FDA approved and investigated drugs by mechanism of action
\\n\\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\nThank you all for being part of the journey. 5,000 times thank you!
\\n\\nNow with 5,000 titles available Open Access, which one will you read next?
\\n\\nRead, share and download for free: https://www.intechopen.com/books
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\nDr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\n\nThank you all for being part of the journey. 5,000 times thank you!
\n\nNow with 5,000 titles available Open Access, which one will you read next?
\n\nRead, share and download for free: https://www.intechopen.com/books
\n\n\n\n
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"4724",leadTitle:null,fullTitle:"Recent Advances in Liver Diseases and Surgery",title:"Recent Advances in Liver Diseases and Surgery",subtitle:null,reviewType:"peer-reviewed",abstract:"This book presents the most recent advances in the field of liver diseases and surgery, including the remarkable advances in Hepatitis C therapy, liver tumors, injuries, cysts, resections, transplantation, and preoperative management of patients with liver diseases. 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\r\n\tFoams had always been a paramount material form for industry and science thanks to their wide application range in several industrial, civil and chemical processes. Foams also have many desirable properties, like lightness, resilience, thermal and acoustic insulation, noise absorption, adjustable airflow resistivity and porosity, resistivity to the diffusion of energy flow like heat and so on. They are also stable materials that can absorb gases or liquids and can be used as filters, bio-scaffolds for tissue engineering. Their principal characteristic is to feature a high surface area capable of storing energy or convert it from one form to another. This property could be used to enhance the performance of foams in terms of life existence, robustness and reliability. For these reasons, this book aim is to offer to readers a broad state-of-the-art situation of the current applications of foams, including thermal and acoustic issues and focusing on their new functions, usages and future trends.
",isbn:"978-1-83969-585-8",printIsbn:"978-1-83969-584-1",pdfIsbn:"978-1-83969-586-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"9495e848f41431e0ffb3be12b4d80544",bookSignature:"Dr. Marco Caniato",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10699.jpg",keywords:"Foaming, Vacuum, Molten Metal, Formability, Lightweight, Insulation, Vibration Reduction, Absorption, Resistance, Shock, Environmental Protection, Recycling",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 24th 2021",dateEndSecondStepPublish:"March 24th 2021",dateEndThirdStepPublish:"May 23rd 2021",dateEndFourthStepPublish:"August 11th 2021",dateEndFifthStepPublish:"October 10th 2021",remainingDaysToSecondStep:"a month",secondStepPassed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:'Dr. Marco Caniato is an internationally-oriented scientist with 10 years of experience in the Italian Universities of Trieste and of Ferrara. 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Worldwide, the number living with chronic HCV approaches 185 million. Until recently, the regimen of pegylated interferon (peg-IFN) and ribavirin (RBV) stood as the standard of care and is still commonly used as first-line therapy in some countries. This is rapidly changing. Direct acting antivirals (DAA) have altered the landscape dramatically. By understanding the genome of the HCV, scientists and researchers have been able to exploit its mechanism of transmission by creating inhibitors against several of the nonstructural proteins that are integral to HCV replication and function. Sustained virological response (SVR), which is commonly defined as a lack of HCV viral detection 12-24 weeks following treatment, with ribavirin and pegylated interferon alone, was marginal but has continued to improve. Despite the improvement, the introduction of DAAs has made the previously reported 50-70% SVR rates fall far short of rates achieved with DAAs.
\n\t\t\t\tNS3/4 Protease Inhibitors\n\t\t\t | \n\t\t\t\n\t\t\t\tNS5A Inhibitors\n\t\t\t | \n\t\t\t\n\t\t\t\tNucleos(t)ide NS5B Polymerase Inhibitors \n\t\t\t | \n\t\t\t\n\t\t\t\tNonnucleos(t)ide NS5B Polymerase Inhibitors\n\t\t\t | \n\t\t
\n\t\t\t\tBoceprevir\n\t\t\t | \n\t\t\tDaclatasvir | \n\t\t\tMericitabine | \n\t\t\t\n\t\t\t\tDasabuvir\n\t\t\t | \n\t\t
\n\t\t\t\tTelaprevir\n\t\t\t | \n\t\t\tElbasvir | \n\t\t\t\n\t\t\t\tSofosbuvir\n\t\t\t | \n\t\t\tDeleobuvir | \n\t\t
\n\t\t\t\tSimeprevir\n\t\t\t | \n\t\t\t\n\t\t\t\tLedipasvir\n\t\t\t | \n\t\t\tVX-135 | \n\t\t\tLomibuvir | \n\t\t
\n\t\t\t\tParotaprevir\n\t\t\t | \n\t\t\t\n\t\t\t\tOmbitasvir\n\t\t\t | \n\t\t\t\n\t\t\t | Tegobuvir | \n\t\t
Asunaprevir | \n\t\t\tSamatasvir | \n\t\t\t\n\t\t\t | ABT-072 | \n\t\t
Faldaprevir | \n\t\t\tACH-2928 | \n\t\t\t\n\t\t\t | BMS-791325 | \n\t\t
Danoprevir | \n\t\t\tBMS824393 | \n\t\t\t\n\t\t\t | GS-9669 | \n\t\t
Grazoprevir | \n\t\t\tPPI-461 | \n\t\t\t\n\t\t\t | \n\t\t |
Sovaprevir | \n\t\t\tPPI-668 | \n\t\t\t\n\t\t\t | \n\t\t |
Vedroprevir | \n\t\t\tGS-5816 | \n\t\t\t\n\t\t\t | \n\t\t |
Vaniprevir | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t |
IDX320 | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t |
FDA approved and investigated drugs by mechanism of action
Legend: Drugs in italics have received FDA approval as of January 2015
Adapted from www.hepatitis.va.gov
As it currently stands, four classes of DAA exist, which can be categorized according to the protein they inhibit. These four include inhibitors of the NS3/4 protease, NS5A polymerase, and NS5B polymerases (nucleoside and nonnucleoside). The approval of two NS3/4 protease inhibitors, telaprevir (TEL) and boceprevir (BOC), occurred in 2011 and marked the beginning of the age of DAAs. This was followed 2 years later by the approval of sofosbuvir (SOF), a nucleoside NS5B inhibitor, and simeprevir (SIM), an NS3/4 protease inhibitor, further expanded the available treatment options. In 2014, a combination of IFN-free regimen utilizing SOF and an NS5A inhibitor, ledipasvir (LED), was approved. Closely following this, the four-drug combination pack of an NS5A inhibitor, NS3/4A inhibitor, and a nonnucleoside NS5B inhibitor of ombitasvir (OMB), paritaprevir (PARr), and dasabuvir (DAS), respectively, gained Food and Drug Administration (FDA) approval in the United States. In addition to the DAAs in the four-drug combination pack, ritonavir has been added due to its potent inhibition of CYP3A4, increasing the effect of paritaprevir. Several other agents are currently undergoing late stage clinical trials and are expected to be approved in the near future (Table 1).
In the most recent National Health and Nutrition Examination Survey (NHANES), the estimated prevalence of HCV infection is approximately 3.6 million in the United States alone, with an estimated 2.7 of these having chronic infection. Worldwide, the World Health Organization (WHO) estimates that nearly 150 million people have chronic HCV infection. In both the United States and worldwide, estimates likely fall significantly short given that nearly half of all infected patients have never been tested for HCV. Additionally, the incidence among prisoners and the homeless are not known and in less developed nations are often not recorded [1]. HCV is thought to be the causal factor of up to one-third of cases of cirrhosis worldwide [2, 3].
In a study done by Shepherd et al. [4], analysis of positive HCV seroprevalence throughout some of the most populous nations of the world revealed an overall worldly prevalence rate of 2%, or roughly 123 million people. Given the limitations that widespread detection and recording pose, one would expect the actual prevalence to be larger. Individual analysis of many nations including China, Pakistan, and Egypt revealed estimated HCV seroprevalence well above this range. Disease transmission patterns again reveal that the majority of transmission of HCV is thought to be from unscreened blood donation, injection drug use, unsafe therapeutic injection, or other health care-related procedures. As medical practices become safer and blood screening continues to occur, the rates of HCV transmission from injection drug use will become the predominant mode of transmission as it has in developed countries like Australia, England, and the United States. Despite its success in the United States, several barriers to improving the safety of blood transfusions have remained throughout nations across the world [4-6]. As it stands, the WHO’s global database estimates that among the 97 of 164 countries that provided data, 89% of donated blood is being screened following basic quality procedures [7].
HCV cirrhosis remains the primary indication for liver transplant (LT) in the United States with over 15,000 patients currently listed on the United Network for Organ Sharing (UNOS) list [8]. In year 2013 alone, over 6,400 patients underwent LT in the United States, increasing steadily from 1,700 in 1988 [9]. The United States leads in amount of deceased donor liver transplantations followed by China, with roughly 2,000 in 2010 [10].
