
Blinding of all patients, trials investigators and assessors were reported in five trials (A.M. Dans et al., 2007; H.F. Huseini et al., 2009; H.F. Huseini et al., 2006; S.A. Hussain, 2007; T. Mackenzie et al., 2007). Eight trials did not report any aspects of blinding at all (V.T. Huyen et al., 2010; A.Khan et al., 2003; R.Kuriyan et al., 2008; F.R. Lu et al., 2008; B. Mang et al., 2006; T.Nagao et al., 2009; S.Suppapitiporn& N. Kanpaksi, 2006; V.Vuksan et al., 2008). While the rest documented blinding of patients and trial investigators (S.M. Blevins et al., 2007) or assessors only (P.Crawford, 2009; S. Zibadi et al., 2008). Both dropouts of patients and intention-to-treat analysis were reported in five trials (S.M. Blevins et al., 2007; P. Crawford, 2009; A.M. Dans et al., 2007; F.R. Lu et al., 2008; S. Zibadi et al., 2008). One trial reported only dropouts of patients but not intention-to-treat analysis (H.F. Huseini et al., 2006).
\n\t\t\t\t\tFour papers did not mention appropriate inclusion, exclusion criteria or both (P.Crawford, 2009; R.Kuriyan et al., 2008; B. Mang et al., 2006; V.Vuksan et al., 2008). A statement of power calculation had been undertaken or give any justification for the numbers of participants needed to detect an effect of differences with intervention was documented in five papers (S.M. Blevins et al., 2007; P. Crawford, 2009; A.M. Dans et al., 2007; T.Mackenzie et al., 2007; V. Vuksan et al., 2008). Potential confounding factors were not elaborated in four papers (S.M. Blevins et al., 2007; P. Crawford, 2009; H.F. Huseini et al., 2009; B.Mang et al., 2006). There was also no uniform tool to assess adjunct dietary management in all these trials.
\n\t\t\t\tIn view of the quality of data and variability of treatment, meta-analysis was not performed. One trial compared single botanical preparation without adjunct oral hypoglycaemics with placebo. The rest of the trials compared the botanical preparation with adjunct oral hypoglycaemicis with placebo. These tested botanicals included preparations of Cinnamon cassia,\n\t\t\t\t\t\tMomordica charantia, Citrullus Colocynthis, Silybum marianum, Gynostemma pentaphyllum, Coccinia cordifolia, trigonella foenum-graecum L, Camelia sinesis (tea) and Pinus maritima. Among them, Cinnamon cassia was tested in 4 trials, while Silybum marianum and Camelia sinesis (tea) were each tested in two trials. The reported outcomes included fasting blood glucose, postprandial blood glucose, HbA1c, fasting serum insulin levels, serum lipids level, symptoms, and adverse effects.
\n\t\t\t\t\tSingle botanical preparations versus placebo
\n\t\t\t\t\tCompared with placebo (maltodextrin capsules), Coccinia cordifolia showed significantly better effect on normalisation of fasting blood glucose. There was a mean decrease of 15.6% in the intervention group compared to mean increase of 6% in the placebo group. Similarly, with the 2 hour postprandial blood glucose, there was a significant mean decrease of 18.5% in the intervention group. No significant change was noted in the placebo control group. There was also significant decrease in the glycosylated haemoglobin level in the intervention group.
\n\t\t\t\t\tMild hypoglycaemic symptoms, perspiration, excessive hunger and slight dizziness, was noted post-prandially in 59% of the participants in the intervention group. However, there was no significant difference in minor gastrointestinal adverse effects between the two groups.
