Article

The Chemical History of Morphine: An 8000-year Journey, from Resin to de-novo Synthesis

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Abstract

Evidence of human use of opium dates back as far as the 6th millennium BCE. Ancient societies through the Renaissance period created a variety of opium products, proliferating its common use and subsequent addiction. Because the active moiety was not known at this time, the potency of these opium concoctions could neither be predicted nor controlled. The first step in identifying opium's active ingredient, morphine, was its chemical isolation in the early 1800s by Wilhelm Sertürner. The subsequent elucidation of morphine's chemical formula and Sir Robert Robinson's derivation of morphine's structural formula, which won him the 1947 Nobel Prize in Chemistry, round out 150 years of the incremental advances in our chemical understanding of morphine. Nevertheless, our attempts to synthesize morphine, despite our advanced knowledge in synthetic chemistry, are still no match for the plant-based extraction of morphine from the poppy plant. The status quo remains problematic socially, economically, and politically; the relationships between the countries laboriously growing poppy plants to extract morphine and those countries importing these painkillers are unstable at best. In this paper, we contrast the cumulative scientific discoveries that have led to our current chemical knowledge of morphine with the centuries-old natural method of morphine production that still dominates the opioid market today.

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... Human usage of opium dates back 8000 years. During the Renaissance, the creation of various opium products resulted in common usage and subsequent addiction [91]. Morphine, the active ingredient of opium, was isolated chemically in the early 1800s by Wilhelm Sertürner, with subsequent elucidation of its chemical and structural formula by Sir Robert Robinson in the 1940s [91]. ...
... During the Renaissance, the creation of various opium products resulted in common usage and subsequent addiction [91]. Morphine, the active ingredient of opium, was isolated chemically in the early 1800s by Wilhelm Sertürner, with subsequent elucidation of its chemical and structural formula by Sir Robert Robinson in the 1940s [91]. Plant-based extraction of morphine from the poppy plant remains a major source of morphine-based therapies [91]. ...
... Morphine, the active ingredient of opium, was isolated chemically in the early 1800s by Wilhelm Sertürner, with subsequent elucidation of its chemical and structural formula by Sir Robert Robinson in the 1940s [91]. Plant-based extraction of morphine from the poppy plant remains a major source of morphine-based therapies [91]. Currently, there is a stark disparity and inequality in the global usage of opiates, with 80% of the world opiate supply consumed by the United States (US) and 80% of the global population having no access to opiates [92]. ...
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Reproductive function depends upon an operational hypothalamo–pituitary–gonadal (HPG) axis. Due to its role in determining survival versus reproductive strategies, the HPG axis is vulnerable to a diverse plethora of signals that ultimately manifest with Central Hypogonadism (CH) in all its many guises. Acquired CH can result from any pituitary or hypothalamic lesion, including its treatment (such as surgical resection and/or radiotherapy). The HPG axis is particularly sensitive to the suppressive effects of hyperprolactinaemia that can occur for many reasons, including prolactinomas, and as a side effect of certain drug therapies. Physiologically, prolactin (combined with the suppressive effects of autonomic neural signals from suckling) plays a key role in suppressing the gonadal axis and establishing temporary CH during lactation. Leptin is a further key endocrine regulator of the HPG axis. During starvation, hypoleptinaemia (from diminished fat stores) results in activation of hypothalamic agouti-related peptide neurons that have a dual purpose to enhance appetite (important for survival) and concomitantly suppresses GnRH neurons via effects on neural kisspeptin release. Obesity is associated with hyperleptinaemia and leptin resistance that may also suppress the HPG axis. The suppressibility of the HPG axis also leaves it vulnerable to the effects of external signals that include morphine, anabolic-androgenic steroids, physical trauma and stress, all of which are relatively common causes of CH. Finally, the HPG axis is susceptible to congenital malformations, with reports of mutations within >50 genes that manifest with congenital CH, including Kallmann Syndrome associated with hyposmia or anosmia (reduction or loss of the sense of smell due to the closely associated migration of GnRH with olfactory neurons during embryogenesis). Analogous to the HPG axis itself, patients with CH are often vulnerable, and their clinical management requires both sensitivity and empathy.
... Known as an alkaloid, Morphine is considered as one of the well-known plant-derived drugs obtained from the ancient medicinal herb, poppy (Brook et al. 2017). ...
... Setigerum was located in Danubian settlements, dated 4400-4000 BC. Also, some poppy seeds were found in northern France along with farming settlements on the shores of lakes in Switzerland that dated back to 3700-3625 BC (Brook et al. 2017). ...
... These capsules should be dried for the use and preparation of the opium inside of them. However, it is still ambiguous how the man discovered the potential medicinal effects of this plant (Brook et al. 2017). ...
Chapter
This chapter aims to demonstrate the high value of natural compounds in modern drug discovery. Although, in today’s global market, the extraction of natural productsNatural products does not count as a primary method to produce medicines, yet nature’sNature selectivity toward producing specific stereoisomers makes this source an interesting target for further studies. The biological and chemical comparison between natural and syntheticSynthetic chiral structures shows thoughtful selectivity of nature toward creating the isomer that possesses the highest therapeutic properties and least side effects. Thus, even the developments of modern techniques in synthetic chemistry and drug designDrug design could not replace or overshadow the importance of these natural treasures in the pharmaceutical industry. In this regard, we devoted this chapter to introduce the essential role of nature in all its forms (plants, bacteria, fungus, or even animals’ organs) in the discovery of some critical therapeutic agents, including a few well-known drugs that saved the lives of many patients.