As is the case with most newly discovered pharmaceuticals, recently approved DAAs carry with them a financial cost so high that it is a barrier to treatment. At around $1,000 U.S. dollars per pill, a 12-week regimen would run the patient and their insurance provider approximately $84,000 with other DAA sharing similar price tags. The endeavor of validating coverage depends upon the tangible and the intangible, the objective and subjective, the cold hard science, and the cold hard dollars. Like prior novel pharmaceuticals before them, DAAs will need full support from the respective government in which the regimen is being distributed, as it does in the United States. Governing medical councils such as the FDA, the Health Products and Food Branch (HPFB) of Health Canada, the State Food and Drug Administration (SFDA) in China, and so on, will need to first approve drug regimens and define which population is to receive them.
It is difficult to estimate the exact savings per patient due to the multitude of confounding variables. All things considered, if a patient with HCV progresses naturally without treatment to the point of being considered to have end-stage liver disease. The equivalent of hundreds of thousands of medical dollars will have been spent in order to treat and care for these patients. In addition to the cost savings achieved by no longer needing to treat the manifestations of chronic hepatitis C, the cure of hepatitis C has been also been shown to provide benefits. Beside the improvement in psychological and social well-being, which accompanies cure of HCV, treatment has been shown to decrease and potentially reverse cirrhosis, esophageal varices, and the risk for the development of hepatocellular carcinoma [11-13].
Notably, incomplete treatment, unsuccessful treatment, and reinfection are always possible, particularly in patients with comorbid psychiatric illness, concomitant drug addiction, and poor social support, all known risks factors for contracting HCV [3]. In the long run, this issue should continue to fade in its controversy given that the minimum manufacturing costs for producing direct acting antivirals have been estimated at $100-250 for a 12-week course of treatment once patent expires and production of generic versions are widely available [14]. Additionally, immediate treatment upon detection as opposed to delay in therapy has shown cost-effectiveness [15].
Over the past several years, more so recently, treatment options for HCV have exponentially grown. Treatment for HCV began with the FDA approval of interferon (IFN) in 1991, followed by combined IFN and RBV in 1998, and later with peg-IFN in 2001. The regimen of peg-IFN and RBV once stood as the standard of care, and still does in many nations, until recently. DAAs, which target nonstructural proteins involved in replication and infection of HCV, were first approved in 2011.
Peg-IFN and RBV historically have been shown to result in SVR rates of 75% in patients with genotypes 2 or 3, but only of 40% in patients with genotype 1 [16]. The duration of therapy often depended on both patient’s genotype and their response to therapy as measured by HCV RNA viral load following initiation of treatment [17]. In one-third of all patients being treated with peg-IFN and RBV, adverse side effects were noted. These ranged from an influenza-like illness, characterized by fatigue, headache, fever, and rigors as well as complaints of depression, irritability, or insomnia. In addition to the side effects, therapy with peg-IFN was a tedious experience. Treatment often included weekly subcutaneous injections of peg-IFN in addition to daily oral RBV for up to 48 weeks. In addition to this, patients required at least monthly appointments for the first 12 weeks for monitoring of side effects and blood work, including HCV viral load monitoring. The tedious schedule and weekly subcutaneous injections lead many to either not enroll for therapy or undergo incomplete treatment.
As it stands now, the time of weekly injections and unfavorable side effects are gone. In 2014, new IFN-free regimens became available. The previous peg-IFN and RBV therapy or even triple therapy involving TEL or BOC is quickly becoming extinct. In 2015 onward, IFN-containing regimens will be replaced by all-oral, IFN-free therapies. Additionally, RBV-free regimens are also becoming widely available, and RBV will likely go the way of peg-IFN due to its unfavorable side effect of anemia.
As noted thus far, the groundbreaking development of DAAs has appeared to instantaneous change a bleak and dismal diagnosis to one filled with hope and promise. HCV seems to be paralleling HIV in that it was once considered a death sentence where treatment was harsh and limited but has now changed to something treatable with a pill. Additionally, one can now expect to live a near normal lifespan and be contributors to society.
The genome of HCV is now well understood, and because of this, scientists have been able create inhibitors against components of the genome integral to HCV replication and function. As it currently stands, four classes of DAAs exist and include the NS3/4 protease inhibitors, NS5A polymerase inhibitors, and the NS5B polymerases (nucleoside and nonnucleoside) inhibitors. Starting with protease inhibitors in 2011, BOC and TEL changed the game and raised SVR to impressive levels in treatment-naive patients. Shortly after, SOF, a nucleoside NS5B inhibitor, and SIM, another NS3/4 protease inhibitor, were approved and progress soared. It was not long before the old regimen of peg-IFN was being disposed of for more convenient and more tolerable agents. In the past months, additional agents have been approved and include LED, OMB, PARr, and DAS. Many more are under investigation and will likely be approved by the time of this publication.
The treatment of HCV centers on achieving SVR because if one can achieve this then life expectancy approaches near normal [18]. Without a detectable HCV viral load, cirrhosis is not expected to be occurring, and therefore neither are the complications thereof. Historically, achieving SVR in unique patient populations has proven difficult. Additionally, patients with certain factors often did not tolerate treatment well. In these populations, treatment was not approved, i.e., post liver transplant HCV patients. Genotypic analysis has also helped to identify unique populations. It has been established that some strains of HCV appear to possess an innate resistance to peg-IFN and RBV. Further exploration into genotypic and polymorphic variation and its effect on treatment response is needed, particularly now that these new agents with different mechanisms of action than peg-IFN and RBV are being utilized.
HCV is classified into 11 genotypes with the first 6 of these garnering the majority of attention. Interestingly, various genotypes possess a geographic predominance [19] (Table 2).
\n\t\t\t\tGenotype\n\t\t\t | \n\t\t\t\n\t\t\t\tGeographic distribution \n\t\t\t | \n\t\t
1 | \n\t\t\tUnited States, Europe, Japan | \n\t\t
2 | \n\t\t\tMediterranean, Europe, Japan, North America | \n\t\t
3 | \n\t\t\tSoutheast Asia, Europe, United States | \n\t\t
4 | \n\t\t\tEgypt, North Africa, sub-Saharan Africa, Middle East | \n\t\t
5 | \n\t\t\tSouth Africa | \n\t\t
6-11 | \n\t\t\tChina, Korea, Taiwan, Southeast Asia | \n\t\t
HCV genotype geographic distribution
Genotype 1 is the most prevalent genotype in the world and until recently had been the most difficult genotype to treat due to its poor SVR rates in response to peg-IFN and RBV. Treatment over the years has evolved significantly and the newest available guidelines support the use of the SOF/LED combination or the OMB/PARr/DAS/RBV combination [20-27]. Alternatively, data also indicate that use of SOF, SIM with or without RBV, achieved acceptable rates of SVR and can also be considered for use [28]. In patients with genotype 1 HCV infection, new SVR targets are now at greater than 90%. Newer therapies will need to measure up to these results. New agents remain under study, but preliminary results have been as impressive as the above regimens, and thus the market for treatment of genotype 1 infection will be saturated before we know it [29, 30] (Table 3).
Genotype 2 is found in clusters in the Mediterranean region and has historically responded well to the previous standard of peg-IFN and RBV. Genotype 3, now becoming the most difficult genotype to treat, has the unique characteristic of being associated with intravenous drug use. Recent studies using the newer DAAs show increased rates of SVR. Current recommendations for treatment suggest ample success is possible by utilizing a SOF and RBV regimen [31-36]. Building on excellent results of a phase II trial, an ongoing phase III trial is pending and expected to show widespread success with the use of daclatasvir (DAC) in combination with SOF [37, 38]. DAC, an NS5A inhibitor, has shown similar promising results throughout all genotypes as expected given its pan-genotypic treatment effect. Other promising regimens include SOF/LED combination, as well as GS-5816, a pan-genotypic NS5A inhibitor in combination with RBV [39, 40] (Table 4).
Genotype 4 is found mostly in Egypt, the Middle East, and northern Africa. Although rare in the United States, in Egypt, the prevalence of HCV is upwards of 15% and thus remains an important research focus. Similarly, genotypes 5 and 6 are rare in the United States and are more frequently found in southern Africa, Southeast Asia, China, and Korea. Given the geographic distribution, few genotype 4-6 patients have been enrolled in clinical trials. More research is needed, but SOF-based regimens are likely to be significantly effective in the meantime [31, 41-46] (Table 5).
