Extraction conditions from various plants using UAE.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\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:"7038",leadTitle:null,fullTitle:"Vitamin D Deficiency",title:"Vitamin D Deficiency",subtitle:null,reviewType:"peer-reviewed",abstract:'Vitamin D is the topic for many discussions in the scientific community. Nowadays, a different interpretation of this secosteroid hormone is needed. Today the term "vitamin" may be considered outdated. This compound may be correctly be called a vitamin only when it is administered to humans or animals that suffer from its deficiency. This book attempts to clarify the role of Vitamin D deficiency in many pathological processes in the whole organism. Chapters in this book cover such issues as the earliest clinical and preclinical investigations of the consequences of Vitamin D deficiency for cognitive, cardiovascular, metabolic, immune, and renal disorders.',isbn:"978-1-83880-776-4",printIsbn:"978-1-83880-775-7",pdfIsbn:"978-1-83880-777-1",doi:"10.5772/intechopen.73799",price:119,priceEur:129,priceUsd:155,slug:"vitamin-d-deficiency",numberOfPages:282,isOpenForSubmission:!1,isInWos:1,hash:"ba24f0913341357b0779ff9529c4bbfc",bookSignature:"Julia Fedotova",publishedDate:"February 26th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/7038.jpg",numberOfDownloads:5077,numberOfWosCitations:1,numberOfCrossrefCitations:3,numberOfDimensionsCitations:3,hasAltmetrics:1,numberOfTotalCitations:7,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 16th 2019",dateEndSecondStepPublish:"August 26th 2019",dateEndThirdStepPublish:"October 25th 2019",dateEndFourthStepPublish:"November 18th 2019",dateEndFifthStepPublish:"January 17th 2020",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,editors:[{id:"269070",title:"Prof.",name:"Julia",middleName:null,surname:"Fedotova",slug:"julia-fedotova",fullName:"Julia Fedotova",profilePictureURL:"https://mts.intechopen.com/storage/users/269070/images/system/269070.jfif",biography:"Julia O. Fedotova, MD, PhD habil., Doc. Biol. Sci, was born in\nSt. Petersburg (Russia), in 1973. She graduated with her Diploma of Pharmacist, Pharmaceutical Faculty, St. Petersburg State\nChemical-Pharmaceutical Academy in 1996. She received her\nPhD in specialties – experimental and clinical pharmacology and\nphysiology of human and animals in 1999. She attended Medical\nSchool, Department of Pharmacology, University of Catania in\n2002, and the Institute of Physiology, Medical School, University of Pecs. She graduated from the special doctoral course in neuropharmacology at the Department\nof Neuropharmacology in the Institute for Experimental Medicine of the Russian\nAcademy of Medical Sciences and she received her doctor of Biological Sciences\n(Ph.D. habil.) in 2008. She is currently a professor at the ITMO University and the\nleading researcher at the I.P. Pavlov Institute of Physiology. She has more 200 publications (mostly in Russian), 2 patents, and 4 journal articles in collaboration, as\nwell as 6 chapters in journals.\nShe is a head of the project “The studying of Vitamin D3 role in development of\naffective-related disorders in women with climacteric period, the search of ways for\npharmacorrection”, from the highly prestige Russian Scientific Foundation.",institutionString:"ITMO University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"ITMO University",institutionURL:null,country:{name:"Russia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"379",title:"Vitaminology",slug:"alimentology-vitaminology"}],chapters:[{id:"68649",title:"Vitamin D and Its Deficiency in Saudi Arabia",doi:"10.5772/intechopen.88745",slug:"vitamin-d-and-its-deficiency-in-saudi-arabia",totalDownloads:531,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Fawzi F. 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The use of ultrasound in regional anesthesia has shown the reduction of complications, which makes it mandatory to knowledge and acquire skills in all ultrasound-guided techniques.
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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:"61397",title:"The Ethics in Repeat Heart Valve Replacement Surgery",doi:"10.5772/intechopen.76844",slug:"the-ethics-in-repeat-heart-valve-replacement-surgery",body:'The treatment of patients with intravenous drug use (IVDU) has evolved to include a wide range of medications, psychiatric rehabilitation, and surgical interventions, especially for life-threatening complications such as infective endocarditis (IE). These interventions, however, remain at the discretion of surgeons, and the healthcare team, whose treatment decisions are influenced by several medical factors, unfortunately not without bias. The stigma associated with substance use disorder is prevalent, especially toward IVDU, which leads to significant biases, even in the healthcare system [1]. This bias is heightened when IVDU patients require multiple or repeat valve replacement surgeries for IE due to continued drug use, which can be quite costly for healthcare institutions.
We explore various barriers when considering repeat heart valve surgeries, especially the implicit bias that can negatively influence the duty of physicians and their decision to provide comprehensive patient care. Patients who receive a valve replacement and continue to use illicit drugs intravenously, often return to their medical providers months to years later with a re-infection of their prosthetic valve; many of these patients have several medical comorbidities and require extensive care. The topic of multiple or repeat heart valve surgeries are the center of many ethical discussions due to the high mortality rates associated with both the inherent mortality from ongoing drug abuse and the risks of often complex and technically challenging high-risk re-operative cardiac surgery.
This chapter examines the ethics of repeat heart valve replacement surgery for patients who are struggling with addiction, and the important factors that ought to guide health care professionals in making future treatment decisions. Considerations of justice, the fiduciary therapeutic relationship, and guiding ethical principles justify medically beneficial repeat heart valve replacement surgeries for IVDU patient populations. We will present and analyze two cases, which were presented to a hospital ethics committee, and provide justification for a narrative-based ethical approach to identify those factors for when patients ought to receive multiple heart valves and the conditions for pursuing this surgical intervention despite chemical dependency challenges.
To better examine the ethical and social issues significant to discussions about heart valve replacement surgery among IVDU populations, particularly those seeking repeat surgeries due to chemical dependency relapse, it is important to understand the current climate in the United States with respect to IVDU and IE, as well as the need for comprehensive surgical and mental health care for patients who are committed to their recovery.
There is an increasing body of literature prompted by the rapid increase of prescription and non-prescription opioid drugs in the United States that emerged in the 1990s and is at epidemic levels today. In 2016, 64,000 Americans died from drug overdoses, which was a 21% increase from the year before [2]. Some states are struggling more than others to combat this leading cause of death among Americans under age 50 [2]. Unfortunately, there is more discussion about public health and law enforcement interventions, rather than focusing on individualized medical care in persons who are in critical need of comprehensive therapy, which includes high-risk surgeries, detoxification programs, and extensive mental health care for chemical dependency among other related mental health disorders. Helping the addict is discussed less frequently as an important step to fight this epidemic [3], which is relevant to our ethical and social examination as to why we need to re-think the standards of medical care and treat patients holistically by incorporating mental health care into every aspect of their overall care. This is especially pertinent to the treatment of IE secondary to IVDU.
With the rise of the opioid epidemic in the past few years, high-risk valve replacement surgeries have become a growing medical, financial, and ethical burden. Historically, IVDU represented a small percentage of patients with IE. In one study, the proportion increased from 14.8% in 2002–2004 to 26% in 2012–2014 during which time, heroin use doubled [4, 5]. Today, approximately 11% of IVDU are at risk for developing IE [6], which is characterized by infection of the inner lining of the heart, leading to the growth of vegetation on heart valves that disrupt the ability to pump blood. Overall, IE is an extremely morbid disease: in-hospital mortality rates range from 11 to 26% with an estimated 5-year mortality of up to 50% [7]. Complications include heart failure, valve insufficiency, embolic strokes, and intracerebral hemorrhage. IE secondary to IVDU is most commonly caused by bacteremia from Staphylococcus aureus and Enterococcus faecalis that are abundantly found on the skin and gastrointestinal tract, or by particulates in illicit drugs that cause micro-damage to tissues as they circulate [8, 9] following injection. Treatment is often sufficient using high-dose antibiotics, but 60 to 70% of severe cases require surgical intervention [4].
Studies have shown that patients with IE secondary to IVDU are younger than patients with no IVDU and more likely to be young Caucasian males, with some regional variability among populations [4]. The average age of patients who suffer from IE secondary to IVDU is 30 years old, and 90% of them are heroin addicts [7, 8]. Approximately 75% of individuals admitted to treatment for heroin abuse or dependency reported using injection as the primary method of drug use [10].
Despite IVDU representing a significantly younger patient population with less cardiovascular and comorbid risk factors, long-term outcomes are compromised by reinfection [4] and continued drug abuse. A patient who receives a valve replacement yet continues to use intravenous drugs is likely to re-infect their bioprosthetic or homograft valves, requiring additional valve replacement surgeries. However, such treatment opportunities may not be offered to this patient population due to high mortality rates. For example, studies have found that patients who resume IVDU after their initial valve replacement have high mortality compared to patients who abstain from drug use after their surgery [11]. A patient who resumes IVDU may get an extra 1–5 years of life out of their new valve rather than the 10–15 years of life that a new valve (mechanical or biological) can give without IVDU. Such decision-making must also be done in the setting of the overall poor and limited (but somewhat incompletely defined) life-expectancy of the habitual use of IV drugs.
In general, many surgical professionals identify repeat valve replacement surgery as non-beneficial for patients with IVDU, and thus, refuse or are reluctant to offer this procedure or refer patients to other surgeons who are willing to treat this patient population. Even when the valve replacement surgery may provide some benefit and give a few more years of quality life for patients, surgical professionals and the healthcare team may feel as though the financial burdens to patients and healthcare institutions is a reasonable justification for not replacing infected valves. This is especially true given the high relapse rates for IVDU and readmission with active IVDU. In addition, because the IVDU patient population contributes to increased unemployment and reliance on publicly funded insurance [12], some health care professionals may feel as though they have a duty to the community by not prolonging the lives of patients with IE secondary to IVDU, and thus adding additional financial burdens for communities and an already resource-limited health system.