... Opium poppy (Papaver somniferum) is a flowering plant in the Papaveraceae family (order Ranunculales) valued for its ornamental beauty, edible seeds and, above all, significant medicinal properties. Archeological evidence shows that opium poppy was cultivated during the Neolithic and Bronze ages, while references to the beneficial uses of the plant are found in ancient Greek, Egyptian, Indian, Chinese, and Roman texts (Brook et al. 2017). Known as the ''joy plant'' in Mesopotamian civilization * 6000 years BCE, humans have long exploited the therapeutic uses of opium poppy and refined its consumption from the dried milky latex (opium), to the sophisticated extraction of the main bioactive principle (morphine), to the industrial semi-synthesis of widely demanded drugs (oxycodone, naltrexone, and naloxone) in a contemporary billion-dollar market (Presley and Lindsley 2018). ...
... setigerum) to a lesser extent. The ''principium somniferum'' was first isolated from opium poppy latex by Friedrich Sertürner more than two centuries ago, whereas the elucidation of the complex pentacyclic structure was accomplished by Nobel Prize in Chemistry recipient, Sir Robert Robinson in 1925 and later confirmed by chemical synthesis in the 1950s (Brook et al. 2017;Presley and Lindsley 2018). However, the final molecular component involved in the biosynthetic pathway leading to morphine from (S)-reticuline has been determined just this year (Dastmalchi et al. 2019a). ...
Article
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For nearly eight millennia, opium poppy (Papaver somniferum) has been bred and cultivated for therapeutic purposes. The medicinal properties of the plant are conferred by specialized metabolites known as benzylisoquinoline alkaloids (BIAs), comprising the narcotic analgesics morphine and codeine, the antimicrobial agent sanguinarine, and the potential anticancer drug noscapine. In addition, naturally occurring thebaine is used for the semi-synthesis of widely prescribed pain-relievers (e.g., oxycodone and hydrocodone), valuable drugs used in the treatment of opioid addiction (i.e., naltrexone), or antidotes for opioid overdose (i.e., naloxone). The complex stereochemistry of many opiates hinders their chemical synthesis and opium poppy remains the sole commercial source of these important pharmaceuticals. For decades, opium poppy has served as a model plant for research aimed at a comprehensive understanding of BIA metabolism. Recent progress in functional genomics has enabled the discovery of a nearly complete collection of BIA biosynthetic genes, many of which are clustered in the opium poppy genome. Advances in synthetic biology have facilitated the successful reconstitution of several BIA biosynthetic pathways in heterologous hosts such as Saccharomyces cerevisiae and Escherichia coli, although the initially low production levels suggest that commercial scale-up will present additional challenges. This review provides an update of key molecular and biochemical aspects of BIA metabolism in opium poppy, including recent biosynthetic gene discoveries, genomic organization, novel BIA transporters, metabolic regulation, and major efforts in the engineering of pathways in plants and microbes.
... L'attribution de cette découverte est néanmoins controversée. En 1804, Armand Séquin et Bernard Courtois présentent à l'Institut de France une méthode d'isolement de la substance active de l'opium, mais ils ne publient ces observations que 10 ans plus tard, en 1814 (Brook, Bennett, & Desai, 2017). Successivement, l'allemand Carl Friedrich Wilhelm Meissner classifie en 1819 la morphine comme le premier alcaloïde, composé organique à base azoté de provenance majoritairement végétale (Meissner, 1819). ...
... Par exemple, celle-ci est omniprésente pendant la première guerre mondiale où elle est donnée aux soldats blessés malgré les risques d'accoutumance. Par ailleurs, depuis la découverte de la structure chimique de la morphine par Sir Robert Robinson en 1925, un grand nombre de dérivés morphiniques ont été développés afin d'obtenir une meilleure analgésie et moins d'effets secondaires (Brook et al., 2017). Cependant, la morphine reste aujourd'hui l'analgésique de référence auquel tous les autres traitements antidouleurs sont comparés. ...
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Les effets de la morphine sont influencés par le sexe. Chez le rongeur, son métabolisme implique sa glucuronidation en morphine-3-glucuronide (M3G). La M3G provoque une hyperalgésie qui pourrait s’opposer aux effets antinociceptifs de la morphine. Nous avons constaté que l’antinociception induite par la morphine est plus forte chez la souris mâle et que la tolérance antinociceptive se développe plus rapidement chez la souris femelle. La M3G possède un effet pronociceptif qui ne semble pas dépendre du sexe. Nous avons quantifié la morphine et la M3G dans le sang et dans des régions cérébrales impliquées dans le contrôle de la douleur après une injection de morphine, et nous avons constaté que les ratios métaboliques M3G/morphine étaient largement supérieurs chez les femelles. Nous avons également observé un métabolisme central de la morphine in vivo. Nous avons conclu que le métabolisme périphérique et central était influencé par le sexe et que le métabolisme central de la morphine pourrait participer aux différences d’antinociception liées au sexe. Cependant, son implication dans la tolérance antinociceptive semble limitée.
... Opium is a mixture of alkaloids extracted from Papaver somniferum, a species of poppy with analgesic and antiallodynic actions; morphine, codeine, and thebaine alkaloids are present in the poppy latex. For many millennia, opium and its derivatives were widely used for medicinal and anesthetic effects [1]. In recent decades, opium has been chemically and physically manipulated to optimize therapeutic efficacy and improve practical routes of administration, and clinicians have been tasked with implementing strategies to minimize adverse effects and mitigate addiction risk. ...
... Mônica R. Gadelha 1,2,3 · Niki Karavitaki 4,5,6 · Jeffrey Fudin 7,8,9,10 · Jeffrey J. Bettinger 11 · Hershel Raff 12,13 · Anat Ben-Shlomo 14,15 1 Endocrine Unit and Neuroendocrinology Research Center, Medical School and Hospital Universitário Clementino Fraga Filho -Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil ...