\n\t\t\t\t\tSingle botanical preparations with oral hypoglycaemic agent (OHA) adjuncts versus placebo
\n\t\t\t\t\tThe effect of Cinnamon cassia preparations and OHA in reducing fasting blood glucose level was not consistent. One trial showed a significant reduction in fasting blood glucose levels (B. Mang et al., 2006). However, two others reported no significant change with trials of 3 to 4 months (S.M. Blevins et al., 2007; S.Suppapitiporn& N. Kanpaksi, 2006). There was no overall effect on HbA1c changes. Only one trial reported significant improvement in HbA1c level after 3 months (Standard mean difference (SMD) 0.12 g%; 95%CI -0.26 to 0.50) (P. Crawford, 2009). However, this change did not translate into an overall significant effect size. Further, three trials of 3 and 4 month durations reported no significance improvement in the HbA1c with this botanical intervention (S.M. Blevins et al., 2007; B. Mang et al., 2006; S. Suppapitiporn& N. Kanpaksi, 2006). Three trials of 3 and 4 months duration did not find any significant effect on the lipid levels (S.M. Blevins et al., 2007; B. Mang et al., 2006; S. Suppapitiporn& N. Kanpaksi, 2006).
\n\t\t\t\t\tAdverse effect of hypersensitivity rash was reported in only one trial (P.Crawford, 2009). Comparison of these studies was difficult in view of different baseline biochemical characteristics (blood glucose, HbA1c, insulin, lipid level), weight, diet and concurent medications.
\n\t\t\t\t\tThere was no significant difference between Camelia sinesis extracts (catechin and theaflavin) with OHA and placebo in HbA1c (T. Mackenzie et al., 2007; T.Nagao et al., 2009) and fasting blood glucose levels ( T.Nagao et al., 2009). Although there was a significant increase in the insulin level in the catechin-rich beverage group, the number of participants was too small (n=23) for further interpretation ( T.Nagao et al., 2009). Adverse effects reported were profuse sweating and rash, which led to withdrawal from the study.
\n\t\t\t\t\tCompared with placebo, combination Silybum marianum and OHA significantly reduced both the FBG and HbA1c levels in two trials of four month durations (H.F. Huseini et al., 2006; S.A. Hussain, 2007). Even so, results of other parameters such as 2HPBG, BMI and lipid levels, were not consistent. No side-effects were reported.
\n\t\t\t\t\tCompared with placebo, the fruits and seeds capsules preparation of Momordica charantia and OHA showed no statistically significant effect on reduction of fasting blood glucose and HbA1c levels (A.M. Dans et al., 2007). Similarly, when compared with placebo, the treatment also showed no statistically significant reduction in secondary outcome measures, total cholesterol levels or body mass index when compared to placebo. However, the minor adverse effects of gastrointestinal discomfort led to discontinuation of treatment.
\n\t\t\t\t\tIngestion of tea prepared from Gynostemma pentaphyllum and OHA for 12 weeks showed a significant reduction in FBG, HbA1c and insulin resistance, compared with placebo and OHA (V.T. Huyen et al., 2010). There were no adverse effects reported.
\n\t\t\t\t\tIntervention with Citrullus colocynthis and OHA in 25 patients for 2 months demonstrated significant reduction in both FBG and HbA1c levels, compared with patients taking placebo and OHA (H.F. Huseini et al., 2009). There were no significant changes in secondary outcome measures of lipid levels. However, three patients reported mild diarrhoea at the beginning of the study.
\n\t\t\t\t\tPatients on Trigonella foenum-graecum capsules and OHA for 12 weeks showed significant improvement glycaemic profile, FBG, 2HPBG and HbA1c, as well as symptoms, compared with placebo (F.R. Lu et al., 2008). However, there were no significant secondary outcomes change of BMI, hepatic and renal functions. Adverse effects of abdominal discomforts and diarrhoea led to withdrawal from intervention.
\n\t\t\t\t\tCompared with placebo, intervention with Panax ginseng extract capsules and OHA, significantly improved glucose tolerance and insulin sensitivity in a double-blind, placebo-controlled crossover randomised clinical trial (V. Vuksan et al., 2008). There were no significant changes in HbA1c as well as safety biochemical parameters of liver and kidneys. Adverse effects of hypoglycaemia was reported. In addition, there was a high number of dropouts (50%). This was attributed to conflicting approaches used in the management of T2DM in mainstream medical practice and traditional herbal practice in the country of the trial.
\n\t\t\t\t\tFinally, Pinus maritima bark extract pill and OHA demonstrated significant reduction in FBG, HbA1c and LDL-cholesterol, compared with placebo and OHA (S.Zibadi et al., 2008). This was over a relatively short duration of 3 months. However, there was no documentation of adverse effects.