Smyth et al. (2010) conducted a prospective study of patients who were dependent on opioids and admitted to a residential chemical dependency service for treatment. The authors found that 91% of 109 patients interviewed had relapsed; 59% relapsed just within one week of discharge [13]. Those who had earlier relapse were characteristic of our patient population; patients are younger in age, have a history of IVDU, did not complete the recommended length of time in the addiction program, and did not enter in or commit to aftercare programs. The authors also found that delayed relapse occurred among those who completed their entire program, as well as those individuals who were in a relationship with an opiate user, which was an unexpected finding and deserves further research [13].
Furthermore, given the significant rise of IVDU with the opiate epidemic in the United States, further research on relapse is needed, including the multitude of factors that contribute to relapse. Without addressing the factors that contribute to relapse, the rate will continue to rise, perpetuate stigma, fuel healthcare professionals’ reluctance to provide multiple heart valve replacement surgeries, among other medical interventions. A study in China examined heroin addiction relapse and the effects of detoxification medications (methadone) combined with psychological counseling and social support measures, which were found to be essential to on-going recovery and reduction of relapse rates along with patient compliance [14]. Additional studies have found that patients who recur to IVDU after the initial valve replacement procedure have very high mortality compared to patients who undergo rehabilitation [15].
From a medical perspective, the relationship between IE and substance use disorder is no different than nephropathy and diabetes, coronary artery disease and smoking, or the countless other chronic medical problems that are worsened by “life-style” choices. However, the negative connotations and stigma associated with IVDU lead to patients being treated differently in the health care system and among physicians, who deny life-saving care and devalue their patients as persons in need of advocacy and support to combat their addictions.
Unfortunately, little research has been done on the value of extensive psychiatric and behavioral health interventions prior to, during, and following surgical treatment and the overall clinical, psychosocial, and legal outcomes (e.g., improved medical compliance, reduced recidivism in drug use and criminal acts). One study found that only 7.8% of patients treated for IE were discharged with plans to receive medication-assisted treatment during the 10-year period of the study. In that same study, 25% of patients were readmitted with active IVDU [16]. Aggressive treatment for IE, including antibiotics and valve transplants, is neither effective nor advantageous without targeting the underlying addictive behaviors that contribute to poor health outcomes and mortality.
Addiction treatment, particularly for opioid users, is limited by factors that are beyond the control of physicians and drug users who may be willing to seek recovery. A study published by Jones et al. in 2015 reported that nationally, 96% of states (48 out of 50) had lower opioid treatment program capacity rates than their corresponding opioid abuse or dependence rates. The study also reported that 38 states had over 75% of their opioid treatment programs operating at an 80% capacity or more [17]. These numbers are indicative of a severe national shortage in treatment options, which could in part explain the ongoing struggle in IVDU achieving or maintaining their recovery.
Furthermore, little theoretical work has been done to identify the complex ethical issues surrounding this IVDU patient population who qualify for valve replacement surgery but who may be denied this life-sustaining intervention due to a number of factors including, but not limited to, financial cost, perceived poor quality of life, suspected non-compliance in post-surgical care and addiction treatment, and social worth. This chapter aims to start closing these gaps and to provide guidance to surgeons and healthcare teams when confronted with difficult medical, social, and ethical dilemmas.
Thus, through the presentation of two cases of IE secondary to IVDU, we will identify the medical, social, and ethical issues, recommendations for whether we should provide repeat valve replacements, and how we ought to treat patients who are struggling with mental health issues, including, but not limited to chemical dependency. Our case analyses will also identify the limits of justice and the duty of health care professionals in providing repeat heart valve surgeries.
The following two case presentations are based on actual patients with identifying information removed so as to protect their identities. These cases were presented to an ethics committee for an initial recommendation; however, the analysis and discussion presented here extends beyond committee consultation or even those guiding ethical principles that contribute to decision-making and resolution. These cases reveal a need for a narrative ethical approach to best understand individual patients and their medical, psychosocial, and value-based needs from diagnosis through recovery. The cases presented in this chapter are montages of health care team members’ stories about their interactions with patients through medical evidence, patient interviewing, and clinical observation. However, there is an equal need for the medical team and the patient to co-author or construct a joint narrative of illness and medical care [18, 19]. These cases, however, do represent the multiple voices of the multidisciplinary medical team about the patient in a brief, accessible case presentation. The features of these cases serve as valuable starting points for understanding the complexity of medical decision-making, unifying repeat heart valve replacement, post-operative care, and mental health treatment, and the need for ongoing recognition of the patient’s story.
A 24-year-old homeless, female patient is brought into the emergency department by a family member and presents for sepsis related to IVDA. The patient has a 10-year history of drug use with previous endocarditis, requiring cardiac surgery and debridement of an infected tricuspid valve approximately 14 months prior to the current admission. She has a history of untreated depression. The patient is admitted for complaints of joint pain, swelling, and general malaise. She reports injecting heroin and crack cocaine in her extremities (feet, arms, and hands) daily. The patient was drug-free for a short period of time with the assistance of residential treatment and hospitalization at a nursing facility where she received IV antibiotics for the endocarditis. However, the patient missed a dose of Suboxone (buprenorphine and naloxone) due to lack of transportation, did not seek support from health care professionals, and was unsuccessfully attempting to stop her persistent drug use on her own. Her continued drug use and failure of medical management have resulted in the need for pre-operative cardiac surgery for large vegetation in the tricuspid valve. The patient is willing to pursue addiction treatment following surgery and post-operative care and has had a history of taking Suboxone as an effort to stay clean and sober. An ethics consult is called to provide a recommendation on whether it is ethically permissible to re-operate in this patient with infective endocarditis from persistent IVDU. The ethics committee further weighed in on recommendations for achieving a unified care model in which the immediate medical needs namely, heart valve replacement, antibiotic therapy, and acute peri-operative pain management. Critical in the discussion was also providing a pathway that includes comprehensive mental health care for the patient’s depression and addiction.
A 29-year-old married male with a history of depression, multiple suicide attempts, polysubstance intravenous drug use (heroin and methamphetamines), and a history of endocarditis was brought to the emergency department by EMS following a suspected overdose. The patient was unresponsive until EMS delivered multiple doses of naloxone in route to the emergency department. Upon arrival, the patient was alert but had difficulty speaking. The patient’s wife, who is a recovering addict, alerted EMS to her husband’s overdose. Upon questioning the patient’s current drug use, he admits to using methamphetamine cut with Fentanyl over the past week. The patient was drug-free for approximately 1.5 months after a prior hospital admission for septic mitral valve endocarditis due to IVDA, as well as renal failure, which was resolved following treatment. He received a bioprosthetic mitral valve and antibiotic therapy. Aside from his brief period drug-free, he has never been in treatment specifically for his chemical dependency and currently feels like he doesn’t need such treatment. The patient suffers from multiple cerebral septic emboli with hemorrhagic transformation, aphasia, and distal limb emboli. He currently reports feeling feverish with body chills, headache, and joint pain; lab results show Serratia bacteremia, hypokalemia, transaminitis, anemia, and thrombocytopenia (I do not think we need these labs after Serratia bacteremia). An ethics committee is called upon to guide the treating surgeon whether this patient should receive a repeat valve replacement if he medically qualifies for this intervention. Additional ethical guidance is sought to determine what are the ethical obligations of the healthcare team when the patient does not believe he needs chemical dependency treatment and is likely to have repeated events of IE secondary to IVDU.
The above cases are representative of several medical, social, and ethical issues presented when patients are suffering from IE secondary to IVDU and who may require a repeat heart valve surgery and extensive mental health care for addiction and other related mental disorders (e.g., depression). In situations where patients have IE secondary to IVDU and need a new heart valve—their first surgical intervention—surgeons and others are more likely to treat the typical young patient with a probable successful surgical outcome without a need to seek ethical counsel. In our experiences, while most patients receive minimal chemical dependency treatment post-surgery, relapse (as discussed above) is likely, and a comprehensive mental health care program with monitoring, social support, and a recognition of the social determinants that contribute to the relapse are often not sufficiently addressed.
Thus, these patients return with IE and in need of a second, third, or more heart valve replacement surgeries. Surgeons and other healthcare professionals, particularly those working in community hospitals with limited financial resources, may question their duties to this patient population while considering their obligations to their medical community and society at large. Heart valve replacement surgeries, post-operative care, and addiction treatment are costly, and the financial burdens to patients, healthcare institutions, and the general community may deter surgeons from moving forward despite the patient’s need. We can add the statistic about how the cost is increasing using the data from NC either here or in the paragraph with all the other statistics. Furthermore, the social stigma and biases against drug-addicted patients impact medical decisions, particularly when combined with the potential risk to health outcome measures, which can affect individual health care professional evaluations, work satisfaction, and trust among the general patient population.
The emotional impact of providing surgical care with the likelihood the patient will be back again for repeat heart valves due to IVDU can prompt moral distress, cynicism, and resentment of this patient population regardless of the moral obligations to treat when medically necessary, or beneficial. All of these considerations for repeat heart valve replacement surgeries should not be dismissed. They are essential for building a case for comprehensive just care, which is guided by core ethical principles of beneficence, non-maleficence, and justice, as well as a recognition of the individual patient’s story through narrative medicine. Narrative medicine prompts healthcare professionals to absorb, interpret, and co-author the dynamic story-telling in patient care. By co-authoring the illness narratives of patients, providers are able to acquire deeper insight into each patient’s understanding of their illness, their goals for recovery, and the triggers that act as obstacles to recovery. Furthermore, through these illness narratives, providers will bear witness to the individuality of medical cases and recognize that some patients really can be helped even with the likelihood of relapse and future harm, which can reduce moral distress and clinical cynicism (e.g., “why try to help if these patients will end up abusing drugs again”) [20, 21, 22]. However, the illness narratives need to be sustained; patients’ stories do not end once they complete their post-operative care (e.g., antibiotic therapy).