Article
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Purpose Opioids are highly addictive potent analgesics and anti-allodynics whose use has dramatically increased in recent decades. The precipitous rise in opioid dependency and opioid use disorder is an important public health challenge given the risks for severely adverse health outcomes. The long-term opioid impact on hypothalamic–pituitary axes is particularly underappreciated among both endocrinologists and primary care physicians. We review the effects of opioids on hypothalamic–pituitary-target gland function and their implications for clinical practice. Methods Experts in hypothalamic–pituitary disorders and opioid pharmacology reviewed recently published literature and considered strategies for diagnosing and managing these opioid-induced endocrine effects. Results Opioid suppression of hypothalamic–pituitary axes can lead to hypogonadotropic hypogonadism, central adrenal insufficiency, and hyperprolactinemia. These important clinical manifestations are often under-estimated, poorly evaluated, and typically either untreated or not optimally managed. Data on biochemical testing for diagnosis and on the effect of hormone replacement in these patients is limited and prospective randomized controlled studies for guiding clinical practice are lacking. Conclusions Patients should be informed about risks for hypogonadism, adrenal insufficiency, and hyperprolactinemia, and encouraged to report associated symptoms. Based on currently available evidence, we recommend clinical and biochemical evaluation for potential central adrenal insufficiency, central hypogonadism, and/or hyperprolactinemia in patients chronically treated with opioids as well as the use of current expert guidelines for the diagnosis and treatment of these conditions.
... During this time it was sold both as an intoxicant and for medicinal uses. A pivotal step in our understanding of opioids as neurochemical agents occurred when the active ingredients of the opium poppy (morphine, codeine and thebaine) were isolated in the early 1800s [1]. The most potent active ingredient in opium dubbed "morphine" after the Greek god of dreams was relatively easy to produce for chemists. ...
... After isolating morphine, it would take another 50 years before its full chemical formula was identified [1]. Morphine's basic structure (protonated amine connected to an aromatic ring in a specific orientation) would become a common feature for future opioid study and synthesis [3,4]. ...
Article
Opioids have been used to treat pain and invoke pleasure for centuries. Modern scientific advancements have led to more potent, synthetic opioids. While certainly more effective in treating pain, they can also be much more addictive. Over the years the scientific community has developed a clearer understanding of the role opioid receptors play in causing and treating opioid use disorders (OUD) and we now know that OUD can develop in individuals taking opioids for "legitimate" pain. Current guidelines suggest that all prescribers (especially those prescribing opioids) be capable treating OUD. Pharmacological advances have led to a wide array of safe and effective treatment options to address OUDs. This paper will discuss the history of opioid development, what is known about the transition from analgesic uses to addiction and modern evidenced based treatment strategies to address OUDs.
... Although the opium poppy had been used medicinally and recreationally by humans for thousands of years, this event marked the beginning of the modern era of medicinal opioids. 1 By the 1850s, the full chemical formula was well established, anddin combination with the invention of the hypodermic needledmorphine became the medicinal choice for a host of ailments. However, its use became problematic when a lack of good surgical and medical options led to overuse. ...
... Subsequently, in 1912, the United States and many other countries signed the International Opium Convention, which controlled the import, manufacture, and sale of morphine, drastically reducing its consumption. 1,2 Many believe that the modern opioid epidemic started in the 1990s, 3,4 with a tenacious movement to improve the evaluation and treatment of non-cancer pain. [5][6][7] At the height of the movement, the Joint Commission revamped their pain-management standards requiring organizations to perform regular systematic assessments of pain (ie, pain on a 10-point scale). ...
Article
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The United States is in the midst of a national opioid epidemic. Physicians are encouraged both to prevent and treat opioid-use disorders (OUDs). Although there are 3 Food and Drug Administration-approved medications to treat OUD (methadone, buprenorphine, and naltrexone) and there is ample evidence of their efficacy, they are not used as often as they should. We provide a brief review of the 3 primary medications used in the treatment of OUD. Using data from available medical literature, we synthesize existing knowledge and provide a framework for how to determine the optimal approach for outpatient management of OUD with medication-assisted treatments.
... Since the beginning of the 19th century, in parallel with the development of the pharmaceutical industry, there was an impetus in the isolation of new compounds possessing a therapeutic or commercial potential. In 1805, morphine was isolated from the latex of opium poppies and went immediately into commercial production in Europe and the United States, where it soon reached widespread popularity as a pain relief medication [4]. After the discovery of morphine, many other compounds with therapeutic effects were isolated and purified from plants. ...
Article
Plants have always been used as medicines since ancient times to treat diseases. The knowledge around the active components of herbal preparations has remained nevertheless fragmentary: the biosynthetic pathways of many secondary metabolites of pharmacological importance have been clarified only in a few species, while the chemodiversity present in many medicinal plants has remained largely unexplored. Despite the advancements of synthetic biology for production of medicinal compounds in heterologous hosts, the native plant species are often the most reliable and economic source for their production. It thus becomes fundamental to investigate the metabolic composition of medicinal plants to characterize their natural metabolic diversity and to define the biosynthetic routes in planta of important compounds to develop strategies to further increase their content. We present here a number of case studies for selected classes of secondary metabolites and we review their health benefits and the historical developments in their structural elucidation and characterization of biosynthetic genes. We cover the cases of benzoisoquinoline and monoterpenoid indole alkaloids, cannabinoids, caffeine, ginsenosides, withanolides, artemisinin, and taxol; we show how the “early” biochemical or the more recent integrative approaches–based on omics-analyses–have helped to elucidate their metabolic pathways and cellular compartmentation. We also summarize how the knowledge generated about their biosynthesis has been used to develop metabolic engineering strategies in heterologous and native hosts. We conclude that following the advent of novel, high-throughput and cost-effective analytical technologies, the secondary metabolism of medicinal plants can now be examined under the lens of systems biology.