\n\t\t\t\tTrial\n\t\t\t | \n\t\t\t\n\t\t\t\tPhase\n\t\t\t | \n\t\t\t\n\t\t\t\t\n\t\t\t\t\tn\n\t\t\t\t\n\t\t\t | \n\t\t\t\n\t\t\t\tRegimen\n\t\t\t | \n\t\t\t\n\t\t\t\tSVR\n\t\t\t | \n\t\t\t\n\t\t\t\tComments\n\t\t\t | \n\t\t
ION-1 [20] | \n\t\t\tIII | \n\t\t\t865 | \n\t\t\tSOF/LED ± RBV for 12 or 24 wks | \n\t\t\t>97% | \n\t\t\tIncluded patients with compensated cirrhosis | \n\t\t
ION-2 [20] | \n\t\t\tIII | \n\t\t\t440 | \n\t\t\tSOF/LED ± RBV for 12 or 24 wks | \n\t\t\t>94% | \n\t\t\tPreviously treated patients with and without cirrhosis. Lower SVR was observed in the 12-week group without RBV. | \n\t\t
ION-3 [21] | \n\t\t\tIII | \n\t\t\t647 | \n\t\t\tSOF/LED ± RBV for 8 or 12 wks | \n\t\t\t>93% | \n\t\t\tIncluded patients with compensated cirrhosis in 12 week arm | \n\t\t
SAPPHIRE-I [22] | \n\t\t\tIII | \n\t\t\t631 | \n\t\t\tOMB/PARr/DAS + RBV for 12 wks | \n\t\t\t>95% | \n\t\t\tAbsence of cirrhosis required | \n\t\t
SAPPHIRE-II [25] | \n\t\t\tIII | \n\t\t\t297 | \n\t\t\tOMB/PARr/DAS + RBV for 12 wks | \n\t\t\t>96% | \n\t\t\tPreviously treated patients without cirrhosis. SVR similar regardless of previously treatment failure. | \n\t\t
PEARL-III [23] | \n\t\t\tIII | \n\t\t\t305 | \n\t\t\tOMB/PARr/DAS ± RBV for 12 wks | \n\t\t\t>90% | \n\t\t\tG-1a patients | \n\t\t
PEARL-IV [23] | \n\t\t\tIII | \n\t\t\t419 | \n\t\t\tOMB/PARr/DAS ± RBV for 12 wks | \n\t\t\t>99% | \n\t\t\tG-1b patients | \n\t\t
TURQUOISE-II [24] | \n\t\t\tIII | \n\t\t\t380 | \n\t\t\tOMB/PARr/DAS + RBV for 12 or 24 wks | \n\t\t\t>92% | \n\t\t\tPatients with compensated cirrhosis | \n\t\t
COSMOS [28] | \n\t\t\tII | \n\t\t\t167 | \n\t\t\tSOF/SIM ± RBV for 12 or 24 wks | \n\t\t\t>90% | \n\t\t\tExtending treatment and RBV did not significantly improve SVR, phase III trial ongoing(OPTIMIST) | \n\t\t
SIRIUS [27] | \n\t\t\tII | \n\t\t\t155 | \n\t\t\tSOF/LED for 24 wks or SOF/LED + RBV for 12 wks | \n\t\t\t>96% | \n\t\t\tPreviously treated patients with and without cirrhosis. 12 week course proved as effective. | \n\t\t
C-WORHTY [26] | \n\t\t\tII | \n\t\t\t253 | \n\t\t\tGRZ/ELB ± RBV for 12 or 18 wks | \n\t\t\t>90% | \n\t\t\tPreviously treated and untreated with and without cirrhosis | \n\t\t
Results of DAA treatment in genotype 1 patients
Legend: Wks: week; GRZ: grazoprevir; ELB: elbasvir
\n\t\t\t\tTrial\n\t\t\t | \n\t\t\t\n\t\t\t\tPhase\n\t\t\t | \n\t\t\t\n\t\t\t\t\n\t\t\t\t\tn\n\t\t\t\t\n\t\t\t | \n\t\t\t\n\t\t\t\tRegimen\n\t\t\t | \n\t\t\t\n\t\t\t\tSVR\n\t\t\t | \n\t\t\t\n\t\t\t\tComments\n\t\t\t | \n\t\t
FISSION [31] | \n\t\t\tIII | \n\t\t\t499 | \n\t\t\tSOF + RBV for 12 wks | \n\t\t\t97% | \n\t\t\tCompared to previous standard, SOF greatly improved SVR rates from 78% to 97% | \n\t\t
POSITRON [32] | \n\t\t\tIII | \n\t\t\t278 | \n\t\t\tSOF + RBV for 12 wks vs placebo | \n\t\t\t78% | \n\t\t\tSVR was higher for G-2(93%) vs G3(61%) | \n\t\t
VALENCE [33] | \n\t\t\tIII | \n\t\t\t419 | \n\t\t\tSOF + RBV for 12 or 24 wks | \n\t\t\t>78% | \n\t\t\tG-2 was treated for 12 wk and G-3 was treated for 24 wks in patients with and without cirrhosis who were and were not previously treated. Lowest SVR(78%) was noted in the previously treated, cirrhotic genotype 3 patients. | \n\t\t
FUSION [32] | \n\t\t\tIII | \n\t\t\t201 | \n\t\t\tSOF + RBV for 12 or 16 wks | \n\t\t\t>86% | \n\t\t\tPreviously treated patients with and without cirrhosis. | \n\t\t
LONESTAR II [34] | \n\t\t\tII | \n\t\t\t47 | \n\t\t\tSOF + RBV + peg-IFN for 12 wks | \n\t\t\t>96% | \n\t\t\tPreviously treated patients with and without cirrhosis | \n\t\t
A144040 [37] | \n\t\t\tII | \n\t\t\t44 | \n\t\t\tDAC + SOF ± RBV for 24 wks | \n\t\t\t>88% | \n\t\t\t\n\t\t |
PROTON [35] | \n\t\t\tII | \n\t\t\t25 | \n\t\t\tSOF + RBV + peg-IFN for 12 wks | \n\t\t\t92% | \n\t\t\t\n\t\t |
ELECTRON [36] | \n\t\t\tII | \n\t\t\t50 | \n\t\t\tSOF + RBV ± peg-IFN for 12 wks | \n\t\t\t100% | \n\t\t\tAmong the SOF + RBV arms of the study SVR was high, the SOF only group reported an SVR of 60% | \n\t\t
Results of DAA treatment in genotypes 2 and 3 patients
Legend: Wks: week; DAC: daclatasvir
\n\t\t\t\tTrial\n\t\t\t | \n\t\t\t\n\t\t\t\tPhase\n\t\t\t | \n\t\t\t\n\t\t\t\t\n\t\t\t\t\tn\n\t\t\t\t\n\t\t\t | \n\t\t\t\n\t\t\t\tRegimen\n\t\t\t | \n\t\t\t\n\t\t\t\tSVR\n\t\t\t | \n\t\t\t\n\t\t\t\tComments\n\t\t\t | \n\t\t
NEUTRINO [31] | \n\t\t\tIII | \n\t\t\t327* | \n\t\t\tSOF + RBV + peg-IFN for 12 wks | \n\t\t\t96% | \n\t\t\tPatients with genotypes 1, 4, 5, and 6. Of these 27/28 genotype 4 patients and 7/7 genotype 5 and 6 achieved SVR. | \n\t\t
Egypt Ancestry Trial [41] | \n\t\t\tII | \n\t\t\t60 | \n\t\t\tSOF + RBV for 12 or 24 wks | \n\t\t\t>79% | \n\t\t\tSVR was lowest in the 12-wk, treatment naïve group. | \n\t\t
RESTORE [42] | \n\t\t\tIII | \n\t\t\t107 | \n\t\t\tSIM + RBV + peg-IFN for 12 wks | \n\t\t\t>65% | \n\t\t\tSVR of 83% in the treatment naïve group, 40% in the prior null responders | \n\t\t
PEARL I [43, 44] | \n\t\t\tII | \n\t\t\t86 | \n\t\t\tOMB/PARr ± RBV for 12 wks | \n\t\t\t>91% | \n\t\t\tPreliminary data, patients in the RBV group achieved 100% SVR | \n\t\t
SYNERGY [45] | \n\t\t\tII | \n\t\t\t21 | \n\t\t\tLED/SOF for 12 wks | \n\t\t\t95% | \n\t\t\tPreliminary data, included previously treated patients | \n\t\t
ATOMIC [46] | \n\t\t\tII | \n\t\t\t316 | \n\t\t\tSOF + RBV + peg-IFN for 12 or 24 wks | \n\t\t\t>82% | \n\t\t\tPatients with genotypes 1, 4, 5 and 6; 9/11 genotype 4 and 5/5 genotype 6 achieved SVR | \n\t\t
Results of DAA treatment in genotype 4, 5 and 6 patients
Legend:*Of the 327, only 28 patients were genotype 4; Wks: week
Large phase III trials convincingly show favorable SVR in patients who are naive to treatment, noncirrhotic, and in non-HIV coinfected. However, what about patients who do not fit into these categories? Furthermore, concern for side effect profile, inadequate practitioner training, and concern for drug-drug interaction have led to avoidance in all but treatment-naive and otherwise healthy patients.
In addition to the unique groups of patients described below, other factors should also be taken into consideration as they can complicate the decision as to which treatment should be initiated. These include patients with renal failure, heart failure, and comorbid psychiatric illness to name a few. The medical comorbidities of each individual is a hornet’s nest of potential failure, and as such, each case embarked upon should be done so with careful consideration of all coexisting medical and psychological conditions. To ensure of this, it is helpful to have a trained multidisciplinary team made up of physicians, pharmacists, nurses, psychologists, and social workers. Aside from making medication dose adjustments when required, current guidelines recommend that in the presence of complex comorbid medical conditions, treatment of HCV be initiated and managed by a hepatologist and potentially at a medical center affiliated with liver transplantation [47].