\n\t\t\t\tFifteen randomised trials were included in this review. The exclusion of 7 trials was due to treatment duration of less than six weeks or reported outcomes not relevant to this review. The included trials compared different botanical preparation with or without combinations with hypoglycaemic agents versus placebo. Not all the trials provided data on dietary and lifestyle modification in patients with type 2 diabetes mellitus. Majority of the trials measured surrogate primary outcomes, some evaluated symptoms or adverse events. Two trials failed to demonstrate any improvements in the blood glucose control in terms of normalisation, reduction of fasting blood glucose, reduction of 2HPBG responses and reduction of HbA1c. This is in contrast with the majority that demonstrated improvements in the surrogate primary outcomes.
\n\t\t\t\t\tOnly some trials examined secondary outcomes such as lipid levels or BMI. Safety biochemical parameters of the kidney and liver were examined in a limited number of trials. The low methodological quality and the general small sample size in these trials contributing to the low power of all the studies. Taken together with the limited number of the trials identified for individual botanical preparations, caution is needed in interpreting the findings of these trials. In all these studies, there were no statements on the health-related quality of life, well-being, socioeconomic status or costs.
\n\t\t\t\t\tCompared with placebo, six botanical preparations with oral hypoglycaemics, Cinnamon cassia,\n\t\t\t\t\t\tCitrullus Colocynthis, Silybum marianum, Gynostemma pentaphyllum, trigonella foenum-graecum L and Pinus maritima seemed to have varying effects on blood glucose control. The hypoglycaemic agents used are sulphonylureas, metformin, thiazoledinediones, glinides, glitazones, acarbose or combination therapies. In addition to the conflicting findings of the four trials using preparations of Cinnamon cassia, the botanical preparations above with potential effects on glucose, warrant further trials.
\n\t\t\t\tThe fifteen trials available for this review were only a small fraction (less than 3%) of the vast resources of potential botanicals for T2DM. For the four trials using Cinnamon cassia intervention, the extracts were of derived from different techniques, dosages and sources. Moreover, the placebos used as control of three of these trials also varied. One trial did not elaborate on the contents (S. Suppapitiporn& N. Kanpaksi, 2006), while two others used wheat flour and microcrystalline cellulose (S.M. Blevins et al., 2007; B. Mang et al., 2006). Another trial did not use any placebo as control (P. Crawford, 2009). In addition, the time point for assessment of the effect of intervention for the four trials was not uniform. This time point was 3 months for two trials (S.M. Blevins et al., 2007; S. Suppapitiporn& N. Kanpaksi, 2006)and 4 months for the other two(T.Mackenzie et al., 2007; B.Mang et al., 2006). Thus, these methodological issues may affect the results.
\n\t\t\t\t\tEven though there were two trials for each of the botanical, Camillia sinensis and Silybum marianum, different preparations were used. This means that none of the preparations of trials in this review were tested at least twice. Furthermore, many trials used the ‘double-blind’design but few reported blinding of outcome assessors. This may predisposed to the possibility of performance and reporting bias (D. Moher et al., 1998; K.F. Schulz et al., 1995).
\n\t\t\t\tSince all the trials in this review did not meet one or more essential risk of bias criteria, these trials were assessed having high risk of bias. There was no trial with moderate or low risk of bias. When quality criteria in terms of minimisation of selection, performance, attrition, and detection biases are met, trial of low risk of bias is indicated. Similarly, categorization into moderate risk of bias required the quality criteria to be partially fulfilled.
\n\t\t\t\tThe botanical preparations evaluated in this review generally did not report severe adverse effects. Thus, the conclusion on the safety of using these botanicals in the management of diabetic patients cannot be made. Further, many of the adverse effects were not sufficiently reported. None of the reviews looked for the effects of ‘botanical-drug’ interaction. It is important that both the beneficial and harmful effects in clinical trials of human given equal attention.