... Morphine was the first alkaloid to be used for pain relief without loss of consciousness in 1800s. 4 Besides being a potent pain killer opiates derived from poppy have many other medical benefits and are used as anti-diarrheal, antitussives, anti-spasmodic. In addition to other adverse effects, opiates are also found to cause early greying of hair, aging, chronic digestive disease, psychiatric and dental problems. ...
Article
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Objective: To assess the trend of poppy use as folk remedy for children at Mardan and surroundings. Study design: Cross-sectional observational study. Duration and Place of Study: This study was carried out from August 2019 to January 2020 at Mardan. Material and Methods: A door to door survey of 500 families residing in Mardan, was carried out. Eligible families/households (having 0 – 12 years aged children) were selected randomly from all these locations of Mardan. A pre-test structured questionnaire proforma was formulated which contained information about trend of using poppy parts (pods) as a remedy for children. Chi square was applied to analyze qualitative variables and independent T test was applied to analyse quantitative variables. P value less than 0.05 was considered significant. Results: Total 500 questionnaires were filled. Out of these, 250 belonged to urban/city areas (group A) and 250 from rural areas (group B). Out of 250 urban families, 93 (37.2%) families used poppy for their children in comparison to 226 (90.4%) families of rural areas. The research showed significantly more use of poppy for children in rural areas as compared to urban areas (p=0.000). People used poppy primarily for treating cough. There was strong association between education status of parents, poppy use being significantly more in children of uneducated parents (p=0.000). Conclusion: Poppy is commonly used by people as household remedy to treat cough, fever and crying babies as folk remedy. Its use is more in rural areas as compared to urban areas. Key Words: Poppy, Cross-sectional, Survey, Therapy
... Plants are the source of approximately 25% of modern drugs and in many cases remain the most cost effective method for their production [313]. Examples include the antimalarial drug artemisinin [314] and the anesthetic morphine [315]. Many of these high-value medicinal compounds are produced from nonmodel plants, but plant engineering efforts have nonetheless been successful in improving their yield [316], which remains economically competitive with chemical and microbial synthesis [317]. ...
Article
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Human life intimately depends on plants for food, biomaterials, health, energy, and a sustainable environment. Various plants have been genetically improved mostly through breeding, along with limited modification via genetic engineering, yet they are still not able to meet the ever-increasing needs, in terms of both quantity and quality, resulting from the rapid increase in world population and expected standards of living. A step change that may address these challenges would be to expand the potential of plants using biosystems design approaches. This represents a shift in plant science research from relatively simple trial-and-error approaches to innovative strategies based on predictive models of biological systems. Plant biosystems design seeks to accelerate plant genetic improvement using genome editing and genetic circuit engineering or create novel plant systems through de novo synthesis of plant genomes. From this perspective, we present a comprehensive roadmap of plant biosystems design covering theories, principles, and technical methods, along with potential applications in basic and applied plant biology research. We highlight current challenges, future opportunities, and research priorities, along with a framework for international collaboration, towards rapid advancement of this emerging interdisciplinary area of research. Finally, we discuss the importance of social responsibility in utilizing plant biosystems design and suggest strategies for improving public perception, trust, and acceptance.
... Since the discovery of this class of natural products, several biological activities associated with alkaloids have been reported, including analgesic [13], antibacterial [14], antifungal [15], antiinflammatory [16], anticancer [17], and antiviral [18] activity. Among the alkaloids that have antiviral activity, berberine has shown activity against the chikungunya virus, human cytomegalovirus (HCMV), and hepatitis C virus (HCV) [19][20][21], tomatidine against dengue virus (DV) [22], michellamine B against human immunodeficiency virus (HIV) [23], oxymatrine against influenza A virus [24], and palmatine against zika virus (ZV) [25]. ...
Article
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Alkaloids are a class of natural products known to have wide pharmacological activity and have great potential for the development of new drugs to treat a wide array of pathologies. Some alkaloids have antiviral activity and/or have been used as prototypes in the development of synthetic antiviral drugs. In this study, eleven anti-coronavirus alkaloids were identified from the scientific literature and their potential therapeutic value against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is discussed. In this study, in silico studies showed an affinity of the alkaloids for binding to the receptor-binding domain of the SARS-CoV-2 spike protein, putatively preventing it from binding to the host cell. Lastly, several mechanisms for the known anti-coronavirus activity of alkaloids were discussed, showing that the alkaloids are interesting compounds with potential use as bioactive agents against SARS-CoV-2.
... The isolation, characterization and application of bioactive natural products play a highly significant role in drug discovery and development process. The revolution of herbal drug discovery mainly started since starting of 19th century (Wachtel-Galor and Benzie, 2011;Pal and Shukla, 2003), when many drugs were isolated from plants as well as fungi such as Penicillin (antibiotic) from the fungus Penicillium notatum (Fleming, 1929) Paclitaxel from bark of pacific yew tree Taxus brevifolia (Pulici et al., 1997), morphine from Papaver somniferum (Brook et al., 2017), colchicine from Gloriosa superba ( Joshi et al., 2010;Balkrishna et al., 2019), ephedrine (Ephedra species), quinine from Cinchona cordifolia, atropine from Atropa belladonna, caffeine from Coffea Arabica and many more, for the treatment of various diseases (Bapu, 2018). Isolation of these drugs from various plant sources created a vast scope for researcher for discovery and development of bioactive molecule naturally as well as synthetically. ...