It is our general position that repeat heart valves for patients with IE secondary to IVDU ought to be given if they are medically beneficial and if the patient is willing to commit to addiction recovery and ongoing, comprehensive mental health treatment that aims to address the social triggers, existing mental health disorders, and other factors that influence the chemical dependency. This is not the responsibility of the surgeon alone, but a medical team that has access to hospital and community resources, appropriate skills, knowledge to address the whole patient and their medical and psychosocial needs, and the ability to combat social stigma by treating the patient as a person with a very specific narrative. When repeat heart valves are not medically necessary or ethically beneficial, may cause undue suffering, and/or the patient is unwilling to commit to a comprehensive treatment program after thorough guidance by the health care team, then it is ethically justifiable to refuse surgery. However, each case is unique, and there may arise unique considerations that have not yet been previously addressed or ethically analyzed. Thus, it is essential that a narrative ethical approach that calls attention to the nuances of the case, i.e., the elements of the patient’s story, is automatically part of the medical assessment and a sustainable chronic care plan.
In this first case, there are a number of social factors that are contributing to the patient’s current medical state. First, this is a young, homeless patient who does not have the means to acquire sustainable basic human needs. Regardless of whether her drug use led to the homelessness or vice versa, she is surviving in an unhealthy, unsupportive, and harmful environment, which is an obstacle to addiction recovery and overall health. When living in a residential treatment facility, she was able to have security, shelter, food, warmth, and community support, in addition to, medical treatment, all of which are essential for a recovering addict who, unfortunately, did not have these resources prior to her first valve surgery. However, these resources are limited; they are only available for the duration of her medical treatment for the endocarditis, and not for the ongoing recovery for her addiction. Her lack of essential resources, social instability, and homelessness are likely to have played a role in her subsequent relapse while on Suboxone; this demonstrates the necessity for holistic and comprehensive care in order to fully rehabilitate a patient with a chronic condition. Furthermore, this patient has a history of untreated depression—another significant factor that could have led to her current medical state.
The use of IV drugs to combat feelings of depression and despair are not uncommon among untreated patients. Reasons for why she did not seek medical attention for her depression are unknown, but given the difficulties of navigating the health care system, federal insurance programs, and community programs that can aid a patient in accessing mental health care, it is not surprising that her depression went untreated. A person already addicted to IV drugs may have even more difficulty accessing mental health care due to the cognitive effects of the drugs, the stigma of drug use, and the lack of social support in seeking help. This patient tried to stop her drug use, but could not stop without the necessary social support and addiction therapy. Because she was previously successful at recovery, is a good surgical candidate for a medically indicated tricuspid valve replacement, and has a strong commitment to seeking post-operative care and addiction treatment, the surgical intervention should be granted. An ethics committee convened with this case and further recommended that it is critical for a team-based approach to be utilized for patients with IVDU who are seeking valve replacements.
A range of medical specialists and addiction experts, along with the surgical team, are essential for developing and implementing a treatment plan. It is also recommended that these patients sign a behavioral agreement in addition to the standard surgical consent form that details the patient’s level of understanding about the risks and benefits of the surgery, addiction interventions, and any other medical and psychosocial care that promotes a good clinical outcome. Clinical outcomes are often determined by the success of the surgeries and post-operative care. However, we need to begin to look more critically at the long-term success of recovery, factors contributing to relapse, and how a team-based approach can aid the patient in quickly getting back into recovery. Recovery is a life-long process and a good clinical outcome may take years to fully measure and understand despite the more immediate surgical successes.
In the end, this patient did receive re-operative tricuspid and aortic tissue valve replacement. However, the behavioral contract, a non-legally binding contract, was not used. This contract prompts the patient to understand the need to get comprehensive treatment beyond a valve replacement, as well as empower the patient to take charge of her life, and maintain physical and mental health through ongoing counseling, therapy, and pharmaceutical interventions to treat her depression and addiction. The value of the contract is that it is a way to understand the patient’s illness narrative and her commitment to recovery; although not used for this particular patient, it is a useful tool that can be beneficial for other patients. Of course, basic human needs (home, food, social support) are also needed, yet securing these resources for patients can be a challenge without having social work, nursing, and community support. There are limitations to what a surgeon can do beyond immediate surgical care, so it is critical for a wider health care community to recognize their ethical obligations to this patient population.
In regard to the second case, this young male patient is struggling with mental health issues—particularly untreated depression and addiction—and is married to a recovering addict, who either can be a positive or negative influence in his recovery depending on their willingness to work together toward mutual recovery. Without mental health treatment, his depression, suicidal ideations, and addiction will continue. One of the primary problems with this case is the patient’s reluctance (which might be confounded by potential neurologic dysfunction due to his embolic strokes) to mental health treatment, feeling as though he does not need it despite the magnitude of health complications arising from his pervasive drug use. Specifically, the IVDU has led to multiple hospitalizations, a mitral valve replacement, and multiple, serious co-morbidities that have left him with ongoing physical pain and cognitive impairment. Prior to testing for valve functionality, this patient, too, was presented to an ethics committee, which prompted discussion regarding whether valve re-operation would be beneficial to this patient with serious comorbidities that may increase his surgical risk and lead to a poorer quality of life.
Similar to the first case, discussions surrounding addiction stigma, the need for social support, a need for the patient’s commitment to seek addiction treatment, and a team-based approach to patient care were presented. However, unlike the first case, this particular patient is suffering from a number of medical issues that each need to be taken into consideration in the evaluation for a replacement valve, as well as an acknowledgment of the patient’s lack of commitment to comprehensive mental health treatment. The ethical guidance sought is grounded in the principles of beneficence and non-maleficence, as well as a narrative-based justice approach that details the specifics of the patient’s medical history, social support, quality of life, and his preferences and commitment to recovery. The goals of the medical team, from an ethical perspective, are to very carefully look at his medical condition, and whether he even has a chance for survival and future quality of life with a second valve replacement surgery. Second, it is critical for the medical team to revisit the topic of comprehensive mental health care, including treatment for depression and chemical dependency. Objective consideration must also be given if there are overwhelming evidence of medical/surgical futility—but this concept can be extremely difficult to determine in young patients.
The need for aggressive inpatient chemical dependency treatment is essential to this patient’s recovery. However, unlike the first case in which valve replacement surgery and addiction treatment are simultaneously discussed as a holistic approach to patient care, for this patient, the addiction treatment becomes an interesting topic of discussion due to the gravity of his medical condition and his resistance to treatment. That is, the first case had less medical ambiguities in terms of the surgical candidacy for valve replacement combined with a clear indication of the patient’s commitment to recovery. Thus, due to the immediate and justifiable medical need, the decision to move forward with surgery came simultaneously with a team-based plan and patient contract for recovery. Here, the patient’s condition warrants an initial discussion about whether replacement valve surgery would be non-beneficial treatment. Causing further harm either during surgery or postoperatively should be avoided so as to ensure the best quality of life while living with a terminal condition. Furthermore, if the replacement valve surgery would be deemed beneficial, there remains the issue of the patient’s lack of commitment to recovery. If there is persistent resistance to mental health care, ethically it would be unjust to proceed with a surgical intervention.
Following the ethics consult, the patient’s valves with small vegetation were functioning, and his bacteremia was responding well to antibiotic therapy. The surgical team determined that after he completed extended care, he then should seek aggressive inpatient chemical dependency treatment to limit the risk of relapse and recurrence. However, the medical team may be at an impasse given the patient’s current resistance and lack of commitment to addiction recovery.
While it is recommended the medical team should have ongoing dialog with the patient to understand his reluctance at undergoing mental health treatment, and continuing to identify providers, care facilities, etc., that could aid in his recovery, additional steps may be needed before proceeding with any future medical interventions (e.g., valve replacement). If medical therapy alone fails e.g. progression of disease, worsening valve functioning, or recurrent emboli that lead to further complications, treatment options will need to be re-evaluated. Depending on his medical state, the patient may not be a future candidate for a replacement valve, and thus other medical resources and personnel, such as palliative care, may be required for the care of this patient.
In our first case, it is recommended the patient sign a behavioral contract to strengthen her existing commitment toward recovery, which further illustrates she does not have to go through recovery alone, i.e., the medical team will not give up on her if she maintains her commitment. In this second case, however, a behavioral contract may not be enough, since such non-legally binding contracts are symbolic gestures of the medical team’s medical/social/legal relationship to a patient the shared responsibilities of both parties. When a patient is not willing to share responsibilities in the relationship and is resistant to addressing serious mental health disorders, the first step is to understand why.
Valve replacements in IVDU must be administered regardless of the negative connotations associated with addiction or illicit drug use, with the patient’s health, surgical success, and access to comprehensive addiction treatment being the goals of treatment. Both conscious and unconscious biases can affect clinical judgments that lead to unjust decision-making and disrespectful treatment of patients.
Similar to the health disparities we see in organ transplantation cases, where racial and ethnic biases have affected the length of time on a transplant waiting list, or lifestyle behaviors (e.g., alcohol addiction) have affected judgments about probability of success for organ replacement surgeries, medical judgments are not immune to bias when determinations about medical outcomes are being made. That is, it is all too easy for a surgeon to determine that her patient does not qualify for a valve replacement because of the high surgical risk, which may be based on the patient’s untreated addiction, probability of relapse, and co-morbidities due to the effects of IVDU (e.g. the inherent risks of recurrent overdoses), rather than on the patient’s survivability on the surgical table and success of the valve replacement itself. A surgeon may also exhibit conscious biases toward her patient when considering the continued burden of having to provide ongoing treatment, which increases the financial and personnel cost to the medical institution. Thus, such attitudes and feelings lead to a biased clinical judgment, but may also be generated out of concern for professional evaluation and outcomes-based, performance measures.