\n\t\t\t\t\tPrevious reviews examined the use the different modalities of complementary and alternative medicine (R. Nahas& M. Moher, 2009) or the use herbs and dietary supplements (G.Y. Yeh et al., 2003). This review differs in the respect that we are focussed on the update of the clinical trials of botanical preparations for type 2 diabetes mellitus of the last five years. This included randomised controlled clinical trials comparing botanical preparation with placebo or hypoglycaemic drugs in type 2 diabetes mellitus of duration exceeding six weeks. Previous reviews included both randomised and non-randomised controlled trials with interventions consisting of herbs, dietary supplements as well as minerals (vanadium and chromium) in both types of diabetics and healthy individuals. However, we limited our focus to potential botanicals for T2DM. Furthermore, our search strategy has no restriction to language. This is important as many of the trials with botanicals may appear in the languages in the regions where the use of botanicals is common, particularly in Asia. Finally, stringent criteria for quality assessment were used in this review based on recommendations by several authors (A.R. Jadad et al., 1996; L.L. Kjaergard et al., 2001; K.F. Schulz et al., 1995).
\n\t\t\t\t\tCurrent approaches to the use of botanical preparations differ with the type of medical practices. The expectation of mainstream medical practice is standardisation of extracts of botanicals extracts of predominantly specific parts of single plant (P. Talalay, 2001). This preparation is further investigated based on a set of criteria, which include preparation consistent with the description in the pharmacopoeia, chemical standardisation, biological assays, animal models, and clinical testing for the particular condition. In comparison, traditional medical practices may include non-herbal or herbal modalities or combination (H.T. Debas et al., 2006). The focus may be on symptoms, well-being and customising for each individual patient based on the differentiation of the patients’ ’syndrome’ based on the particular traditional medicine practice philosophy. However, in many communities in Asia, the use of plural practices for management of type 2 diabetes is common (K.L. Tackett& M.C. Jones, 2009). Since there is evidence of the potential of botanicals contributing to management of T2DM, it is important to further understand their uses. The pleiotropic properties may have other benefits for these diabetics. Further insight may allow the use as possible expanding armamentarium of the glucose lowering therapeutic agents or complementing other aspects of treatment such as medical nutritional therapy. Improving the morale of the patients rather than creating conflict with the patient’s use of other approaches, is important to ensure continuity of treatment and ultimately control of disease.
\n\t\t\t\t\tIn summary, the selected studies in this review showed variability of treatment interventions, control interventions and generally small effect sizes. None of the preparations were tested twice. As a result, there is insufficient evidence for any reliable conclusion of the potential benefits or harmful effects of these botanicals for type 2 diabetes mellitus.
\n\t\t\t\tThis systematic review has several limitations. First, there are limited trials available for selection. This may be due to the fact that research of these botanicals is still in the early days or publication bias. With the included trials, methodological issues were predominant. The poor quality of randomisation and blinding may exaggerate effects of the interventions due to systematic errors (bias). Potential bias may also occur during selection of patients, administration of treatment, and assessment of outcomes. Therefore, these methodologically less rigorous trials may show inappropriately skewed larger significant intervention effects than trials with more rigors (M. Egger et al., 2003; L.L. Kjaergard et al., 2001).
\n\t\t\t\t\tSmall sample size of the trials leads to diminished power of the results. This may explain the absence of a statistically significant difference between botanical preparations used for interventions (E. Christensen, 2007; G. Piaggio& A.P. Pinol, 2001). In other words, the analyses from the size of these trials may not establish with confidence that two interventions have equivalent effects.
\n\t\t\t\t\tAll the selected trials reported end-of treatment responses, ranging from six weeks to four months. Important long-term responses beyond this period are not known. Finally, not all the trials provide information on ethnicity of the participants. The recruitment of patients was limited to the respective centre of study. In addition, all the preparations used in the intervention arms were tested only once, which made it impossible to pool data. Thus, the applicability of the results to other ethnic groups or populations is not known.
\n\t\t\t\tSome of the botanical preparations in this review may have beneficial effects on glycaemic glucose control in people with T2DM. However, at this point of time, we cannot recommend any for routine clinical use. All the trials had low methodological quality. The beneficial effects need to be confirmed by large rigorous randomised controlled trials of high-quality. In addition, the adverse effects also need to be further elucidated. Nevertheless, results from ongoing studies may provide more information on the potential clinical use of Cinnamon cassia, Momordica charantia and Camellia sinesis (Table 2).