Patients who have been previously treated pose perhaps one of the most common dilemmas that practitioners face. Often times, patients get retreated due to initial therapeutic failure (typically to peg-IFN and RBV) or HCV relapse. Patients may be presenting for retreatment following previous partial treatment or after being lost to follow-up. Rarely, patients can become reinfected with HCV. In all scenarios, therapy with new HCV drug regimens should be offered.
Initial studies with TEL, BOC, and SIM showed encouraging results. In the REALIZE trial, nonresponders, partial responders, or those who have suffered a relapse were randomized into three treatment groups separated by treatment duration. An SVR rate of 66% was achieved in the 12-week treatment arm of TEL, peg-IFN, and RBV [48]. Similarly, BOC in combination peg-IFN and RBV was able to achieve rates of SVR of 63% overall, however only 38% in prior nonresponders [49]. Larger trials and trials utilizing SIM showed similar results [50-53]. In general, all studies reported adverse side effects of severe anemia, requiring treatment discontinuation, dose reduction, or transfusion. Given the poor response of prior null responders, treatment utilizing TEL, BOC, or SIM in combination with peg-IFN and ribavirin is not recommended in the treatment experienced population.
Several promising trials evaluating the therapeutic benefit of newer DAAs have been reported with high overall SVRs, few side effects, and minimal drug interactions. (Tables 3-5). Based on these trials, recommendations regarding appropriate therapy as tailored to the genotype have been made. In general, genotype 1 patients have several options as convincing results as to effectiveness has been produced with either SOF/LED, SOF/SIM, or the four-drug combination of PARr/OMB/DAS/RBV. For those with genotype 2 or 3, reassuring data from the LONESTAR-2 trial that achieved SVR rates of 83-96% in these patients confirmed that a 12-week regimen of SOF, RBV, and peg-IFN be used [34]. For those not eligible for peg-IFN, SVRs of 80-90% were still achievable with SOF and RBV alone [32, 33]. In genotype 4 patients, options include SOF/LED, SOF/RBV with or without peg-IFN, or the four-drug combination of PARr/OMB/DAS/RBV. As with the treatment-naive patients, genotype 5 or 6 has few reported data, but an SOF-based regimen will likely be efficacious.
Cirrhosis, regardless of its level of compensation, is known to result in a decreased SVR in patients being treated for HCV. On decompensation with the development of ascites, variceal hemorrhage, encephalopathy, or coagulopathy, the probability of survival is only 50% at 5 years, with a median survival of only 2 years [54, 55]. Thus, it remains imperative to provide rapid and effective treatment for HCV.
A meta-analysis done by Vierling et al. [56] examined several phase III clinical trials of patients undergoing HCV treatment with biopsy proven cirrhosis. In the trials of patients receiving the standard therapy of peg-IFN and RBV, an overall SVR of 20% was found. In 2011, riding the momentum of improved SVR in noncirrhotic patients receiving triple therapy, BOC, TEL, and SIM were given in combination with peg-IFN and RBV, and the rate of SVR increased significantly to 55% and 74%, respectively, in this previously dismal population [53, 56]. Improvement in SVR was not without its drawbacks. In the BOC- and TEL-treated groups, significant side effects of anemia and diarrhea were noted. Slightly less severe side effects of flulike illness and pruritus were noted in those treated with SIM; however, significant resistance was found in genotype 1A patients who possessed a specific genetic polymorphism known as the Q80K mutation. A screening test for detection of this mutation is available, and given that nearly 50% of United States and 20% of European patients had the mutation at baseline, testing should be conducted prior to treatment with SIM [57].
Following on the success of a trial conducted by Gane et al. [58], which showed an SVR in 9 out of 9 patients with decompensated cirrhosis treated with SOF, LED, and RBV, the SOLAR-1 trial was conducted. This trial was a multicenter, randomized trial of 108 patients with genotypes 1 and 4 HCV whom also had Child-Pugh class B or C cirrhosis. Excluding 6 patients who underwent eventual liver transplant, an SVR of 87% and 89% was attained in the 12- and 24-week treatment groups, respectively. Given the larger chance of adverse events observed in the 24-week group, consensus guidelines for treating genotypes 1 and 4 patients with decompensated cirrhosis support a 12-week course of SOF, LED, and RBV [47]. Most importantly, the patients with virologic response had significant improvement in liver function, including improvements in bilirubin, albumin, modified end-stage liver disease (MELD) scores, and Child-Pugh scores. These guidelines recommend that for genotypes 2 and 3, daily SOF and RBV should be utilized up to 48 weeks for treatment. These recommendations are based on sparse data showing an achieved SVR in 10 of 11 patients [59]. Further data is needed in this group and is expected to change guidelines further. Preliminary data reported on the use of SOF, LED, and RBV for 12 weeks in genotype 3 patients showed favorable results with an SVR being achieved in all 26 patients treated [60].
Further research is needed in this group, including studies evaluating larger groups of patients to delineate a specific regimen. As it stands, similar to other unique populations, it appears that second-generation agents such as SOF, LED, and the like provide a superior benefit to first-generation protease inhibitors like SIM, TEL, and BOC. In addition to the pan-genomic action, improved dosing regimens, less drug-drug interactions, and more tolerable side effect profiles make them a first choice in patients with decompensated cirrhosis regardless of liver transplant candidacy.
HIV-infected individuals with concomitant hepatitis C are known to have an increased morbidity and mortality [61]. Following the development of highly active antiretroviral therapy (HAART), there has been an ever-increasing percentage of HIV-infected patients who are dying from liver disease. In HIV-infected patients, death from liver disease remains far more prevalent than death attributable to HIV-related complications [62, 63].
Historically, having coinfection with HIV also leads to poor responses to peg-IFN and RBV therapy [64, 65]. Additionally, coinfection with HIV also lead to increased risk for progression to cirrhosis [66]. On a molecular level, it has been postulated that the higher viral load of HCV RNA noted in this population is secondary to both increased replication of HCV RNA by HIV proteins as well as a generalized state of immunodeficiency [67, 68].
Up until recently, treating patients with coinfection of HIV was felt to be difficult secondary to the historically poorer responses to peg-IFN and RBV. Recently, however, concern regarding potential drug-drug interactions has existed and has lead to practitioner trepidation [69, 70]. This has fortunately not panned out, and several large trials have shown excellent results in treatment of the HCV/HIV coinfected.
With protease inhibitors approved first, trials utilizing a triple therapy of either TEL or BOC in combination with peg-IFN and RBV were conducted. Sulkowski et al. [71] treated 62 coinfected genotype 1 patients with TEL, peg-IFN, and RBV achieved an SVR of 74%. In another study, using triple therapy with BOC in combination with peg-IFN and RBV, an SVR of 63% was attained; however, significant side effects leading to dropout in 12 of 65 patients occurred. This dropout continues to be a concern and is thought to be secondary to side effects, high pill burden, and pharmacokinetic interactions between HCV NS3/4A protease inhibitors and antiretroviral drugs [72, 73].
Following on the success of first-generation DAAs, trials utilizing SOF were later conducted. In a study of genotype 1 patients, Osinusi et al. [74] treated 50 HCV and HIV coinfected patients with 12 weeks of SOF and LED. Grouping based on HAART naive versus on HAART showed no difference in the 100% SVR rates achieved in both groups. No adverse events or discontinuations were noted during the treatment period. Sulkowski et al. [75] was able to achieve an SVR of 67-88% based on genotype following a 12- to 24-week course of SOF and RBV. Of note, this approach was void of significant drug-drug interactions. In an even larger trial conducted by Molina et al. [76], 275 patients with genotypes 1-4 HCV underwent treatment with a 12-week course of SOF and RBV. The overall SVR rate achieved was 85% in genotype 1, 88% in genotype 2, 89% in genotype 3, and 84% in patients with genotype 4. Given the results of these trials, an SOF-based regimen, free of peg-IFN, is recommended; however, with new drug regimens being approved, further studies and head-to-head trials will need to be conducted in order to truly determine the best choice for these select patients.
Graft failure and fibrosis remain a feared complications among patients transplanted for HCV. Invariably, HCV recurs in all patients following transplantation. Similar to the pretransplant state, patients with HCV progress to fibrosis and eventual decompensation of the transplanted liver. Patients who undergo liver transplantation as a whole have been shown to have higher rates of mortality for this reason [77-79]. Routine monitoring has gone far to anticipate these changes; however, treatment needs continued improvement. Until recently, treatment with peg-IFN and RBV was only marginally effective, and use in this population was off-label. With the newly discovered DAAs, great promise for treatment exists. In addition to the superb ability to achieve SVR, DAAs offer favorable side effect profiles with manageable drug interactions with common immunosuppressive regimens. Some of the DAAs have been shown to do this better than others.