The first step in reducing the need for repeat valve replacement and improving patient health outcomes and survivability is to understand the patient’s own unique story that prompted the IVDU, their goals for treatment, and their overall understanding of their own responsibilities toward successful, comprehensive treatment. By motivating them with a behavioral contract that speaks to the healthcare team’s responsibility to the patient’s care and the patient’s own commitment, this may be a positive step.
Second, patients will not have a chance for successful recovery if they are not provided with needed resources and appropriate guidance to motivate them to seek long-term treatment. Such treatment should involve methods ranging from psychotherapy to pharmaceutical interventions.
Unfortunately, most current care is focused on the infective pathology; in IE patients only the acute problem is addressed, but no effort seems to be placed on preventing readmissions or improving the patient’s quality of life. Addressing the lack of care and support IVDU patients are receiving, rather than trying to limit patient access to replacement procedures provides the just treatment these patients deserve, in addition to reducing the financial burden on healthcare systems and society. Health care providers often fail to identify addiction as the significant comorbidity that it is, and do not treat it as aggressively and appropriately using drugs that specifically target opioid use disorders; this results in under-treatment of addiction [16]. Such a limited care approach needs to change.
Third, surgeons and the healthcare team also require the support of ethics teams when complex social and ethical questions arise with patients. Personal biases lead to social stigmatization of patients with IVDU, influence medical decisions, lead to provider burnout, moral distress, and cynicism among health care providers. Having ongoing team-based discussions about these negative experiences, attitudes, and emotions is one step in the right direction, Recognizing the ethical and social issues that penetrate the medical problems can also help navigate and resolve dilemmas and elicit a deeper understanding of the individual patient and their illness narrative. It is important for healthcare providers to engage in self-care, and to have the opportunity to address issues before they devolve into negative emotions and attitudes that can be harmful to self and other.
Finally, it is critical for the health care team to know when additional treatment is futile. There are limits to justice. However, such limits to therapies must be based upon objective evidence supported by the medical literature rather than poorly grounded assumptions, biases, and outdated, or erroneous knowledge or datasets.
Unless physicians treat the chronic and acute illnesses in patients with IE due to IVDU, their ethical duties toward their patients remain unfulfilled, and they fail to provide just care. This issue becomes more precarious when considering patients who require additional valve replacements due to continued IVDU.
The American Medical Association’s Code of Medical Ethics states that is the physician’s ethical obligation “to place patients’ welfare above their own self-interest and above obligations to other groups and to advocate for their patients’ welfare” [23]. It is the duty of physicians to promote the health of their patients through comprehensive, beneficial treatment based on evidence-based medicine, and to respect them as persons with dignity, uninfluenced by social stigma and clinical bias. For patients with IE secondary to IVDU, it is important to treat both the psychiatric, social and infectious etiologies: the substance use disorder, homelessness, and food insecurity, as well as the IE, along with any additional comorbidities that are present. Although every patient with IE secondary to IVDU differs in the severity of presentation and comorbid conditions, patients with a positive prognosis should have the opportunity to achieve health and life with medical assistance.
Unfortunately, it is not unusual for patients with recurrent IE secondary to IVDU to experience social stigmatization and bias at the hands of the healthcare system and to be denied the comprehensive care that is needed in such cases. While some patients are justifiably denied due to a significant medical risk over benefit, patients are also denied simply because they are perceived as non-compliant, or because their potentially risky surgical treatments may negatively affect the health reviews and ratings of the surgeons performing the valve replacements. It is not ethically just to penalize viable surgical candidates when their addiction has neither been addressed nor treated. Citing high rates of treatment failure and non-compliance is not a valid excuse when the substance use disorder has not been treated as aggressively as the IE, especially when taking into considerations the lack of resources available for these patients to seek and maintain recovery.
The authors have no conflict of interest.
Over the centuries, humans have depended on nature for their essential needs of food supplies, shelters, apparel, transport means, fertilizers, flavors and fragrances, and the last not but least, medicines. Sophisticated traditional medicine systems have been generated by the plants over thousands of years. Moreover, plants maintain the significant sources of modern remedies for humanity. Additionally, according to WHO, 80% of the world’s population—primarily those of developing countries rely on plant-derived medicines for their healthcare [1]. People continue to consider nature as a source of potential chemotherapeutic agents. Over 50% of clinical drugs all over the world are the product of natural plants and their derivatives. While more than 25% of the total are extracted from higher plants [2].
\nHistory of pharmacy was for centuries identical with the history of pharmacognosy, or study of materia medica, which were obtained from natural sources—mostly plants but minerals, animals, and fungi. Chirality is one of the universal phenomena in nature. For instance, chiral biomolecules such as amino acids, sugars, proteins and nucleic acids have created living organisms. In natural surroundings, these biomolecules are present in one of the two possible enantiomeric forms, e.g., amino acids in the L-form and sugars in the D-form. Living organisms show variation in biological responses to one of a couple of enantiomers in medicines due to the chirality [3].
\nA range of chemicals that accurate enzymatic metamorphosis defines stereochemical configurations. Consequently, there is a certain chirality in most organic compounds in nature. It is important to emphasize that some phytochemicals exist in only one enantiomeric form, while others the optical rotation of the metabolite can be different [4].
\nAlkaloids are cyclic organic compounds that contain nitrogen in a negative oxidation state. They are generally distributed in flora and are an essential role in plant protection, sprouting and stimulating plant growth. Alkaloids-containing plants are often used as traditional medicines and these compounds usually have marked pharmacological activity [5]. Over 21,000 alkaloids have been identified, which thus constitute the largest group among the nitrogen-containing secondary metabolites [6]. Alkaloids are significantly pharmaceutical, e.g. morphine as pain relief medicines, codeine as an antitussive in cough medicines, colchicine in the treatment of gout and familial Mediterranean fever (FMF), Quinine as an anti-malarial and a muscle relaxant, Quinidine, as an
The first isolations of alkaloids in the nineteenth-century new investigation into medicine of several alkaloid-containing drugs and were accidental with the advent of the separation process for the extraction of drugs. In 1803, the French apothecary Derosne probably isolated narcotine. Several years later, the Hanoverian apothecary Sertürner further investigated opium (1806) and isolated morphine (1816) [7].
\nBased on their structures, alkaloids are divided into several subgroups: non-heterocyclic alkaloids and heterocyclic alkaloids, which are again divided into 7 major groups according to their basic ring structure [8]. Families reported to be rich in alkaloids are: Liliaceae, Amaryllidaceae, Apocynaceae, Berberidaceae, Leguminosae, Papaveraceae, Ranunculaceae, Rubiaceae and Solanaceae [9]. Most of alkaloids are chiral compounds and are clinically administered as the racemic mixture, although its enantiomers have been shown to exert different pharmacological activity.
\nPhenylethylamine alkaloids in medicinal herbs (i.e. Citrus species and Ephedra sinica) are used ubiquitously for their effects on the metabolic process of humans by stimulating lipolysis and thus supporting to reduce the fat mass in obese people. Particularly, Ephedra Herba (Ma Huang) contain several alkaloids such as (1R, 2S)-(−)-ephedrine, (1S, 2S)-(+)-pseudoephedrine, (1R, 2S)-(−)-norephedrine, (1S, 2S)-(+)-norpseudoephedrine, (1R,2S)-(−)-N-methylephedrine, and (1S, 2S)-(+)-N-methylpseudoephedrine [10]. Each of these six compounds also has an enantiomer that does not occur naturally in the plant [11, 12]. Separation and quantification of optical isomers of ephedrine-type alkaloids are important since ephedrine-type alkaloids in natural have been found to be strengthened with inexpensive (racemic) synthetic similarity, and these enantiomers could exhibit important differences in pharmacological activities. To diminish essential public health risk, adulteration of Ephedra products could be discovered by the presence of both enantiomers, such as naturally occurring (−)-ephedrine and synthetic (+)-ephedrine in the samples [13].
\nIn the case of C. urantium alkaloids, synephrine has also effect on human metabolism that could help to reduce fat mass in obese people, since it stimulates lipolysis, raises the metabolic rate and promotes the oxidation of fat through increased thermogenesis [14]. Synephrine is a chiral compound and is clinically administered as the racemic mixture, although its enantiomers have been illustrated to apply different pharmacological activity on α- and β-adrenoreceptors. Particularly, (R)-(−)-synephrine is from 1 to 2 orders of magnitude more active than its (S)-(+)-counterpart (Figure 1) [15].
\nMolecular structure of synephrine and ephedrine alkaloids (*chiral center).
Solanaceae contain mainly tropane alkaloids such as atropine, anisodamine and scopolamine; these plants are extensively used both in traditional medicine and as sources for the extraction of the pharmacologically important (parasympatolytic and anti-cholinergic) alkaloids [10]. Atropine is existed in racemic mixture of (S)-hyoscyamine and (R)-hyoscyamine. (S)-hyoscyamine is original in plants and (R)-hyoscyamine forms under alkaline conditions. (S)-hyoscyamine functions competitive antagonist of muscarinic receptors, thereby inhibiting the parasympathetic activities of acetylcholine on the salivary and sweat glands, as well as gastrointestinal tract, while the (R)-hyoscyamine is mostly inactive. Atropine, which is more often applied than (S)-hyoscyamine, exhibits approximately half of the pharmacological activity of (S)-hyoscyamine. In reverse, Scopolamine is mostly applied as pure enantiomer, e.g. (S)-scopolamine bromide [16].
\nAnisodamine, a tropane alkaloid isolated from Solanaceae family (Scopolia tangutica Maxim.). In China for decades, Anisodamine is an effective cholinoceptor antagonist and has been used as a spasmolytic drug to effect on smooth muscle by feature of its weaker side effect on the central nervous system than atropine. This kind of alkaloids have biological characteristic including cholinoceptor agonists and antagonists, like most chiral drugs, depend strongly on their stereochemistry. The effectiveness differences among four isomers of anisodamine racemic on muscarinic receptors have been perceived (Figure 2) [17].