... It is known that it can prolong extubation time, especially by causing respiratory depression and drowsiness at high doses and also may lead to addiction. It should also be noted that opioids have a narrow therapeutic window with side effects such as nausea, vomiting, constipation, itching, and bladder dysfunction [5,6]. Therefore, although they are beneficial in postoperative pain management, opioids should be used at minimum doses, times, and with caution [7]. ...
Article
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Introduction: Effective treatment of postoperative pain due to median sternotomy speeds up hemodynamic healing of patients. For this purpose, opioids with a wide range of side effects are widely used at high doses. The aim of this study is to investigate the effect of continuous local anesthetic (bupivacaine) infusion on opioid use on cardiac surgery patients undergoing median sternotomy. Methods: A total of 215 patients undergoing isolated coronary artery bypass grafting surgery were included in the study; and 105 patients who underwent parasternal continuous local anesthetic infusion (0.5% bupivacaine at 4 mL/h, for 48h) were determined as local anesthesia group and other patients were as control group. The primary outcomes evaluated between the groups in the postoperative period were pain scores (VAS: Visual Analogic Score, PHHPS: Prince Henry Hospital Pain Score) and the number of opioids used. Secondary outcomes were mechanical ventilation time, intensive care unit and hospital stay duration, development of atrial fibrillation and atelectasis. Results: Postoperative pain was found to be significantly lower in the local anesthesia group compared to the control group (VAS: 3 ± 1.9 vs 6.4 ± 1.8, p < 0.001; PHHPS: 0.9 ± 0.8 vs 1.62 ± 0.82, p < 0.001). As a result of this, opioid drug use was significantly lower in the local anesthesia group compared to the control group (0 (0 - 4) vs 1 (0 - 8), p < 0.001). Mechanical ventilation time, intensive care unit and hospital stay duration, and development of atelectasis were significantly lower in the local anesthesia group. In terms of the development of atrial fibrillation, no significant difference was found between the groups. Conclusion: Parasternal continuous local anesthetic infusion reduces postoperative opioid use and speeds up hemodynamic healing by preventing possible side effects of opioids. It is a simple and effective method in the treatment of postoperative pain due to median sternotomy.
... Sumerian clay tablets bearing descriptions of opium, veneration of the Minoan goddess of poppies, use of opium as a therapeutic treatment by Al-Razi (Rhazes), Ibn-Sina (Avicenna) and Maimonides, and the creation of laudanum by Sydenham in 1676 punctuate an estimated 8 millennia history of medicinal opioid use (Macht 1915;Kritikos and Papadaki 1967;Brownstein 1993;Askitopoulou et al. 2002;Salehi et al. 2016;Brook et al. 2017;Bandyopadhyay 2019). In the absence of more effective and less controversial alternatives, opioid analgesics remain the cornerstone of modern pain relief (Inturrisi 2002), despite the well-recognized problems associated with analgesic tolerance and consequently, the potential need for escalating doses (Yaksh and Onofrio 1987;Mercadante et al. 2002;Trujillo 2002;Chapman and Bradshaw, 2013;Arthur and Hui 2018). ...
Article
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The use of morphine as a first-line agent for moderate-to-severe pain is limited by the development of analgesic tolerance. Initially opioid receptor desensitization in response to repeated stimulation, thought to underpin the establishment of tolerance, was linked to a compensatory increase in adenylate cyclase responsiveness. The subsequent demonstration of cross-talk between N-methyl-d-aspartate (NMDA) glutamate receptors and opioid receptors led to the recognition of a role for nitric oxide (NO), wherein blockade of NO synthesis could prevent tolerance developing. Investigations of the link between NO levels and opioid receptor desensitization implicated a number of events including kinase recruitment and peroxynitrite-mediated protein regulation. Recent experimental advances and the identification of new cellular constituents have expanded the potential signaling candidates to include unexpected, intermediary compounds not previously linked to this process such as zinc, histidine triad nucleotide-binding protein 1 (HINT1), micro-ribonucleic acid (mi-RNA) and regulator of G protein signaling Z (RGSZ). A further complication is a lack of consistency in the protocols used to create tolerance, with some using acute methods measured in minutes to hours and others using days. There is also an emphasis on the cellular changes that are extant only after tolerance has been established. Although a review of the literature demonstrates a lack of spatio-temporal detail, there still appears to be a pivotal role for nitric oxide, as well as both intracellular and intercellular cross-talk. The use of more consistent approaches to verify these underlying mechanism(s) could provide an avenue for targeted drug development to rescue opioid efficacy.
... Do jakościowej i ilościowej zmiany tego zjawiska przyczyniły się przede wszystkim otwarcie granic, wzrost zamożności ludności, powiększająca się grupa osób wykluczonych społecznie oraz narastająca atrofia norm społecznych [6]. Na początku XIX wieku odkryto morfinę, a następnie (1938) wyizolowano związek sporyszu, który posiadał właściwości halucynogenne [7]. Obecnie otrzymuje się z niego LSD, będący środkiem półsyntetycznym o ogromnej sile oddziaływania [8]. ...
... Opium poppy medicinal effects have been known since the early men, and pharmacologic formulations were being sold in the mid-1800s, although the active substance of opium had not been identified yet. The isolation of opium's active ingredient, the alkaloid morphine, was published for the first time in 1805 by the German apothecary Friedrich Wilhelm Adam Sert€ urner [1]. Opioids are chemical substances that can bind to opioid receptors. ...