\n\t\t\tAlthough preclinical and early clinical trials suggest that the botanicals in this review may contribute to the management of T2DM, a potential methodological problem is the issue of the quality of these botanical preparations. An example is the varying effect of C. cassia preparations from different sources on glycaemic control. Some of the differences may arise with the varying climates, conditions for growing, harvesting and processing (U.Solimene et al., 2007). Different parts of the plant may have a different proportion of bioactive compounds present. This may add to the complexity of characterisation, production of reliable and consistently effective products. Therefore, there is a need to address the standardisation and the quality of the products used in clinic trials.
\n\t\t\t\tRef | \n\t\t\t\t\t\t\tStudy design | \n\t\t\t\t\t\t\tCountry | \n\t\t\t\t\t\t\tIntervention | \n\t\t\t\t\t\t\tControl | \n\t\t\t\t\t\t
(P. Crawford, 2011) | \n\t\t\t\t\t\t\tDBRCT | \n\t\t\t\t\t\t\tUSA | \n\t\t\t\t\t\t\tCinnamon bark and Cinnulin PF dietary supplements | \n\t\t\t\t\t\t\tmetformin | \n\t\t\t\t\t\t
(A. Tsiami, 2009) | \n\t\t\t\t\t\t\tDBRPCT | \n\t\t\t\t\t\t\tUK | \n\t\t\t\t\t\t\tCinnamon capsules | \n\t\t\t\t\t\t\tStarch capsule placebo | \n\t\t\t\t\t\t
(R. Ridout et al., 2007) | \n\t\t\t\t\t\t\tDBRPCT | \n\t\t\t\t\t\t\tCanada | \n\t\t\t\t\t\t\tCinnamonforce capsule | \n\t\t\t\t\t\t\tPlacebo | \n\t\t\t\t\t\t
(K. Khawaja, 2009) | \n\t\t\t\t\t\t\tDBRPCT | \n\t\t\t\t\t\t\tPakistan | \n\t\t\t\t\t\t\tMomordica charantia capsule | \n\t\t\t\t\t\t\tWheat flour placebo capsule | \n\t\t\t\t\t\t
(C.H. Hsu, 2007) | \n\t\t\t\t\t\t\tDBRPCT | \n\t\t\t\t\t\t\tTaiwan | \n\t\t\t\t\t\t\tepigallocatechin gallate predominant green tea extract | \n\t\t\t\t\t\t\tGreen tea extract placebo | \n\t\t\t\t\t\t
Ongoing clinical trials of botanical interventions for type 2 diabetes mellitus.
The trials in this review did not examine the effect of the botanical interventions over a prolonged period (over 4 months). Thus, the effects on the micro and macro-complications well as other benefits in the patients with T2DM are not known. Moreover, with the different methodologies used, the presence of confounders, the varieties in the diet and the difficulty in recording dietary intake make it difficult to interpret the results. Furthermore, there is also the practicality of maintaining a ‘stable’ oral hypoglycaemic agents regime over a long period. Introduction of relevant clinically important outcome measures for long-term follow up may improve the quality of the trial.
\n\t\t\t\tDesign of future trials comparing such botanical interventions with established hypoglycaemic drugs should be based on ’equivalence principle’. In view of the findings of preclinical studies suggesting benefits beyond glycaemic control, when comparing these botanical interventions combined with one or more established oral hypoglycaemic agents, verifying these potential benefits is suggested. Particularly, for the middle-aged and older patients with T2DM, relevant outcome measures should include functional outcomes, quality of life, well-being, socioeconomic status and costs.
\n\t\t\t\tThe quality of assessment of adverse events may be improved with a standardised format. Several components of selection bias that affect the quality of randomised controlled trials of this review required attention. This is the detailed reporting of the methods used to generate allocation sequence and allocation concealment. Adequate descriptions of withdrawal or drop-out during the trial and use of intention-to-treat analysis will also contribute to the quality of the trial.
\n\t\t\tMeSH, Medical Subject Headings; CAM, Complementary and Alternative Medicine; CCT, controlled clinical trial; DBRPCT, double-blind randomised placebo-controlled trial; DBRCT, double-blind randomised controlled trial; SBRPCT, single-blind randomised placebo-controlled trial; RCT, randomised controlled trial; T2DM, type 2 diabetes mellitus; UK, United Kingdom; USA, United States of America
\n\t\tThe authors would like to acknowledge the kind support given by Institute of Gerontology, Universiti Putra Malaysia.