\nMolecular structure of (S)-hyoscyamine, (S)-scopolamine, and anisodamine.
Aconitum plants (Ranuncolaceae) are generally distributed across Asia and North America. In the Chinese Pharmacopeia, two species of them, A. carmichaeli Dexb. and A. kusnezoffiiare were listed. Aconitine and the congener mesaconitine and hypaconitine (Figure 3) are the important diester-diterpene alkaloids of aconitum plants. Although they have toxic effects on human health, they can also be used at low doses because their pharmacological effects such as anti-inflammatory and anti-pain are effectively [10].
\nMolecular structure of aconitine, mesaconitine and hypaconitine.
In the legume alkaloids, the largest single group is quinolizidine alkaloids. In distribution to species in the more primitive tribes of the Papilionoideae, they appear to be restricted. Because of their toxicity in humans and animals as components of poisonous plants, these compounds become important. In contrast, some of them are potentially useful in pharmacological activities [18]. Radix sophorae flavescentis (Sophora flavescens) is frequently used in Traditional Chinese medicine for treating acute hepatitis and jaundice; it was found that quinolizidine alkaloids were the main constituents of this herbal drug such as matrine, sophoridine, sophocarpine, lehmannine, sophoranol, oxy-matrine, oxysophocarpine which have some chiral center [10, 19]. In natural, they exist as an isomer, sophocarpine (Figure 4) is an example. The naturally (−)-sophocarpine isolated from the root of the Chinese medicinal herb Sophora flavescens Ait. (Fam. Leguminosae) [20].
\nMolecular structures of four quinolizidine alkaloids.
Bis-benzylisoquinoline alkaloids have fascinated by the significant pharmacological impacts; especially, protoberberines are a structural class of organic cations (quaternary ammonium alkaloids) mostly distributed in Ranuncolaceae (e.g., Rhizoma coptidis), Berberidaceae (e.g. Cortex berberdis), Papaveraceae (e.g. Herba chelidoni) and Rutaceae (e.g. Cortex phellodendri) [10]. The most considered chiral isoquinoline alkaloids are tetrahydroprotoberberine backbone structure such as tetrahydropalmatine (THP), tetrahydroberberine (THB), and corydaline [21]. (DL)-THP and (DL)-THB are highly abundant in C. yanhusuo and a variety of Corydalis plants. (L)-THP can also be isolated from Stephania plants [22]. Tetrahydropalmatine is one of the active ingredients isolated from Rhizoma Corydalis (yanhusuo), a traditional Chinese medicine that has been used for the treatment of chest pain, epigastric pain, dysmenorrhea, traumatic swelling, and pain for thousands of years [23]. The analgesic activity of (−)-THP is much higher than that of (+)-THP. Clinically, THP is used as the racemic mixture (Figure 5) [22].
\nMolecular structures of the enantiomers of tetrahydropalmatine (THP), and tetrahydro-berberine (THB).
Amaryllidaceae alkaloids are an important class of iso-quinoline derivatives; among them galanthamine, that is found in Galanthus and Narcissus species, has been approved for the pharmacological treatment of Alzheimer’s disease [24]. There are several chiral centers in this molecule, but only one S-enantiomer responsible for Alzheimer’s disease, other stereoisomers considered as impurity (Figure 6) [25].
\nMolecular structures of galanthamine.
Morphinane alkaloids (opium alkaloids) such as morphine, codeine, thebaine, papaverine and narcotine belong to isoquinoline derivatives and show a broad range of pharmacological activities; their major application is in analgesia, sedation and cough depression [26]. Although opiate alkaloids have an important place in medicine, the illegal trafficking and abuse of heroin (the diacetyl derivative of morphine) has become a widespread problem [27]. Opium, the exudates from Papaver somniferum, contains more than 30 alkaloids and is the raw material for extraction; also, the dried heads of P. somniferum, so-called poppy straw, is used as a source of morphine and thebaine. Figure 7 show the molecular structure of opium alkaloids, most of them have multi chiral center.
\nMolecular structures of: (1) morphine; (2) codeine; (3) oripavine; (4) thebaine; (5) pseudomorphine.
Although these alkaloids have at present no great medicinal significance, they are important in that they constitute the poisonous hepatotoxic constituents of plants of the genus Senecio (Compositae), well-known for their toxicity to livestock [28]. Pyrrolizidine alkaloids are found in a variety of plant species growing wide world such as Gynura segetum that belongs to the Compositae family and Senecio and Tussilago genera [10]. The majority of naturally occurring pyrrolizidine alkaloids (PA) are hepatotoxic causing liver damage and in some cases liver cancer. Toxic PAs are often responsible for serious health problems through direct consumption of PA-containing herbal teas, herbal medicines, and herbal dietary supplements [29].
\nThe most important pyrrolizidine alkaloids senecionine, seneciphylline, retrorsine and senkirkine, contain the 4-azabicyclo [3.3.0] octane system with senecionine and seneciphylline differing only for the presence in the latter of the C13-C23 double bond (Figure 8) [30].
\nMolecular structures of four toxic PAs. (1) senkirkine; (2) senecionine; (3) retrorsine; (4) seneciphylline.
Indole alkaloids constitute a wide class of natural products most of them pharmacologically important and characterized by very different activities [31]. In the recent years, attention has been focused on the biological activity of yohimbine which is a monoterpenoid indole alkaloid (Figure 9). It displayed the treatment of erectile functional disturbance and anxiogenic [32]. Hydroindole alkaloids such as mesembrine and congeners (mesembrenone, Δ7 mesembrenone, mesembranol and its stereoisomer epimesembranol) have been isolated from Sceletium species used for the psychoactive effects [33].
\nMolecular structure of yohimbine and mesembrine.
The vinca alkaloids were isolated from the Madagascar periwinkle, Catharantus roseus G. Don., which included a class of about 130 terpenoid indole alkaloids [32]. In early 1965, people obviously know their clinical quality. And this group of compounds has been taken advantage of as an anticancer servant for more than 40 years and is a symbol of the compound that gives the trend to drug development [34, 35]. Among these base (+)-vincamine exhibits a valuable therapeutic activity in cerebral insufficiencies. Due to the presence of three stereogenic centers eight stereoisomers (four enantiomeric pairs) are in fact possible (Figure 10) [36].
\nMolecular structure of major vinca alkaloids isolated from Catharanthus roseus: (+)-Catharanthine (A) and (−)-Vindoline (B).
Steroidal alkaloids including verticine and verticinone are distinguished by cholestane carbon skeleton (isosteroid alkaloids) with a hexacyclic benzo [7, 8] fluoreno [2,1-b] quinolizine nucleus (Figure 11). These compounds have been isolated from plants from Liliaceae family typically Bulbus fritillariae used as a traditional medicine in Japanese, Turkish, Pakistani, and south-east Asian folk medicines [10]. Pharmacological studies demonstrate that verticine and verticinone in Bulbus Fritillariaeare the primary active ingredients responsible for the antitussive activity [37].
\nMolecular structures of verticine and verticinone.
Stemona, belonging to Stemonaceae family, is known in the folk medicine of Southeast Asia, China, and Japan since its Phyto-preparations (primary the roots) are used to treat diseases about bronchitis, pertussis and tuberculosis. Interestingly many alkaloids, structurally defined as pyrido[1,2-α]azepines, have been recognized in this plant species and are considered the important pharmacological activity. All the Stemona alkaloids are polycyclic and contain multiple stereocenters [38]. Up to now, there are about 139 Stemona alkaloids which the scientist isolated (Figure 12).
\nMolecular structure of stemonamine and parvistemoline.
Analytical methods usually contain several steps, such as sampling, sample preparation, isolation, and quantification. Remarkably sample preparation just recently is concentration as an important analytical step. According to Wen et al. [39, 40], the main objective of sample preparation are removal of interferences, and preconcentration of the analytes that is considered a bottleneck of analytical processes. In this chapter, we will provide the current state of the art in sample preparation for analyzing alkaloids in herbal matrices, focusing on extraction, clean-up steps and purification.
\nUltrasound Assisted Extraction (UAE) technique is based on the using of acoustic waves in the kilohertz range spreading in liquid medium. These waves created by the ultrasound produces regions of compression and rarefaction in the molecules. Then, the cavitation bubbles are formed and collapse giving rise to smaller bubbles that could act as new cavitation nuclei or simply get dissolved. When the bubbles collapse at the surface of the herbal material, a shockwave having very high temperature and pressure is induced, resulting in plant cell disruption which enhances both the mass transfer of alkaloids into solution and the solvent penetration [41]. In addition, the swelling of plant materials can be enhanced by ultrasound, leading to improving of solvent penetration which increases the extraction yield [42]. The UAE procedure is optimized with regard to extraction solvent, temperature and liquid to solid ratio for the plant sample [41]. UAE has some advantageous properties including high extraction efficiency, good reproducibility, low solvent consumption, low cost and environmental friendliness. However, the major disadvantage of UAE is generating heat, leading to the degradation of thermo labile products and racemization of chiral compounds [43]. To avoid such types of drawback, extraction is carried on under an ice bath to reduce the temperature [44]. Table 1 lists examples of protocols that were developed using MAE from various plants.