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Over the past few years, there has been an emerging number of new psychoactive drugs. These drugs are frequently mentioned as “legal highs”, “herbal highs”, “bath salts” and “research chemicals”. They are mostly sold and advertised on online forums and on the dark web. The emerging new psychoactive substances are designed to mimic the effects of psychoactive groups, which are often abused drugs. Novel synthetic opioids are a new trend in this context and represent an alarming threat to public health. Given the wide number of fatalities related to these compounds reported within the last few years, it is an important task to accurately identify these compounds in biologic matrices in order to administer an effective treatment and reverse the respiratory depression caused by opioid related substances. Clinicians dealing with fentanyl intoxication cases should consider that it could, in fact, be a fentanyl analogue. For this reason, it is a helpful recommendation to include synthetic opioids in the routine toxicological screening procedures, including analysis in alternative matrices, if available, to investigate poly-drug use and possible tolerance to opioids. To address this public health problem, better international collaboration, effective legislation, effective investigation, control of suspicious “research chemicals” online forums and continuous community alertness are required. This article aims to review diverse reported fatalities associated with new synthetic opioids describing them in terms of pharmacology, metabolism, posology, available forms, as well as their toxic effects, highlighting the sample procedures and analytical techniques available for their detection and quantification in biological matrices.
... Morphine as an opioid anesthetic drug is indicated for the relief of severe pain [214] and is one of the oldest medical remedies known to man, used in a breadth of ailments as sedative and analgesic [215]. Morphine has some unique chemical properties involved in multiple therapeutic functions, from clinical pain management associated with cancer [216] to potent antioxidant effects in vitro in a concentration-dependent manner [217]. ...
Article
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Anesthetics are extensively used during cancer surgeries. The progression of cancer can be influenced by perioperative events such as exposure to general or local anesthesia. However, whether they inhibit cancer or act as a causative factor for metastasis and exert deleterious effects on cancer growth differs based on the type of cancer and the therapy administration. Recent experimental data suggested that many of the most commonly used anesthetics in surgical oncology, whether general or local agents, can alter gene expression and cause epigenetic changes via modulating miRNAs. miRNAs are single-stranded non-coding RNAs that regulate gene expression at various levels, and their dysregulation contributes to the pathogenesis of cancers. However, anesthetics via regulating miRNAs can concurrently target several effectors of cellular signaling pathways involved in cell differentiation, proliferation, and viability. This review summarized the current research about the effects of different anesthetics in regulating cancer, with a particular emphasis on the role of miRNAs. A significant number of studies conducted in this area of research illuminate the effects of anesthetics on the regulation of miRNA expression; therefore, we hope that a thorough understanding of the underlying mechanisms involved in the regulation of miRNA in the context of anesthesia-induced cancer regulation could help to define optimal anesthetic regimens and provide better perspectives for further studies.
... In other plants of other families, such as the Apocynaceae (Martin et al. 2020), the Asteraceae (Chen et al. 2018b), the Papaveraceae (Yu et al. 2014b), the Routaceae , Solenaceae (Heinig and Aharoni 2014), Erythroxylaceae (Oliveira et al. 2010), and the Fabaceae , alkaloids can also be used in plants of various plant families. Several biological actions have been described since this class of natural products was discovered with alkaloids such as analgesia (Brook et al. 2017), antibacterial (Cushnie et al. 2014), antifungal activity (Khan et al. 2017), antifungal activity (Thompson and Nidorf 2018), anticancer activity (Manayi et al. 2019) and antiviral activity (Xu et al. 2019). Among the antiviral alkaloids, the activity of berberine has included chikungunya, human cytomegalovirus (HCMV), and Hepatitis C Virus (HCV), dengue virus tomatidine (DDV) (Hung et (McMahon et al. 1995), and root tubers of Stephania cepharantha Hayata, which promote the lifespan of herpes simplex virus type 1 mice (HSV1). ...
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The human coronavirus disease (COVID-19) pandemic is caused by a novel coronavirus; the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Natural products, secondary metabolites show positive leads with antiviral and immunotherapy treatments using genomic studies in silico docking. In addition, it includes the action of a mechanism targeting the SARS-CoV-2. In this literature, we aimed to evaluate the antiviral movement of the NT-VRL-1 unique terpene definition to Human coronavirus (HCoV-229E). The effects of 19 hydrolysable tannins on the SARS-CoV-2 were therefore theoretically reviewed and analyzed utilising the molecular operating surroundings for their C-Like protease 3CLpro catalytic dyad residues Angiotensin converting enzyme-2 (MOE 09). Pedunculagin, tercatan, and castalin were detected as interacting strongly with SARS-receptor Cov-2’s binding site and catalytic dyad (Cys145 and His41). SARS-CoV-2 methods of subunit S1 (ACE2) inhibit the interaction of the receiver with the s-protein once a drug molecule is coupled to the s-protein and prevent it from infecting the target cells in alkaloids. Our review strongly demonstrates the evidence that natural compounds and their derivatives can be used against the human coronavirus and serves as an area of research for future perspective.
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Opioid analgesics are the historical mainstay for postoperative cardiothoracic surgery pain relief. Although opioids are efficacious, they are linked with adverse effects, including sedation and respiratory depression. Emerging research is helping clinicians move toward evidence-based, opioid-sparing management strategies, including peripheral nerve blocks and multimodal analgesia. Good communication is essential to understanding patients' perceptions of pain and attitudes toward different pain-relief methods. Preoperatively educating patients and families on expected nociception and treatment options decreases postprocedural pain. Discussing use of nonopioid analgesics for mild pain and instructions on tapering opioid medications at discharge may prevent future misuse.
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Opioid receptors and opioid agonists are widespread throughout nature. Endogenous opioids mediate complex functions in animals and in humans. The opioid system in humans plays a central role in pain control and is a key mediator of hedonic homeostasis, mood, and well-being. This system also regulates responses to stress and several peripheral physiologic functions, including respiratory, gastrointestinal, endocrine, and immune systems. This article provides an overview of the basic physiology of opioids, reviews opioid pharmacology, and attempts to address several issues of current importance in the management of patients with established long-term opioid therapy.