\n\t\tThe finite element method (FEM) consider is the most of flexibility common technique used for dealing with various kinds of application in many fields, for instance, in engineering, in chemistry and in biology. The derivation of a posteriori error estimates for linear and nonlinear parabolic problems are gaining increasing interest and there is a significant implementation of the method now are understandable and available in the literature [1, 2, 3, 4, 5, 6, 7, 8, 9]. However, There is less progress has been made comparatively in the proving of a posteriori error bounds for semilinear parabolic problems [10, 11, 12, 13]. These estimations play a crucial rule in designing adaptive mesh refinement algorithms and consequently leading to a good accuracy while reducing the computational cost of the scheme.
The key technique used in the proofs is the elliptic reconstruction idea, introduced by Makridakis and Nochetto for spatially discrete conforming FEM [2] and extended to fully discrete conforming FEM by Lakkis and Makridakis [3] These ideas have been carried forward also to fully discrete schemes involving spatially non-conforming/d
The aim of this Chapter is to derive a posteriori error bounds for the fully discrete in two cases Lipschitz and non Lipschitz. Continuation Argument will be used to deal with nonlinear forcing terms.
Before we proceed with the error analysis, we require some auxiliary results that will be used in our analysis.
Let
such that
Lemma 1.1 (Continuous Gronwall inequality). Let
then
where
Proof: See [15].
Theorem 1.2 Given some
Proof: See [16].
Consider the semilinear parabolic problem as
where
Returning to the (6), multiplying by a test function
for all
By using Cauchy-Schwarz inequality, the convercitivity and continuity of the bilnear form
with
To introduce a backward Euler approximation of the time derivative paired with the standard conforming finite element method of the spatial operator. To this end, we will discretize the time interval
where
is the basis functions. After plugging (11) into (10), yields a nonlinear system of ordinary differential equations
where
where
We give here some essential definitions in the error analysis of the discrete parabolic equations.
for all
Discrete elliptic operator: The elliptic operator defined
Using the above projections, (10) can be expressed in distributional form as
The aim of this section will be introduced the elliptic reconstruction operator and then discuss the related aposteriori error analysis for the backward Euler approximation. To do this, we define the elliptic reconstruction
for a given
The following lemma is the elliptic reconstruction error bound in the
Lemma 1.3 (Posteriori error estimates). For any
where
and
Lemma 1.4 (Main semilinear parabolic error equation). The following error bounds hold
Proof: To begin with, we first decompose the error as
By recalling (17), this becomes
where
Using elliptic reconstruction to split the error, gives
After using triangle inequality, the proof will be concluded.
The proof of the following Lemmas 1.5, 1.6, 1.7 in details, we refer to [3].
Lemma 1.5 (Temarol error estimate). Let
then
where
Lemma 1.6 (Space-mesh error estimate). Let
we have
where
Lemma 1.7 (Mesh change estimates). Let
such that
where
The aim of this section is to study a posteriori error bound in
Let us suppose that
where
Lemma 1.8 (Data approximation error estimate). Suppose that the nonlinear reaction
where
Proof: Using triangle inequality,
Applying Cauchy–Schwarz inequality and (36) along with Young’s inequality and Poincar’e-Friedrichs inequality,
The second term
Finally,
Collecting all the results together, the proof will be finished.
Lemma 1.9 Let
where
Proof: Now, setting
Integrate the above from
where
By introducing
therefore
Now, using Lemmas 1.5, 1.6, 1.7 and 1.8, reads
Selecting now
with
then
and by taking
The proof already will be finished.
Theorem 1.10 Let
where
Proof: By decomposing
To be able to bound the first term on the right hand side of (56), using (13), this becomes
and
Let
Lemma 1.11 (Estimation of the nonlinear term). If the nonlinear reaction
where
Proof: Applying triangle inequality, reads
Now, we have
To estimate
Applying the elementary inequality
Similarly,
Collecting all these terms, we obtain
Using Holder’s inequality and Young’s inequality, we deduce that
Therefore,
Substituting this into our grand inequality yields
where
valid for all
Finally,
Putting all of the results together the proof will be finished.