\nPlant | \nCompounds | \nSolvent | \nSolvent: biomass (mL: g) | \nTemp (°C) | \nTime duration (min) | \nRef. | \n
---|---|---|---|---|---|---|
Macleaya cordata | \nProtopine Allocryptopine Sanguinarine Chelerythrine Dihydrochelerythrine Dihydrosanguinarine | \n1-hexyl-3-methylimidazolium tetrafluoroborate ([C6MIM][BF4]) aqueous solution | \n500: 1 | \n80 | \n15 | \n[45] | \n
Catha edulis | \nNorephedrine Cathine Cathinone | \n0.1 N HCl | \n600: 1 | \n— | \n45 | \n[46] | \n
Ipomoea genera | \nErgot alkaloid (ergine, ergometrine, lysergic acid α-hydroxyethylamide) Penniclavine Chanoclavine Lysergol | \n70% methanol | \n100: 1 | \n60 | \n30 | \n[47] | \n
Carica papaya | \nCarpaine Pseudocarpaine Dehydrocarpaine I Dehydrocarpaine II | \n100% methanol | \n100: 7.5 | \n— | \n20 | \n[48] | \n
Extraction conditions from various plants using UAE.
The MAE technique uses the electromagnetic radiations with a frequency range of 0.3–300 GHz, that stimulates ion migration and dipole rotation leading to the heating of dielectric materials and the penetration of extraction solvent into the matrix [49]. The released thermal energy is increased gradually with higher dielectric constant, so the effectiveness of MAE is depended on the dielectric properties of both extraction solvent and sample matrix [50]. Therefore, only specific solvents which have high dipole moment as water, methanol and ethanol can be used for extraction solvent in MAE and the moisture of plant sample is an important factor in the extraction efficiency [51]. Basically, higher water content matrices will be expected to give higher extraction yields. Water contained in plant matrices absorbs microwave radiation creating pockets of localized heating in the sample. This heat promotes the plant cell walls rupture which enhances the release of alkaloids into the solvent and the increase of extraction yield [50]. In addition to having a high dielectric constant, the extraction solvents must have a high dissipation factor to reduce the potential of localized sample overheating resulting degradation of alkaloids in plants [43]. Therefore, organic solvent-water mixtures, polar organic solvents and water are usually used as extraction solvent. Moreover, other parameters relating to extraction performance as sample size, sonication power, solid to liquid ratio, extraction time and microwave power should be modified for MAE procedure optimization [34]. The main advantages of MAE are the low solvent consumption, the ability to extract many samples simultaneously and the short extraction time [43, 52]. The major drawbacks of MAE are nonhomogeneous heating distribution and overheating of extract which may cause racemization or thermal degradation of chiral alkaloids [44]. Table 2 lists examples of protocols that were developed using MAE from various plants.
\nPlant | \nCompounds | \nSolvent | \nSolvent: biomass (mL: g) | \nTem (°C) | \nTime duration | \nMicrowave power (W) | \nRef. | \n
---|---|---|---|---|---|---|---|
Peganum harmala | \nVasicine, Harmalin Harmine | \n80% ethanol | \n30: 1 | \n80 | \n8 min | \n600 | \n[53] | \n
Stephania sinica | \nSinoacutine Palmatine Isocorydine L-tetrahydropalmatine | \n65% ethanol | \n24: 1 | \n60 | \n90 s | \n150 | \n[54] | \n
Lotus plumule | \nLiensinine Dauricine Isoliensinine Neferine Nuciferine | \n65% methanol | \n— | \n— | \n4 min | \n200 | \n[55] | \n
Corydalis decumbens | \nProtopine Palmatine Allocryptopine Jatrorrhizine Tetrahydropalmatine Corypalmine Bicuculline | \n90% methanol | \n20: 1 | \n40 | \n5 min | \n— | \n[56] | \n
Menispermum dauricum | \nBianfugedine, Menisporphine, 6-O-demethylmenisporphine Bianfugecine Dauriporphine Dauriporphinoline | \n70% ethanol | \n20: 1 | \n60 | \n11 min | \n— | \n[57] | \n
Extraction conditions from various plants using MAE.
The SFE process utilizes pressurized fluids (mainly CO2) as extraction solvents. In this technique, a fluid is heated and compressed to reach above critical point of it’s creating the fluid having physicochemical properties of both liquid and gas states called supercritical fluid [58]. Specifically, supercritical fluid has a density similar to liquid (0.3–0.8 g/cm3), a viscosity similar to gas (10−4 – 10−3 g/s.cm) and a diffusion coefficient that is intermediate between liquid and gas [59]. Therefore, supercritical fluid has higher transport capacity which facilitate to fluid diffusion through plant materials in comparison to traditional extraction solvents [43]. In addition, the density is related to polarity property of fluid which directly impact in solubility of compounds in extraction solvent. This parameter can be modified by controlling temperature and/or pressure so the flexibility and selectivity of the technique is enhanced, enabling selective extraction of different compounds from the plant matrix [60]. Carbon dioxide is commonly used in SFE because it has ideal properties including low critical temperature (31.3°C) and can be easily remove from extracts [51]. However, carbon dioxide is less effective in extraction of polar compounds from matrix because of its low polarity property. Aiming to extract more polar alkaloids, the modifiers such as methanol, ethanol or water are added to extend the range of the solvating strength [43, 47]. For optimization of SFE procedure, these parameters such as pressure, temperature, modifier, flow of carbon dioxide and modifier [51]. Besides, the extraction time also effects on extraction yield, since an inadequate extraction time can result in incomplete extraction, while too long extraction time can cause the degradation of compounds. The major drawback of SFE are the complexity of system configuration and the requirement for a personal training program to operate the instrument [61].
\nPSE process uses the pressurize solvents to enhance transport capacity of solvents and mass transfer rates which leads to improve extraction performance. In this technique, extraction solvents are heated at/or above the solvent’s boiling points to decrease viscosity while keeping its in liquid state thanks to an elevated pressure [62]. Therefore, the extraction process is enhanced kinetic which leads to decreasing both the extraction time and solvent consumption. Similar to SFE, these parameters such as solvents nature, temperature and pressure should be modified to optimize PSE procedure [51]. Logically, higher temperature would be expected to give higher alkaloid extraction yields. However, excessive temperature may cause degradation and racemization of chiral alkaloids. The main advantages of PSE are utilizing an extensive range of solvents (except strong acids/bases), low solvent consumption, short extraction time, automated instruments and performing an oxygen- and light – free extraction condition. Besides, the major drawbacks of PSE are similar to SFE such as using expensive laboratory equipment and requirement for a professional training to operate instrument [43].
\nDue to the alkaloids usually exist in plants at low concentration and the complication of plant matrices, samples should be purified and enriched which facilitate to identify and/or quantify process right after extraction step. Liquid–liquid extraction (LLE) and solid phase extraction (SLE) are popular clean-up methods utilized for sample preparation of alkaloids. Moreover, other techniques based on LLE and SPE methods, such as Liquid Membrane Extraction (LME) and Solid-Phase Micro Extraction (SPME) have also been developed.
\nLiquid–Liquid Extraction (LLE) is the most simple and traditional clean-up method. LLE method is based on the relative solubility of compounds between two immiscible solvents. The alkaloids have polarity varying between pH, so the solubility of alkaloids in specific solvent are also affected by pH [34]. In the acid solutions (pH is lower than pKa of alkaloids), the analytes are protonated which leads to better water solubility so this aqueous phase can be washed with less polar organic solvents such as ethyl acetate, n-hexane and diethyl ether to eliminate hydrophobic interferences. After that, this aqueous layer is alkalinized which leads to the alkaloids becoming non-polarity and can be extracted by organic solvents to eliminate hydrophilic interferences [63]. For enrichment, the organic solvents layer can be collected, vaporized and reconstituted into new solvents which is suitable for analytical instrument. The main disadvantages of this method are requirement for repetitive extraction causing time consuming and solvent wasting [51].
\nTo overcome the drawback of LLE method, solid phase extraction (SPE) has been developed and applied in sample preparation since the 1970s. In this method, extract is loaded onto a sorbent phase which will retain alkaloids. Then, interferences in extract are washed away and the analytes is eluted by suitable solvents [64]. In fact, cartridge is the most popular SPE type due to its convenience. The SPE procedure have five step including conditioning, loading, washing and elution step. Several factors can affect to the extraction efficiency such as concentration of analytes in solvent, loading solvent nature, sorbent types, particle size, volume used for loading – washing – eluting, flow rate and elution solvent. Each factor has specified role which depends on the affinity of analytes and solid phase. Because the chemical structures of alkaloids always have secondary or tertiary amine groups, the strong cation exchange (SCX) sorbents are an ideal choice for sample preparation. When using these sorbents, washing solvent will be water and organic solvent to eliminate both hydrophilic and hydrophobic from plant matrices. After that, alkaloids will be deprotonated for elution by alkalized solvent which has pH at 2 units above pKa of analytes and evaporated to enrich sample [64].
\nIf the analytes are unstable in strong alkaline solutions, the weak cation exchange (WCX) will be use instead. The WCX sorbent has carboxylic acid as functional group which has pKa value about 4.8, so these sorbents should be conditioned by solutions having pH above 6.8 for sorbent ionization. In addition, the loading and washing solvent pH should be adjusted at the value above 6.8 and below 2 value of analytes’s pKa to maintain the ionized state of both sorbent and analytes. Finally, the alkaloids will be eluted by the acidic solutions [63]. Besides, the C18 and C8 sorbents are also applied to extract aromatic alkaloids and eliminate hydrophilic interferences from matrices. In some case, those sorbents could be used for eliminating hydrophobic interferences by loading unretained alkaloids through cartridges [64].
\nHigh performance liquid chromatography (HPLC) is currently the most widely used chromatographic enantio-separation technique [65]. HPLC has become one of the most common modern chemical analysis techniques because of its versatility, efficiency, stability, reproducibility and sensitivity. With these advantages, HPLC continues to be one of the best choices for chiral analysis and separation. Basically, chiral separation by HPLC techniques included direct and indirect methods. The indirect method is based on diastereomer formation by the derivatization reaction of analytes and a chiral reagent, then the separation of diastereomeric derivatives is performed by using a column having an achiral stationary phase. In addition, the direct method uses a chiral stationary phase for chiral separation or forms diastereomer by using a chiral mobile phase additive (CMPA).