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Chronic pain is a pathological condition that requests specific medical attention. Its treatment has been imperative since the origin of our species, taking advantage of herbs and natural remedies available in the primitive environment. Morphine has stood the test of time as has been continuously used for the past 8 millennia. The anatomical knowledge of the nociceptive sensation pathways led to the introduction of some surgical techniques directed to stop this pain transmission. Due to their aggressiveness and to the fact that they are irreversible, these techniques were soon replaced by neurostimulation procedures. Being reversible and allowing a change in stimulation parameters soon became the preferred treatment strategy. Over the years a small subset of patients continues to suffer from chronic pain refractory to the usual neurostimulation and pain-controlling medications. These patients can perhaps benefit from one of the surgical ablative procedures. Some of these techniques have been proven particularly effective throughout the years. For some limited income patients in underdeveloped countries, these techniques may be their only accessible option. Doctors have to keep in mind these surgical techniques to put them at the service of our patients in the very few cases in which they are needed. Letting these ablative techniques to die in oblivion would be a disservice to our patients.
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A novel approach is introduced for reliable prediction of the retention time of morphine and its derivatives, which have widespread use in medical and pharmaceutical applications. A core correlation is introduced based on the number of carbon and hydrogen atoms as well as the number of ester, noncyclic ether, and ketone functional groups from experimental data of 42 compounds. An improved correlation is developed to increase the reliability of the core correlation by inserting a correcting function. The reliability of two correlations is tested and compared with the best available complex method based on a backpropagation artificial neural network (BP-ANN) for further 15 compounds. The values of root mean squared error (RMSE) of core and improved correlations for the test set are 0.5681 and 0.4832 min, which are lower than those reported by BP-ANN (0.6052 min). Cross-validations of the improved correlation corresponding to the coefficients of determination for leave-one-out (Q²LOO) and the fivefold cross-validation (Q²5CV) are close to its the coefficient of determination (R² = 0.982), which confirms goodness-of-fit, goodness-of-prediction, accuracy, and precision of the novel model.
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Background Bakuchiol is a phytochemical that has demonstrated cutaneous anti‐aging effects when applied topically. Early studies have suggested that bakuchiol is a functional analog of topical retinoids, as both compounds have been shown to induce similar gene expression in the skin and lead to improvement of cutaneous photodamage. No in vivo studies have compared the two compounds for efficacy and side effects. Objectives To compare the clinical efficacy and side effect profiles of bakuchiol to retinol in improving common signs of cutaneous facial aging. Methods This was a randomized, double‐blind, 12‐week study in which 44 subjects were asked to apply either 0.5% bakuchiol cream twice daily or 0.5% retinol cream daily. A facial photograph and analysis system was used to obtain and analyze high‐resolution photographs of subjects at 0, 4, 8, and 12 weeks. Subjects also completed tolerability assessment questions to review side effects. During study visits, a board‐certified dermatologist, blinded to study group assignments, graded pigmentation and redness. Results Bakuchiol and retinol both significantly decreased wrinkle surface area and hyperpigmentation, with no statistical difference between the compounds. The retinol users reported more facial skin scaling and stinging. Conclusion Our study demonstrates that bakuchiol is comparable to retinol in its ability to improve photoaging and is better tolerated than retinol. Bakuchiol is promising as a more tolerable alternative to retinol. This article is protected by copyright. All rights reserved.
Article
Fentanyl rose to prominence as an alternative analgesic to morphine nearly 50 years ago; today, fentanyl has re-emerged as a dangerous recreational substance. The increased potency and analgesic effect of fentanyl are advantageous in the treatment of pain but are also responsible for the rise in unintentional opioid overdose deaths. In response to this crisis, fentanyl, its analogues, and even precursors are under heightened regulatory scrutiny. Despite this controversial history, derivatization of fentanyl has resulted in numerous synthetic analogues that provide valuable insights into opioid receptor binding and signaling events. In this review, the impact of fentanyl on chemical neuroscience is shown through its synthesis and properties, manufacturing, metabolism, pharmacology, approved and off-label indications, adverse effects, and the responsibility it has in the opioid epidemic.
Chapter
For as long as the species has existed, humans have been making use of the abundant resources found in nature. Mankind has harnessed the chemical properties of timber to produce fire, transformed straw and water reeds into thatched roofing, and spun the fibers of plants into cloth and fabric. As is evident in such examples, human society has consistently learned to adapt to its surroundings. In addition to utilizing nature to meet basic survival needs, humans have treated both major and minor ailments using the power of phytochemicals found in medicinal plants—an age-old practice which has persisted through time. The identification of medicinal plants for humans and their livestock is a tradition that has been conserved and passed on over the generations, whether in the form of written documents (bark, stone, leather, and paper), preserved monuments, or original plant medicines/formulations. These naturally derived sources of medicine are even used today to create some of the most important drugs on the market, ranging from cardiovascular medications to anticancer agents. Science has acknowledged these substances’ bioactivity, with modern pharmacotherapy containing a wide variety of plant-derived drugs from different parts of the world. Many of these medications were first developed by ancient civilizations and subsequently used throughout history. In addition to the pharmacological attributes of natural products, there is a growing trend of incorporating plants into daily diets in the form of functional foods and dietary supplements. Such products are used to strengthen general health and support the functions of the human immune system.