Complicating factors that must be discussed in this patient population include donor and recipient variables. Independent of the treatment regimen, certain characteristics have been shown in large retrospective analysis to negatively impact progression to fibrosis and cirrhosis following LT. The presence of advanced donor age or steatosis as well as specific genetic polymorphisms in both the donor and the recipient can lead to advanced progression of fibrosis [80-83]. Factors such as living vs. deceased donor, human leukocyte antigen (HLA) matching, and HCV positive donor status have not been shown to reliably contribute to fibrosis progression [84, 85]. Within the context of HCV-related liver transplantation, several studies have also attempted to identify specific allelic variants that may contribute to either poor response to standard antiviral therapy or a more rapid progression of fibrosis [86, 87]. Further studies are needed to confirm these, however, and as it stands due to the limited supply, the allocation of available livers for transplant based on the presence of nucleotide polymorphisms is not practiced (Table 6).
\n\t\t\t\tDonor Factors\n\t\t\t | \n\t\t\t\n\t\t\t\tRecipient Factors\n\t\t\t | \n\t\t
Age >50 years | \n\t\t\tGenotype 1B | \n\t\t
Liver steatosis >30% | \n\t\t\tIL28B Genotype CT and TT | \n\t\t
IL28B Genotype CT and TT | \n\t\t\t\n\t\t |
Lack of DDX58 polymorphism | \n\t\t\t\n\t\t |
Factors leading to worse outcomes following liver transplantation
Currently, three treatment strategies for management of HCV in the transplant setting are being used. The first strategy involves treatment of patients currently listed for transplantation. Until recently, the barrier with this strategy has been that with peg-IFN, RBV and the early DAAs patients often either do not tolerate therapy or do not achieve SVR [88]. The second strategy that is not being used thus far involves treating HCV recurrence immediately following liver transplantation. Whether or not this method of treatment increases in popularity will be determined by the tolerability and side effects of the new DAAs. The third and most commonly used strategy involves initiating treatment after several months following transplantation and noted progression of HCV.
Several trials have evaluated the effectiveness of using peg-IFN and RBV in order to treat HCV recurrence in patients following LT. The results have not been favorable, and side effects, particularly anemia, have posed barriers to treatment completion. Overall SVR, in patients with minimal fibrosis, following 48 weeks of therapy was only 48% [89]. Follow-up studies have had even less favorable results [90]. Therefore, peg-IFN and RBV alone is not recommended in this treatment group.
In the largest series evaluating the use of TEL and BOC for the treatment of HCV recurrence following liver transplantation, Burton et al. [91] successfully treated 81 patients with genotype 1 HCV and achieved an SVR at 12 weeks of 63%. Despite its success, TEL and BOC in combination with peg-IFN and RBV led to severe side effects of anemia requiring a transfusion in nearly 50% of patients. Additionally, close monitoring of immunosuppressant drug levels was required, and frequent dose adjustments were needed. Given these results, the use of BOC and TEL are not recommended unless newer, better-tolerated agents are unavailable.
Recent trials report favorable tolerability and highly effective results with the use of new DAAs. In a trial evaluating 40 patients treated with RBV and SOF, an SVR12 of 70% was achieved [92]. Slightly better results were achieved in the HCV-TARGET consortium, which evaluated 189 patients being treated with SOF-based regimens. Overall, SVR among the groups ranged from 69% to 88%. Additionally, SOF and SIM regimens achieved SVR12 of 80-88% depending if RBV was used [93]. The utilization of SOB in combination with LED is also being looked at and has shown that in patients with compensated disease and minimal cirrhosis, a highly favorable SVR12 of 96% could be attained. This regimen is also appealing as it only required 12 weeks of therapy [94]. Current guidelines put in place by the AASLD-ISDA recommend treatment of genotype 1 infection with combination SOF and SIM. For genotype 2 or 3, SOF or RBV alone is recommended [47]. These recommendations are likely subject to change given approval of LED as well as favorable results of a trial looking at ritonavir-boosted paritaprevir, coformulated with ombitasvir, plus dasabuvir [95]. The treatment of post-LT patients with more advanced cirrhosis (Child-Pugh B or C) continues to require further study; however, preliminary results reveal that even in this highly difficult-to-treat group, an SVR of 81% could be achieved [94]. Other regimens continue to be under investigation at this time.
It is anticipated that all-oral DAA regimens will be both highly effective as well as highly tolerated in the liver transplant setting. Continued research evaluating safety profiles of these medications should be done, but in the meantime, given the amount of evidence currently available and in accordance with current guidelines, the initiation of a sofosbuvir-based regimen in this patient population is highly recommended.
As alluded to in the sections above, DAA research is producing large quantities of favorable data, particularly in genotypes prevalent in Europe and the United States. Numerous clinical trials have been completed. More trials are ongoing or are recruiting. Naturally, head-to-head trials are needed to differentiate between many of the already known successful regimens, but few will agree to this in the short term. Future research should aim to improve the currently available classes of HCV drugs with the goal of limiting significant side effects. Specifically, we hope that all newly developed NS3-4A protease inhibitors, nucleoside/nucleotide analogues, nonnucleoside inhibitors of HCV NS5B, and NS5A inhibitors share a similar high-potency, pan-genotypic antiviral activity, and high barrier to resistance. In the distant future, perhaps DAAs will have lost their utility as research on vaccination continues [96].
Therapy for HCV has seemed to exponentially grow over the past 4 years. Because of DAAs, IFN-free as well as all-oral regimens are being used to treat HCV. In addition to this, ribavirin-free regimens are also available. Thus far, these highly effective therapies have proven to provide fewer side effects and achieve better results, all the while in less time. Hope for cure and eradication remains paramount and is now achievable. With appropriate allocation of resources, physician training, and available treatment, the cure of HCV is possible. Doing so will drastically decrease overall health care costs, improve quality of life, and decrease the number of liver transplants needed.
Chromium is a unique transition metal with relatively high abundance on earth crust (1.4 × 10−2%). Chromium can form several species with different oxidation states from −4 to +6. Chromium with 0, +3, and +6 oxidation states are most commonly found and utilized in ambient conditions [1]. In industrial sectors, chromium-based materials have been used as coating material for corrosion resistant, pigments and dyes, wood preservatives, tanning agent, catalyst, and medical apparatus [1]. Chromium, especially for chromium(III), also showed certain biological activity especially in regulating carbohydrates and lipid metabolism [2, 3]. As an essential micronutrient, a low dietary of chromium will exhibit several adverse effects such as glucose intolerance, growth disorders, diminished longevity, etc. [3, 4].
Chromium toxicity has been a controversial problem due to its status as an essential micronutrient [5]. Various studies have shown that numerous acute and chronic adverse effects can be caused by any dermal or systemic exposure of chromium species in human organ systems [6]. The toxicity and biological activity of chromium seem to be correlated directly with the concentration of corresponding chromium species [7]. In this case, chromium species have its optimum concentration to produce beneficial effects. Meanwhile, accumulation of less toxic chromium species in relatively high concentration will still produce a negative effect in the accumulation site [8, 9]. Chromium picolinate, for instance, has been mainly used as food supplement. Chromium(III) in this compound tend to accumulate in male Sprague-Dawley rats’ cells over the period of investigation [10] and may be oxidized to more carcinogenic chromium(V) and chromium(VI) within the cells [11].
As the outermost organ that protects the human body from various pollutants, the skin is usually exposed to various sources of chromium, and it causes many dermatological acute and chronic negative effects such as contact dermatitis [12], systemic contact dermatitis [13], and possibly skin cancer [14]. In the same way, any topical or systemic administration of chromium compounds also can exhibit a beneficial effect for the skin such as antiacne [15], rapid wound healing [16], and anti-aging [17]. In this chapter, both toxicity and biological activity of chromium species in the skin are described starting from the source and route of exposure, toxicity and its possible treatment, and biological activity.
In modern life, chromium has been used in many forms and applications with Cr(0), Cr(III), and Cr(VI) as the main oxidation states. Various sources of chromium that affect or may affect the skin have been identified and tabulated in several review [12, 18, 19]. In general, exposure route of chromium that comes from these sources can be classified into two pathways including dermal and systemic pathways. In these cases, direct dermal exposure would cause contact dermatitis, irritation, and skin cancer, while systemic administration would elicit systemic contact dermatitis and skin tumor.