\nHPLC using CSPs has demonstrated to be extremely useful, accurate, versatile, and it has been a widely used technique in diverse fields and applications, emphasizing (Table 3). The CSP mode is generally the most straightforward and convenient means for chromatographic enantiomer separation; it is the method of choice for both analytical and preparative applications [66, 67, 68, 69]. A hundred CSPs have been developed and commercialized thirty years ago [70]. Besides, the larger number of CSPs are made in laboratory for specialized separation. CSPs are divided into nine major types by Snyder basing on the interaction mechanism between stationary phase and analytes [71].
Macromolecular selectors of semisynthetic origin (polysaccharides)
Macromolecular selectors of synthetic origin (poly(meth)acrylamides), (poly-tartramides)
Macromolecular selectors of natural origin (proteins)
Macrocyclic oligomeric or intermediate-sized selectors (cyclodextrins, macro-cyclic antibiotics, chiral crown ethers)
Synthetic, neutral entities of low molecular weight (Pirkle-type phases, brush-type CSPs)
Synthetic, ionic entities of low molecular weight that provide for ion exchange
Chelating selectors for chiral ligand-exchange chromatography.
Type | \nCSP | \nTypical column trade name | \nApplication | \n
---|---|---|---|
I | \nPolysaccharide | \nAD, OD, OJ, AS, IA, IB, IC | \nAlkaloids, tropines, amines, beta blockers, aryl methyl esters, aryl methoxy esters | \n
II | \nSynthetic-Polymer CSPs | \nKromasil CHI-DMB and CHI-TBB | \nAcidic, neutral, and basic compounds | \n
III | \nProtein Phases | \nChiral HSA, Chiral AGP, Ultron ES-OVM, Chiral CBH | \nBenzodiazepine, Warfarin and oxazepam, beta blockers | \n
IV | \nCyclodextrin | \nCyclobond I, II, III | \nBeta blockers | \n
V | \nMacrocyclic Antibiotic | \nChirobiotic V, T, R, TAG; vancomycin | \nPolar compounds such as underivatized amino acids | \n
VI | \nChiral Crown-Ether | \nChiroSil RCA(+); SCA(−); ChiralHyun-CR-1 | \nAmino acids, amino acid esters, amino alcohols | \n
VII | \nDonor-Acceptor Phases | \nWhelk-O 1, ULMO, Sumichiral 2500, Sumichiral OA 4900 | \nAmides, epoxides, esters, ureas, carbamates, ethers, aziridines, phosphonates, aldehydes,ketones, carboxylic acids, alcohols | \n
VIII | \nChiral Ion-Exchangers | \nChiralpak QN-AX; Chiralpak QD-AX | \nChiral carboxylic, sulfonic, phosphonic, and phosphoric acids | \n
IX | \nChiral Ligand-Exchange | \nChiralpak MA+, Nucleosil Chiral-1 | \nAmino acids | \n
Application of nine major types of CSP and their commercial CSP [72].
Polysaccharide-derived CSPs are widely used in enantio-separation of a large number of chiral compounds [71]. The development of polysaccharide-derived CSPs has continued for about three decades. It can be roughly divided into two stages (i) the coated CSPs stage, and (ii) the immobilized CSPs stage.
\nPolysaccharide selectors have been used for enantioselective liquid chromatography technique for a long time. In 1973, a polymeric selector (without supporting matrix) was introduced by Hesse and Hagel named as microcrystalline cellulose triacetate (MCTA) used for enantioselective liquid chromatography. MCTA are widely applied in enantio-recognition and preparative separations due to its ideal loading capacities. However, this material has major disadvantages including poor pressure stability, slow separations, and low chromatographic efficiency. To overcome the mechanical stability problem of MCTA, a solution was found by Okamoto and co-workers in 1984, in which the surface of macro-porous silica beads (100 or 400 nm pore size) was coated by the cellulose derivatives at about 20 wt%. Thanks to this coating, the mechanical stability of this material was remarkably improved resulting in better efficiencies qualified for HPLC enantiomer separations. Such coated polysaccharide-based CSPs were the highest level of polymeric selector developments for several decades [71].
\nNowadays, about 200 kinds of polysaccharide derivatives were introduced by using different polysaccharides which includes cellulose, amylose, chitin, chitosan, galactosamine, curdlan, dextran, xylan, and inulin [72] (Figure 13). These materials have been coated on a surface of macro-porous silica gel to create CSPs and followed by the evaluation of chiral recognitions on HPLC.
\nStructures of the various kinds of polysaccharides: (1) cellulose; (2) amylose; (3) chitin; (4) chitosan; (5) Galatosamine; (6) Curdlan; (7) dextran; (8) Xylan; (9) inulin.
Each of coated polysaccharide-based CSPs exhibit the different enantioselectivity and elution order of the various enantiomers due to the structural differences of CSPs including sugar units, linkage position, and linkage type. In particular, the derivatives of cellulose and amylose usually perform higher recognition abilities than the others, though this property also depends on the structure of a specific racemate. The most useful and successful derivatives of cellulose and amylose are triesters and tricarbamate. It has been claimed by Aboul-Enein and Ali that for the resolution of about 500 test racemates, about 80% of them have been successfully resolved on only two kinds of polysaccharide derivative-based CSPs (cellulose and amylose tris (3,5-diphenylcarbamate) CSPs) [72]. More specifically, three famous commercially available CSPs, CHIRALCEL OD, OJ, and CHIRALPAK AD, have fully or partially resolved 70% racemates among over 100 racemates tested [71].
\nA current strategy introduced by Snyder for chiral separation method development includes trial-and-error experiments of various polysaccharide-type CSPs under multiple respective mobile-phase conditions using fully automated column- and solvent-switching. Nowadays, more and more studies have focused on developing a more efficient screening procedure to enhance the chance for success and shorten the experiment time: the most favorable CSP in the normal phase mode is
\n\n\n
The separation efficiency of column should be tested before conducting screening experiment if serial instead of parallel screening is utilized. The application of coated polysaccharide-derived CSPs has been reviewed in Table 4 including the names of CSPs and their most frequent applications.
\nThe coated CSPs are formed by coating the polysaccharide derivatives onto surface of silica gel. Due to the weak linkages and interactions between the polysaccharide derivatives (chiral selector) and silicagel (substrate), a number of organic solvents including chloroform, dichloromethane, tetrahydrofuran and ethyl acetate which can dissolve or swell the chiral selector are not allowed using as mobile phase components. Besides, the mixtures of alkanes (n-pentane, n-hexane or n-heptane) and alcohols (2-propanol (IPA), ethanol or methanol (n-pentane, n-hexane or n-heptane)) and alcohols (2-propanol (IPA), ethanol or methanol) are favorable mobile phase solvents used in normal phase mode. The addition of “prohibited solvents” may lead to better separation and greater solubility of racemic analytes than the standard solvent combinations so the performance of separation method is improved. Besides, the better solubility of racemic analytes also facilitates preparative separations. In addition, the spectroscopic techniques used for chiral recognition should ideally be in the “prohibited solvents”. As a result, chemical immobilization of polysaccharide derivatives becomes an interesting research topic to overcome the drawbacks of the coated CSPs (see in Figure 14). In 2005, Daicel and Chiral Technologies introduced a set of three immobilized polysaccharide CSPs as [71]:
Chiralpak®IA (immobilized version of Chiralpak AD)
Chiralpak®IB (immobilized Chiralcel OD) [61]
Chiralpak®IC based on the cellulose tris (3,5-dichlorophenylcarbamate) selector that is not available in coated form.
Effect of column type (immobilized vs. coated polysaccharide-based CSP) and mobile phase on enantioselectivity. Enantiomer separations of N-benzyloxycarbonyl-phenylalanine (a–c) with Chiralpak IB (immobilized) and Chiralcel OD (coated). Flowrate: 1 mL/min; temperature: 25°C; UV detection at 230 nm. Note that the mobile phases used in (a) is forbidden mobile phases for the coated version Chiralcel OD [71].
Finally, it should be noted that polysaccharide CSPs have now also been established as the first-choice of chiral phases for enantiomer separation.
\nAnalytical applications, including CSPs, separation conditions and analyte, are summarized in Table 5. A review focused mainly on the latest examples of chiral alkaloids separations on CSPs for efficient analyses was prepared.