Theorem 1.12 Let
where
Proof: Now, setting
Using Lemma 1.11, along with lemmas 1.3, 1.5, 1.6 and 1.7, imply
Setting
Upon observing that
Now combining two equations, we obtain
To bound of the nonlinear term of above equation, we shall employ a continuation argument in the spirit of [17, 18]. To do that, we consider the set
where
and Grönwall inequality, thus, implies
Since
This leads to
Then, (81), becomes
This leads to contradictions, because of
The triangle inequality along with Lemma 1.3, imply that
By recalling (76), the proof already finished.
This section aims to explain an adaptive algorithm aiming to investigate the performance of the presented a posteriori bound from Theorems 1.10 and 1.12 for the backward-Euler
The adaptive algorithm from [15], starts with an initial uniform mesh in space and with a given initial time step. Starting from a uniform square mesh of
Once the time-step is adapted, the algorithm performs spatial mesh refinement and coarsening, determined by the space indicator
Algorithm 1. The backward Euler method for solving the semilinear parabolic equation
1: Create a mesh with
2: We disctize
3:
4: for
5: Calculate the mass and stiffness matrices
6: Solve
7: end for
Algorithm 2. Space-time adaptivity.
1: Input
2: Pick
3: Compute
4: Compute
5: while
6: if
7:
8:
9:
10:
11: end if.
12: Compute
13: Compute
14: end while
15: put
16: while
17: Calculute
18: while
19: if
20:
21;
22:
23;
24: end if
25: Compute
26: end while
27: Create
28: Compute
29:
30:
31: end while
The aim of this Chapter is to derive an optimal order a posteriori error estimates in term of the
It is pleasure to thank Prof. E. Greogoulis (Department of Mathematics, University of Leicester,
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\\n\\nNote: This full-time position will have an immediate start. In your cover letter, please indicate when you might be available for a block of two hours. As part of the interview process, all candidates that make it to the second phase will participate in a writing exercise.
\\n\\n*IntechOpen is an Equal Opportunities Employer consistent with its obligations under the law and does not discriminate against any employee or applicant on the basis of disability, gender, age, colour, national origin, race, religion, sexual orientation, war veteran status, or any classification protected by state, or local law.
\\n"}]'},components:[{type:"htmlEditorComponent",content:'We are looking to add further talent to our team in The Shard office in London with a full-time Social Media Community Manager and Marketing Assistant position. The candidate will bring with them a creative and enthusiastic mindset, high level problem-solving skills, the latest marketing and social media platforms skills and strong involvement in community-best practices to engage with researchers and scholars online. The ideal candidate wll be a dynamic, forward thinking, approachable team player, able to communicate with all in the global, growing company, with an ability to understand and build a rapport within the research community.
\n\nThe Social Media Community Manager and Marketing Assistant will report to the Senior Marketing Manager. They will work alongside the Marketing and Corporate Communications team, supporting the preparation of all marketing programs, assisting in the development of scientific marketing and communication deliverables, and creating content for social media outlets, as well as managing international social communities.
\n\nResponsibilities:
\n\nEssential Skills:
\n\nDesired Skills:
\n\nWhat makes IntechOpen a great place to work?
\n\nIntechOpen is a global, dynamic and fast-growing company offering excellent opportunities to develop. We are a young and vibrant company where great people do great work. We offer a creative, dedicated, committed, passionate, and above all, fun environment where you can work, travel, meet world-renowned researchers and grow your career and experience.
\n\nTo apply, please email a copy of your CV and covering letter to hogan@intechopen.com stating your salary expectations.
\n\nNote: This full-time position will have an immediate start. In your cover letter, please indicate when you might be available for a block of two hours. As part of the interview process, all candidates that make it to the second phase will participate in a writing exercise.
\n\n*IntechOpen is an Equal Opportunities Employer consistent with its obligations under the law and does not discriminate against any employee or applicant on the basis of disability, gender, age, colour, national origin, race, religion, sexual orientation, war veteran status, or any classification protected by state, or local law.
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