Dermal exposure (Figure 1) is initiated from direct contact of chromium sources on the skin. Chromium species are then accumulated on the skin surface or penetrated into the skin layers mediated by sweat or other biological fluids. The penetration of chromium species either as particulate or soluble forms occurred via three possible routes including transcellular by crossing the cell, intercellular by partitioning into the lipid matrix, and transappendageal by entering hair follicle and sebaceous glands [20, 21]. There are many factors involved in the penetration process including concentration of chromium species, medium (solvent and pH), intrinsic properties of chromium species (molecular volume of chromium species, counter ion, nature of chemical bond and polarity, solubility, and valence), reactivity towards protein, previous penetration or accumulation, skin characteristics (gender and race, age skin, density of sebaceous gland, thickness of skin, and anatomy of skin), and environmental factors (temperature, humidity, and UV radiation) [21, 22]. In a normal skin condition, Cr(VI) ions tend to have higher solubility [23] and percutaneous permeability than Cr(III) ions [24, 25]. However, Cr(III) have higher protein affinity to form metal-protein complex which tends to make it retain in the skin epidermis [26]. After penetrating the skin, Cr(VI) species are reduced by proteins or endogenous antioxidants to form Cr(III) [27] which then react further with any DNA or protein to form Cr(III)-protein complex as the actual allergen (haptens) [28].
Several pathways of dermal exposure: (A) deposition of Cr(VI) in the skin surface causes irritation or chemical burn; (B) penetration of Cr(VI) through transcellular and intercellular pathways induces cell apoptosis and contact dermatitis, while Cr(III) tend to suspended in the skin surface due to strong affinity to skin protein; (C) deeper penetration to blood stream causes organ disruptions, (D) Cr species from systemic administration trigger systemic contact dermatitis, (E) deposition of Cr species on hair causes hair discoloration; (F) penetration of Cr species into hair follicle induces rapid hair fall. Figure is drawn using ChemBioDraw Ultra version 14.0 software.
In systematic exposure, chromium mostly enter the human body via oral consumption of certain chromium sources such as food or food supplement [29], foodstuff [30], and drinking water [31] or from applications of chromium-based implants [32]. In the digestive system, most of Cr(III) consumed are excreted to feces and some of it (~2%) is absorbed by epithelial cells covering the stomach and enterocytes covering the intestines through passive absorption (diffusion) [33]. This absorption was affected (increased or decreased) by the presence of various ligand such as amino acids, vitamins, carbohydrates, plasma proteins, certain metals, and other chelating agents [34]. After the absorption, Cr(III) complex would be accumulated inside the cells or actively transported to the blood stream by still an unknown transporter. Cr(III) ions then bound to transferrin (siderophilin) or other plasma proteins in the blood stream and travel to the whole body [33, 34].
Contact dermatitis is a common skin disease caused by repeated dermal contact with certain allergens (haptens) leading to delayed-type hypersensitivity effect [35]. Many haptens have been identified to cause contact dermatitis such as metals, fragrances, and flavors, preservatives, plastics, rubber, pharmaceutical, cosmetics, woods and plants, textile, etc. [35]. Chromium-induced contact dermatitis is characterized by the presence of certain clinical manifestations in feet and hands. Acute dermatitis is usually indicated by the formation of erythema, oedema, papules, vesicles, and weeping, while chronic dermatitis tends to form scaly, dry, and fissured skin [36]. Various chromium-induced contact dermatitis cases have been reported involving different chromium sources such as cement [37, 38], leather [38, 39, 40, 41, 42, 43], tattoo ink [44], cellular phone [45, 46], etc. Concentration threshold for soluble chromium in each chromium-containing product should not exceed 1 ppm to minimize elicitation of contact dermatitis [47].
In general, chromium-induced contact dermatitis is formed through several steps which can be described as the following (Figure 2) [48, 49]: initially, after penetrating the skin, Cr(VI) ions are reduced by endogenous antioxidant to form Cr(III) and oxygen reactive species (ROS). Cr(III) as the real allergen is bound to certain proteins to form the hapten, while ROS induces the releasing of interleukin-1β (IL-1β) which then activates antigen-presenting cells (Langerhans cells (LC)). Activated antigen-presenting cells bind with the hapten, mature, travel to the regional lymph nodes, and stay in paracortical T-cell areas. After that, activated antigen presenting cells-hapten complex activates naïve T cells by helping in vigorous blast formation and proliferation to become chromium-specific T cells. Activated chromium-specific T cells then travel through blood stream and recirculate to give hypersensitivity effect detecting a lower concentration of hapten in different parts of the skin.
Simplified elicitation mechanism of chromium-induced contact dermatitis adapted from several references [48, 49].
Treatment of chromium-induced contact dermatitis could be conducted in several approaches including avoiding direct contact to chromium source and topical application of chelating agent and barrier creams to prevent any cutaneous permeation, corticosteroid to relieve inflammation, and antioxidant to reduce oxidative stress [36, 50]. Various antioxidants have been tested in treating chromium-induced contact dermatitis such as N-acetylcysteine [51], ascorbic acid [52], pine bark extract (pycnogenol®) [53], and pterostilbene [54]. Two chelating agents, ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA), also have been examined for preventing contact dermatitis, but both of these ligands showed a low effectiveness as a protecting agent [55, 56]. The developments in chromium-induced contact dermatitis are still widely opened. These developments could be focused on finding natural antioxidant and chelating agents that effectively relieve oxidative stress and reduce the reactivity of chromium ions, respectively.
Systemic contact dermatitis is a kind of dermatitis elicited by systemic administration of certain allergen that previously sensitizes the skin through direct dermal contact [57]. Several groups of allergens have been identified to cause this inflammatory disease such as metals, medications, food, plants and herbals, and certain chemicals [57, 58]. Systemic administration of these allergens is also described in various routes including oral, subconjunctival, intramuscular, pulmonary inhalation, intranasal, intrauterine, endocardial, arthroplastic, intravenous, intraarticular, subcutaneous, intradermal, dental, intratubal, and endovascular [59]. The pathophysiology of this disease still remains unclear, but several mechanisms have been proposed [60, 61, 62, 63, 64, 65]. Moreover, the theory suggesting type 3 immune response (antigen-antibody complexes) involved in systemic contact dermatitis (SCD) has not fully been proven [58].
Chromium as a metal allergen has been found to cause systemic contact dermatitis either through oral, dental, or arthroplastic routes [13, 66, 67]. Consumption of Cr(III)-based supplements in the form of chromium picolinate [68] and chromium chloride [69] has been shown to cause SCD. Oral ingestion of potassium dichromate previously used as a homeopathic drug also induces dermatitis as clinical manifestation of SCD [70, 71]. In certain case, SCD is also induced by various metal alloys applied in orthopaedical, cardiac, neurological, and abdominal associated devices [72]. In these cases, chromium-containing alloys such as stainless steel SAE 316 L, cobalt-chromium-molybdenum steel, and Vitalium™ release metal ion [73] are reported to cause SCD [74, 75, 76, 77, 78, 79]. These reported SCD cases are identified with the presence of several manifestations including erythroderma [74], and localized/generalized eczema or urticarial [76, 77, 78]. These findings suggested that any chromium sources applied in systemic routes could elicit SCD with certain clinical manifestations and degrees of severity.
Treatment of chromium-induced systemic contact dermatitis may be conducted in several approaches including managing diets and lifestyles by gut remediation and avoiding the food and sources that contain chromium; systemic or topical treatment using immune-suppressants such as corticosteroid; phototherapy; and hyposensitization therapy [80, 81]. Sharma developed a guideline for the preparation of low chromate diet that could help in controlling daily chromium consumption from food and ameliorating skin condition [82]. In case of SCD from arthroplastic routes, revision or removal of implant needs to be conducted by considering the time of hypersensitivity incidence after surgery and degree of severity [74]. Revision of implant could be conducted by using less allergenic implant such as titanium-based implant or chromium-based implant coated with certain biocompatible materials such as polytetrafluoroethylene, ZrN multilayers, diamond-like carbon, titanium nitride, graphite-like carbon, and tantalum [74, 79, 83]. Revision or removal of implants may not produce rapid disappearance [76] probably due to the presence of soluble or particulate debris of implant that produce inflammations [84, 85].
Chromium, especially Cr(VI), is a potent human carcinogen. In a human cell, carcinogenesis of chromium(VI) (Figure 3) occurs through the penetration of chromium(VI) species into the cell via sulphate/phosphate anion transport system, reduction of chromium(VI) by endogenous antioxidant to produce ROS and chromium(III), and alteration of DNA directly by chromium(VI) or indirectly by ROS [86]. The alteration of DNA then produces different types of products including Cr-DNA adducts, DNA–protein and DNA interstrand cross-links, DNA breaks, and DNA base damage [87]. Carcinogenicity of chromium(VI) has induced lung cancer in workers from various chromium-based industries [88, 89, 90] and has been associated to incidence of other cancers [91]. However, the meta-analysis study showed that the correlation between exposure of chromium(VI) and the high mortality in skin cancer is not significant [91]. This study indicated that there is no supporting data confirming the chromium species as carcinogen in inducing skin cancer in human.
Simplified mechanism of chromium carcinogenesis adapted from several references [86, 95].