\n\nTrade name | \nChemical name | \nApplications | \n
---|---|---|
Cellulose CSPs | \n||
Chiralcel OB | \nCellulose trisbenzoate | \nSmall aliphatic and aromatic compounds | \n
Chiralcel OJ | \nCellulose tris(4-methyl benzoate) | \nAryl methyl esters, aryl methoxy esters | \n
Chiralcel OC | \nCellulose trisphenylcarbamate | \nCyclopentanones | \n
Chiralcel OD | \nCellulose tris(3,5-dimethylphenylcarbamate) | \nAlkaloids, amines, \n | \n
Chiralcel OD-H\nb\n\n | \nCellulose tris(3,5-dimethylphenylcarbamate) | \nAlkaloids, amines, \n | \n
Chiralcel OD-R\nc\n\n | \nCellulose tris(3,5-dimethylphenylcarbamate) | \nAlkaloids, amines, \n | \n
Chiralcel OD-RH\nd\n\n | \nCellulose tris(3,5-dimethylphenylcarbamate) | \nAlkaloids, amines, \n | \n
Chiralcel OF | \nCellulose tris(4-chlorophenylcarbamate) | \n\n\n | \n
Chiralcel OG | \nCellulose tris(4-methylphenylcarbamate) | \n\n\n | \n
Chiralcel OA | \nCellulose triacetate on silica gel | \nSmall aliphatie compounds | \n
Amylose CSPs | \n||
Chiralpak AD | \nAmylose tris(3,5-dimethylphenylcarbamate) | \nAlkaloids, tropines, amines, \n | \n
Chiralpak AD-R\na\n\n | \nAmylose tris(3,5-dimethylphenylcarbamate) | \nAlkaloids, tropines, amines, \n | \n
Chiralpak AD-RH\nb\n\n | \nAmylose tris(3,5-dimethylphenylcarbamate) | \nAlkaloids, tropines, amines, \n | \n
Chiralpak AD-H | \nAmylose tris-(3,5-dimethylphenylcarbamate) | \nAlkaloids | \n
Chiralpak AR | \nAmylose tris(R)-1-phenylethylcarbamate | \nAlkaloids, tropines, amines | \n
Chiralpak AS | \nAmylose tris(S)-1-methylphenylcarbamate | \nAlkaloids, tropines, amines | \n
Columns supplied by Daicel Chemical Industries, Tokyo, Japan, Dimension are column size 25 cm X 0,46 cm, particle size 10\n
Column size 25 cm X 0,46 cm, particle size 5\n
Column size 15 cm X 0,46 cm, particle size 10\n
Column size 15 cm X 46 cm, particle size 5\n
Columns | \nAnalyte | \nPlant | \nSeparation conditions | \nRef. | \n
---|---|---|---|---|
CHIRALPAK AS-H column | \n(12S,22S)-Dihydroxyisoechinulin A (2) and (12R/S)- Neoechinulin A | \nCannabis sativ L | \nHexane/isopropanol/diethylamine (4:1:0.05) | \n[73] | \n
CHIRALPAK AD-H column | \nMucroniferanine A | \nCorydalis mucronifera | \nn-hexane−2-propanol (70:30) | \n[74] | \n
(±)-homocrepidine A | \nDendrobium crepidatum | \nn-hexane/2-propanol (95:5) | \n[75] | \n|
(+)-(3R,6R)- and (−)-(3S,6S)-3α,6β-tropanediol | \nErythroxylaceae species | \nn-hexane and 2-propanol (9:1) with 0.1% of diethylamine | \n[76] | \n|
Chirobiotic V, Chiralpak-AY3 column | \n(−) and (+) hyoscyamine | \nSolanaceaes seeds | \nEthanol, 0.1% DEA | \n[77] | \n
Chirex 3019 chiral column | \nS-(−)-canadine and R-(+)-canadine | \n\nHydrastis Canadensis L. | \nHexan:DCE:EtOH:TFA (75:40:7:0.1) | \n[78] | \n
CHIRALPAK AGP column | \n(R)-nicotine; (S)-nicotine; anabasine, and anatabine | \nTobacco | \nNH4OH- methanol (90:10) | \n[79] | \n
A Phenomenex Lux Cellulose-2 chiral column | \n(+)- and (−)-5-hydroxyl-8-oxyberberine | \nCoptis chinensis | \nCH3CN:H2O (40:60) | \n[80] | \n
Chiralpak IA column | \nintermedine and lycopsamine | \nSymphytum uplandicum | \nACN/methanol (80:20) and methanol/methyl-t-butyl ether (90:10) | \n[81] | \n
Phenomenex-Chirex-3126 column | \ndihydrocarneamide A and iso-notoamide B | \nPaecilomyces variotii | \nMeCN–H2O (5:95). | \n[82] | \n
Summary of CSPs, mobile phase compositions, and applications.
Novel column materials also improved enantiomer separation of tropane alkaloids. Separation of (R, S)-hyoscyamine was achieved using chiral stationary phase with immobilizing α-1-acid glycoprotein (Chiral AGP®) [83], alternatively, enantiomer separation of atropine could be achieved by a chirobiotic V column packed with vancomycin as chiral selector [84]. Anisodamine, the 6β-hydroxyl derivative of (S)-hyoscyamine was separated from its synthetic enantiomer and diastereomers by a Chiralpak AD-H column as chiral stationary phase, which uses an amylose derivative as chiral selector [85]. Satropane, 3α-paramethylbenzenesulfonyloxy-6β-acetoxy-tropane, could be resolved in 3S, 6S-isomer named lesatropane and 3R, 6R-isomer named desatropane. Lesatropane as a novel muscarinic agonist is being under preclinical development in China as a single enantiomer drug for the treatment of primary glaucoma. The separation of lesatropane from desatropane was conducted by both Chiralpak AD-H and Chiralpak AS-RH column [86].
\nChiral separation of isoquinoline alkaloid has also achieved by using chiral stationary phase. For example, the determination of tetrahydropalmatine (THP) was performed by using a Chiralcel OJ column with quantification by UV at 230 nm. This developed method was used for determining the pharmacokinetics of THP enantiomers in rats and dogs after oral administration [87]. Another report of isoquinoline alkaloid group is sanguinarine derivatives. Chiral determination of Benzophenanthridine alkaloids from methanol extracts of Hylomecon species was conducted by Chiralcel OD (4.6 x 250 mm) column with mixture of isopropanol-hexane-diethylamine (20/80/0.1, v/v/v) as a mobile phase [88]. The stereochemistry of L-isocorypalmine and the D/L ratio of tetrahydropalmatine, stylopine, and corydaline were established unambiguously by using a chiral Chiralcel OD (4.6 x 250 mm) column; 50% ethanol as mobile phase; wavelength 230 nm [89]. Cularinoids are a group of isoquinoline alkaloids consisting of about 60 members. The HPLC enantiomeric separation of the racemic cularinoid alkaloids N-p-methoxy-1,α-dihydroaristoyagonine and 4′,5’demethoxy-1,α-dihydroaristoyagonine was accomplished using five chiral stationary phases (CSPs), the good enantioselectivity and resolution factor obtained with a polysaccharide-derived CSP (Chiralpak AD) [90].
\nIndole derivatives are widely used in chiral synthesis, chemical asymmetric catalysis, biological and medicinal chemistry. Recently, the enantiomeric separation of several chiral plant growth regulators and related compounds, such as 3-(3-indolyl)-butyric acid, abscisic acid and structurally related molecules including a variety of substituted tryptophan compounds was reported. Chiral stationary phases such as coated and immobilized were suitable for the separation of indole derivatives; however, the coated CSP possesses a higher resolving power than the immobilized one [91]. Tangutorine, a biogenetically interesting indole alkaloid, was found in the leaves of Nitraria tangutorum in 1999. It was separated from its synthetic enantiomer by chiral stationary phases two polysaccharide-derived CSP (Chiralcel OD and Chiralpak AD) and a network polymer incorporating a bifunctional C2-symmetric chiral selector (Kromasil CHI-DMB) [92]. The HPLC enantiomeric separation of racemic indole alkaloids tacamonine, 17α-hydroxytacamonine, deethyleburnamonine, and vindeburnol was accomplished using Chiralpak AD and Chiralcel OD as chiral stationary phases [93].
\nThe enantiomers of homocamptothecin (hCPT) derivatives which constitute a promising series of potent anticancer agents targeting DNA topoisomerase I were separated by using the combination of two silica-based normal phase column including Chiralcel OD-H (celluloses tris-3,5-dimethylphenylcarbamateand) Chiralcel OJ (celluloses tris-methylbenzoate) or Chiralpak AD (amyloses tris-3,5-dimethylphenylcarbamate) and Chiralpak AS (amyloses tris-(S)-1-phenylethylcar-bamate) [94]. A method for the simultaneous determination of eight Cinchona alkaloids (quinine, quinidine, cinchonine, cinchonidine, and their corresponding dihydro analogs) using a novel strong cation-exchange-type chiral stationary phase (cSCX) column in HPLC has been developed and exemplarily applied to impurity profiling of a commercial alkaloid sample [95].
\nMost of alkaloids are chiral compounds and are clinically administered as the racemic mixture, although its enantiomers have been shown to exert different pharmacological activity. The complication of sample matrices and low concentration of chiral alkaloids are major challenges for analytical processes. To improve the performance of analytical procedure, we provide the current state of the art in sample preparation focusing on extraction and purification to remove interferences and enrich analyte concentrations. HPLC using CSPs has demonstrated to be extremely useful, accurate, versatile, its mode is generally the most straightforward and convenient means for chromatographic enantiomer separation. The development of CSPs for HPLC is a continuous and challenger issue covering various types of CSPs.
\nThe authors would like to express their hearty gratitude to Can Tho University of Medicine and Pharmacy. We also thank all of our colleagues for their excellent assistance.
\nThe authors declare no conflict of interest.
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\n\nQUALITY CONTENT
\n\nOver the years we have learned what is important. What makes a difference to the researchers that work with us, what they value. Something that is very high not only on their lists, but our own, is the quality of the published content.
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\n\nThe need for up to date information available at the click of a mouse is one thing that sets IntechOpen apart. By developing our own technologies in order to streamline the publishing process, we are able to minimize the amount of time from initial submission of a manuscript to its final publication date, without compromising the rigor of the editorial and peer review process. This means that the research published stays relevant, and in this fast paced world, this is very important.
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\n\nThe utilization of CC licenses allow researchers to retain copyright to their work. Researchers are free to use, adapt and share all content they publish with us. You will never have to pay permission fees to reuse a part of an experiment that you worked so hard to complete and are free to build upon your own research and the research of others. The Edited Volume helps bring together research from all over the world and compiles that research into one book - accessible for all. The research presented in chapter one can inspire the author of chapter three to take his or her research to the next level. It is about sharing ideas, insights and knowledge.
\n\nCan collaboration be inspired by a publishing format? At IntechOpen, the answer is yes. The way the research is published, the way it is accessed, it’s all part of our mission to help academics make a greater impact by giving readers free access to all published work.
\n\nOur Open Access book collection includes:
\n\n3,332 OPEN ACCESS BOOKS
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\n\nNot sure if this is the right publishing option for you? Feel free to contact us at book.department@intechopen.com.
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