Several studies, however, showed that chromium species could induce skin cancer in rats and mice either as single carcinogen or cocarcinogen. Oral administrations of drinking water containing sodium dichromate dehydrate to male F344/N rats for 2 years showed that the sample developed various types of skin cancer [92]. Two other studies using hairless SK1-hrBR mice also exhibited that chromium(VI) could act as cocarcinogen in promoting UV-induced skin tumor [93, 94]. Davidson and co-workers [93] showed that oral administration of chromium(VI)-containing drinking water and UV irradiation to hairless mice have synergistic effect in promoting skin tumor. Exposure of chromium(VI) or UV radiation alone did not induce skin tumors [93]. Uddin and co-worker also conducted the same experiment and found that systemic administration of exogenous antioxidant (vitamin E and selenomethionine) did not improve skin condition [94]. It indicated that chromium(VI) cocarcinogenicity may be occurred in different mechanisms without involving ROS [94]. These three studies indicate that acute or chronic oral administration of chromium(VI) species has a great potency in promoting skin cancer in mammals including humans.
Irritation and chemical burn are caused by dermal exposure of chromium(VI) particle, solution, or mist in large quantities. Solid deposition of chromium(VI) would develop to “chromium ulcers” or “chrome holes” [67], while high concentration of chromium(VI) solution would lead to chromium burn. A mechanism for this ulcer formation is still unclear, but it may be related to the disruption of actin cytoskeleton by chromium(VI) leading to mitochondria-dependent apoptosis in skin fibroblasts cells [96]. Several reports exhibited these irritation and burning effects from different chromium species such as solid CrO3 [97], chromic acid solution [98, 99, 100], hot chromium(III) sulphate solution [101, 102], and chromium acid mist [103].
Management of irritation is conducted by considering preventive and treatment approaches. Prevention of irritation is conducted by using barrier creams, moisturizers, etc., while treatment could be done by using moisturizers and corticosteroids [50]. For chromium burn, treatment is conducted by combining mechanical excision, hemofiltration, and systemic administration of chelating agent and antioxidant [100].
Human hair is naturally exposed to a certain amount of chromium [104] that come from various sources [105, 106, 107]. Excessive and repeated exposures of chromium in certain environmental condition cause discoloration of blond, dyed-blond, and white hair (to become green) [108, 109, 110] and cause rapid hair fall [111, 112]. The mechanisms of these two effects are still unclear. Hair discoloration is probably the result of interaction between chromium ions (and also copper and nickel) and protein in hair (keratin) [113], while rapid hair fall may be related to several mechanisms such as promoting premature end of hair cycle [114] or disruption of hair shaft formation [115].
Acne vulgaris is a common dermatological condition that affects physical and psychological aspects of patients [116]. Several diseases that show the presence of a certain degree of acne also relate with depression and emotional stress such as type-2 diabetes, rheumatoid arthritis, and polycystic ovarian syndrome (PCOS) [117, 118, 119]. Pathophysiology of this disease involves several key mechanisms including excessive sebum production due to hormonal and environmental conditions, alteration of fatty acids composition due to sebum metabolism by Cutibacterium acnes, hyperkeratinization within the follicle that clogs up the pore in the form of whitehead or blackhead comedones, inflammation induced by bacterial colonization, and malfunction of locale innate and adaptive immune system [120]. The presence of acne vulgaris is also correlated to the clinical depression in patients [116]. In this case, depression or stress can influence the regulation of sebaceous gland as the main part in sebum production [121]. Catecholamines (epinephrine and norepinephrine) as the main stress hormones also affect the growth of certain Cutibacterium acnes strains [122, 123, 124]. Catecholamine-treated C. acnes strain also can stimulate a limited but significant increase of lipid production in sebaceous gland. However, the increase of intrinsic cytotoxicity or inflammatory potential of C. acnes is statistically significant [124].
Several reports exhibited that certain chromium(III) compounds have high activity in improving acne vulgaris. Initially, chromium has been used in the form of high-chromium yeast or chromium GTF (glucose tolerance factor) by consuming 400 μg chromium daily which exhibited comparable improvement in acne conditions [15]. This form of treatment, recently, is considered as a complementary and alternative medicine (CAM) for the treatment of acne vulgaris [125]. Further improvements used different chromium compounds including chromium picolinate [126, 127] and chromium salt such as chromium (III) chloride [128].
In most cases, the usage of chromium compound as antiacne is usually combined with other active compounds such as vitamins, certain minerals, and herbal medicine sources in the form of oral [129, 130, 131] or topical [128] formulation to get more effective treatment results. Application of topical formulation containing chromium (III) chloride and magnesium sulphate showed total improvement in acne vulgaris with temporal mild to moderate irritation as a side effect [128]. Oral capsule containing methionine-bound zinc complex, chromium, and vitamins also exhibited 80–100% improvements for mild to moderate acne vulgaris [131]. In another study, a combination of several nutrients with potential antiacne and anti-depressant properties (eicosapentaenoic acid, epigallocatechin-3-gallate, zinc gluconate from green tea extract, selenium, and chromium) may also improve inflammatory acne lesions and mood aspect of patients [132].
Treatment of acne vulgaris in polycystic ovary syndrome (PCOS) showed mix results. A study by Amr and Abdel-Rahim showed that using 200 μg/day oral consumption for 8 weeks has no significant improvement in acne and hirsutism [126]. In a different study, chromium supplementation by women with polycystic ovary syndrome (PCOS) in a randomized, double-blind, placebo-controlled trial exhibited that the treatment gives beneficial effects on acne and hirsutism using 1000 μg/day oral consumption for 6 months [127]. These two studies indicated that the treatment of acne vulgaris in PCOS patients needs greater dose and longer duration.
Action mode of chromium in ameliorating acne vulgaris has not been fully elucidated yet, but there are two mechanisms proposed including (1) by decreasing serum testosterone concentration and (2) lowering the depression of patients. In the first mechanism, chromium can decrease serum testosterone level possibly due to the reduction of testicular steroidogenic enzymes activities [133]. In this case, a lower level of serum testosterone reduces sebum production in sebaceous glands [134]. The second mechanism explains that chromium as an anti-depressant [135, 136, 137] may reduce sebum production [138] and affect C. acnes growth in sebaceous glands [122, 123, 124]. It is clearly showed that these two mechanisms may have direct or indirect synergistic effects [139] in ameliorating skin condition with acne vulgaris.
Aging is a complex multifactorial process of damage accumulation that causes the deterioration of fitness [140, 141]. Aging has been the main risk factor for several deadly diseases such as cancer, cardiovascular disease, diabetes, and neurodegeneration [141]. In the skin, aging is identified by the presence of folds and wrinkles due to the declining and degradation of collagen [142], loss of elasticity [143], and decreasing of various skin functions [144]. At least, there are seven factors that may produce these clinical manifestations including passage of time, genetics, radiation such as ultraviolet and infrared radiations, lifestyle, chronic debilitating diseases, dysfunction of hormonal system, and gravitational force [145]. Several mechanisms have been proposed to explain the effect of these factors on aging including oxidative stress, telomere shortening, epigenetic dysregulation, DNA damage, genetic mutation, inflammation, mitochondrial dysfunction, and accumulation of glycation end product [146, 147].
Treatment for skin aging can be conducted through three approaches including adjusting lifestyle by routine exercise, calorie restriction, and maintaining mental health; gene therapies; and medications. Among other approaches, medication could be the simplest approach in fighting skin aging such as by using topical or systemic agents [148]. Chromium as dietary supplement (50–200 μg) has been used in preventing skin aging by controlling and regulating blood sugar and lipid levels [17]. Either in topical or systemic applications, chromium is usually combined with different vitamins and minerals to obtain optimum results based on certain parameters such as improving insulin function using chromium picolinate [149], promoting mitochondrial biogenesis and lipid metabolism using oligomannuronate-chromium(III) complexes [150], replacing or removing excess iron production using chromium(III) chloride or chromium picolinate [151, 152], and activating telomerase [153].
Antioxidant activity of chromium may also contribute to its anti-aging properties since oxidative stress has a certain role in the damaging process. Supplementation of chromium(III) in adult male and female with type-2 diabetes mellitus minimized the increase of oxidative stress (thiobarbituric acid reactive substances—TBARS) and increased total antioxidant status [154, 155]. Several combinations have been made by formulating chromium(III) with zinc [156], niacin [157], and vitamin C/E [154] and showed a protective effect against skin damage against oxidative stress.
Antioxidant activity of chromium(III) is correlated to the dose applied as shown in several experiments. Incubation of BALB/3 T3 clone A31 cells and HepG2 cells with chromium(III) chloride concentration higher than 400 μM would induce the formation of oxidative stress, while lower optimized concentration (M = 100–200 μM) would increase superoxide dismutase and catalase antioxidant activities [7]. In vitro study on the effect of chromium(III) and chromium(VI) on catalase activity also showed this dose-dependent activity in which treatment of cell-free catalase using chromium(III) (dose range 1–5 × 10−5 mol/L) and chromium(VI) (dose range 1–4 × 10−5 mol/L) separately increased the catalase activity [158]. These two studies clearly describe that either chromium(III) or chromium(VI) has a certain optimum concentration to exhibit their beneficial effects.
Cutaneous wound is the skin defect or skin opening that is caused by external forces [159]. Formation of this wound triggers a set of complex biochemical processes to repair the damage that are called as wound healing or wound repair. In normal condition, there are five consecutive phases occurred in wound healing process including (1) homeostasis phase (immediately) through the migration of thrombocytes and formation of fibrin clot to stop the bleeding; (2) first inflammatory phase (day 1–day 6) by sensing the injury, sending the danger signal, and initializing the inflammation; (3) second inflammatory phase (day 1–day 6) through elimination the pathogens and cleaning the wound; (4) proliferation phase (day 4–day 14) through epithelialization, angiogenesis, granulation tissue formation, and collagen deposition to repair the damage and initialize the tissue remodeling process; and (5) remodeling phase (day 8–year 1) through the deposition of collagen to reach maturation of tissue structure [160, 161, 162]. Several internal and external factors have been identified to affect the wound healing process including oxygenation, infection and foreign body, lifestyle, hormonal effect, age, and gender [163].
Several studies have shown that chromium(III), in a certain condition, could improve cutaneous wound either in normal or diabetic Wistar rats using a single dose of a combination of zinc(II) (1.5 mg/kg weight) and chromium(III) (0.02 mg/kg weight) [164] and C57BL6/J mice using chromium(III) chloride (80 μg/kg weight/day) for 21 days [16]. The mechanism of this effect has not been fully elucidated yet, but it may be related to chromium(III) activity in increasing insulin sensitivity, insulin-like growth factor 1 (IGF-1) serum concentration, and protein deposition [16, 165]. In this case, high glucose concentration could inhibit proliferation and differentiation of skin keratinocytes [166] and increase the stiffness of collagen [167] which further inhibits wound healing. In healing acetic acid-induced colitis wound, chromium(III) also acted as an anti-inflammatory agent by inhibiting several inflammatory markers and downregulating pro-inflammatory cytokine genes and antioxidant by suppressing oxidative stress without any significant side effect [168].
In different situations, the use of chromium-based skin clips [169] and orthopedic implant [74] gave an adverse effect by delaying surgery wound healing process. These cases represented a hypersensitivity effect as a manifestation of systemic contact dermatitis. In vitro study using human skin keratinocyte cell line (HaCaT cells) in a medium containing chromium(III) solution (10−6 M) showed that chromium(III) ions can decrease wound closure rate and be further decreased when the medium was replaced with another chromium(III) ion-containing medium [170]. Chromium(III) ions also caused downregulation of toll-like receptor-2, -4, and -9 messenger ribonucleic acids (TLR-2, -4, and -9 mRNA), upregulation of matrix metalloproteinase 2 and 13, and upregulation of intercellular adhesion molecule 1 messenger ribonucleic acid (ICAM-1 mRNA) [170].
There’s no exact explanation for these opposite effects. However, it may be related to the local concentration of chromium species in wound location. An enhancing effect of wound healing was obtained by applying a relatively small concentration of chromium species via oral administration. In human, for instance, there is only 2% of oral chromium(III) that will be absorbed through stomach and intestine and distributed throughout the body. In the same time, an adverse effect was obtained when local chromium concentration was high due to a particulate and soluble chromium released from the implants.
Chromium as versatile heavy metals showed contradictive properties dealing with its dermatologic toxicity and biological activity properties. The main factors that probably correlate to these properties are concentrations and species of chromium. Significant increment of local chromium concentration (more than 1 ppm for chromium[VI] species) either from dermal or systemic administration would increase the risk of dermatologic toxicities, while topical or oral administration of small recommended dietary concentration of chromium (50–200 μg for chromium picolinate) would give several beneficial effects. More studies need to be conducted to know the exact effect of the local concentration of corresponding chromium species in many systems.
The financial support from Ministry of Research, Technology and Higher Education of the Republic of Indonesia who has funded the research in calixarene- and resorcinarene-based heavy metal adsorbents is acknowledged.
The authors state that there is no conflict of interest.
Edited by Jan Oxholm Gordeladze, ISBN 978-953-51-3020-8, Print ISBN 978-953-51-3019-2, 336 pages,
\nPublisher: IntechOpen
\nChapters published March 22, 2017 under CC BY 3.0 license
\nDOI: 10.5772/61430
\nEdited Volume
This book serves as a comprehensive survey of the impact of vitamin K2 on cellular functions and organ systems, indicating that vitamin K2 plays an important role in the differentiation/preservation of various cell phenotypes and as a stimulator and/or mediator of interorgan cross talk. Vitamin K2 binds to the transcription factor SXR/PXR, thus acting like a hormone (very much in the same manner as vitamin A and vitamin D). Therefore, vitamin K2 affects a multitude of organ systems, and it is reckoned to be one positive factor in bringing about "longevity" to the human body, e.g., supporting the functions/health of different organ systems, as well as correcting the functioning or even "curing" ailments striking several organs in our body.
\\n\\nChapter 1 Introductory Chapter: Vitamin K2 by Jan Oxholm Gordeladze
\\n\\nChapter 2 Vitamin K, SXR, and GGCX by Kotaro Azuma and Satoshi Inoue
\\n\\nChapter 3 Vitamin K2 Rich Food Products by Muhammad Yasin, Masood Sadiq Butt and Aurang Zeb
\\n\\nChapter 4 Menaquinones, Bacteria, and Foods: Vitamin K2 in the Diet by Barbara Walther and Magali Chollet
\\n\\nChapter 5 The Impact of Vitamin K2 on Energy Metabolism by Mona Møller, Serena Tonstad, Tone Bathen and Jan Oxholm Gordeladze
\\n\\nChapter 6 Vitamin K2 and Bone Health by Niels Erik Frandsen and Jan Oxholm Gordeladze
\\n\\nChapter 7 Vitamin K2 and its Impact on Tooth Epigenetics by Jan Oxholm Gordeladze, Maria A. Landin, Gaute Floer Johnsen, Håvard Jostein Haugen and Harald Osmundsen
\\n\\nChapter 8 Anti-Inflammatory Actions of Vitamin K by Stephen J. Hodges, Andrew A. Pitsillides, Lars M. Ytrebø and Robin Soper
\\n\\nChapter 9 Vitamin K2: Implications for Cardiovascular Health in the Context of Plant-Based Diets, with Applications for Prostate Health by Michael S. Donaldson
\\n\\nChapter 11 Vitamin K2 Facilitating Inter-Organ Cross-Talk by Jan O. Gordeladze, Håvard J. Haugen, Gaute Floer Johnsen and Mona Møller
\\n\\nChapter 13 Medicinal Chemistry of Vitamin K Derivatives and Metabolites by Shinya Fujii and Hiroyuki Kagechika
\\n"}]'},components:[{type:"htmlEditorComponent",content:'This book serves as a comprehensive survey of the impact of vitamin K2 on cellular functions and organ systems, indicating that vitamin K2 plays an important role in the differentiation/preservation of various cell phenotypes and as a stimulator and/or mediator of interorgan cross talk. Vitamin K2 binds to the transcription factor SXR/PXR, thus acting like a hormone (very much in the same manner as vitamin A and vitamin D). Therefore, vitamin K2 affects a multitude of organ systems, and it is reckoned to be one positive factor in bringing about "longevity" to the human body, e.g., supporting the functions/health of different organ systems, as well as correcting the functioning or even "curing" ailments striking several organs in our body.
\n\nChapter 1 Introductory Chapter: Vitamin K2 by Jan Oxholm Gordeladze
\n\nChapter 2 Vitamin K, SXR, and GGCX by Kotaro Azuma and Satoshi Inoue
\n\nChapter 3 Vitamin K2 Rich Food Products by Muhammad Yasin, Masood Sadiq Butt and Aurang Zeb
\n\nChapter 4 Menaquinones, Bacteria, and Foods: Vitamin K2 in the Diet by Barbara Walther and Magali Chollet
\n\nChapter 5 The Impact of Vitamin K2 on Energy Metabolism by Mona Møller, Serena Tonstad, Tone Bathen and Jan Oxholm Gordeladze
\n\nChapter 6 Vitamin K2 and Bone Health by Niels Erik Frandsen and Jan Oxholm Gordeladze
\n\nChapter 7 Vitamin K2 and its Impact on Tooth Epigenetics by Jan Oxholm Gordeladze, Maria A. Landin, Gaute Floer Johnsen, Håvard Jostein Haugen and Harald Osmundsen
\n\nChapter 8 Anti-Inflammatory Actions of Vitamin K by Stephen J. Hodges, Andrew A. Pitsillides, Lars M. Ytrebø and Robin Soper
\n\nChapter 9 Vitamin K2: Implications for Cardiovascular Health in the Context of Plant-Based Diets, with Applications for Prostate Health by Michael S. Donaldson
\n\nChapter 11 Vitamin K2 Facilitating Inter-Organ Cross-Talk by Jan O. Gordeladze, Håvard J. Haugen, Gaute Floer Johnsen and Mona Møller
\n\nChapter 13 Medicinal Chemistry of Vitamin K Derivatives and Metabolites by Shinya Fujii and Hiroyuki Kagechika
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