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Battlefield pain management changed markedly during the first twenty years of the Global War on Terror. Morphine, long the mainstay of combat analgesia, diminished in favor of fentanyl and ketamine for military pain control, but the options are not hemodynamically or psychologically equivalent. Understanding patterns of prehospital analgesia may reveal further opportunities for combat casualty care improvement. Using Department of Defense Trauma Registry (DoDTR) data for the Afghanistan conflict from 2005-2018, we examined 2,402 records of prehospital analgesia administration to assess temporal trends in medication choice and proportions receiving analgesia, including subanalysis of a cohort screened for indication with minimal contraindication for analgesia. We further employed frequency matching to explore for the presence of disparities of analgesia by casualty affiliation. Proportions of documented analgesia increased throughout the study period, from 0% in 2005 to 70.6% in 2018. Afghan casualties had the highest proportion of documented analgesia (53.0%), versus US military (31.9%), civilian/other (23.3%) and non-US military (19.3%). Fentanyl surpassed morphine in frequency of administration in 2012. Median age of those receiving ketamine was higher (30 years) than those receiving fentanyl (26 years) or nonsteroidal anti-inflammatory drugs (23 years). Amongst the frequency matched sub-analysis, the odds ratio for ketamine administration with Afghan casualties was 1.84 (95% CI 1.30-2.61), and higher in sensitivity analysis at 2.60 (95% CI 1.73-3.89). We observed heterogeneity of prehospital patient care across patient affiliation groups, suggesting possible opportunities for improvement toward an overall best practice system. General increase in documented prehospital pain management likely reflects efforts toward complete documentation, as well as improved options for analgesia. Current combat casualty care documentation does not include any standardized pain scale.
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Frequently, aches, and pain are symptoms, like alarms alerting the occurrences of dangerous events which can cause cell death, tissue destruction, and inflammation. Physicians treat the underlying diseases which cause the pain and aches in order to restore health. On some occasions, the treatments are directed at aches and pains themselves, and are thus symptomatic relief. For surgeons, pain is an inevitable consequence of what we do in the operating room. Postoperative pain management represents an important part of the Enhanced Recovery After Surgery (ERAS) protocols. Furthermore, opioid epidemic has cost a great burden on the society and the healthcare system, which also places an emphasis on using non-opioid analgesics to achieve adequate pain relief. Unlike other vital signs, there is no objective, direct measurement of pain, even though pain is considered the fourth vital sign. Pain is a perceived sensation, as a result of nociception, a complex process which can extend from other somatosensory modalities such as thermoception, chemoception, and mechanoception. Whenever the stimulus magnitude exceeds nominal physiologic boundaries, cell death, and tissue injury follow, as does afferent nociceptive signals. This review is to provide craniofacial surgeons with an update on pain, what pain is, how to assess it, pharmacology of pain relief, and specifically, the proper use of opioids and non-narcotic analgesic agents. The goal is to allow for the optimal, rational use of these medications to relief pain with the minimum short and long term risks. With evidence-based, data-driven approach, supplemented by group experience pooled from senior surgeons after 100,000 patient-hours, the objective is to answer the following: (1) What is pain? (2) How does opioid work? (3) What is the role of narcotic analgesics in craniofacial ERAS? (4) When should non-opioids be used and how?
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Fractionation of essential oils is technically challenging due to enormous scaffold diversities and structural complexities as well as difficulties in the implementation of the fractionation in the gas phase. Packing beads with multi-dimensional hierarchical nanostructures have been developed herein to pack fractional columns for atmospheric distillations. Activated alumina beads were coated with a porous TiO2 thin film. Growth of Cu-BTC (benzene-1,3,5-tricarboxylate) crystals in resultant porous surfaces leads to the generation of new nanopores and increased metal centers for differential coordination with diverse components of essential oils. The TiO2 thin film is not only an integral part of the composites but also induces the oriented growth of Cu-BTC metal organic framework (MOF) crystals through coordinative interactions. These Al2O3@TiO2@Cu-BTC MOF beads show very strong absorptive capability for major components of essential oils, except for a single cyclic ether eucalyptol with steric hindrances. The eucalyptol was fractionated by using the column packed with those modified alumina beads from raw materials of Artemisia argyi, and Rosmarinus officinalis with high purities up to 96% and 93%, respectively.
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Among analgesic drugs, the opioid class of compounds still remains one of the most important medicines for severe and chronic pain treatment. Hence, developing novel and effective synthetic method of morphine and its related compounds is still an important task in modern synthetic organic chemistry. Achieving this goal demands a comprehensive knowledge of these valuable alkaloids. The present review study aims to summarize the history of five major opioid alkaloids and their pharmacologic effects, as well as various synthetic and biosynthetic methods.
Chapter
Phenotypic drug discovery has never lost its place in the span of drug invention/discovery. This method involves using a known natural product that is proven to have bio‐activity, as the base for the invention of new molecules/leads. This chapter reviews the role and the importance of the natural products in the field of medicinal chemistry, basics of drug discovery research with well‐known and well‐established molecules like morphine, and finally, a discussion on the current research on a molecule named Piperine is made.
Chapter
Naturally occurring naphthoquinones are known for their various biological and pharmacological activities and has been reported and studied intensely. In this chapter, we have gathered possible literature and representing brief and detailed account of biological activity profile of 1,4‐naphthoquinones and their cognate hetero atom (O, N, and S) as well as halo (Cl, Br, and I), cyclic, noncyclic, and five or six membered rings against several pathogenic fungi, bacteria, viruses, plasmodium, leishmanial, and cancer. The literature available suggests that the biological action of 1,4‐naphthoquinone is mainly related to redox cycling of naphthoquinone; however, hetero‐substituted derivatives of 1,4‐naphthoquinone modify the activity comparable to an extent. Quinones are known to have a similar electronic energy level with metals. This feature allows them to form redox isomers by intramolecular electron transfer; hence, quinones are used in many biological processes.
Chapter
Amide pharmacophore has gained significant consideration in the field of current medicinal chemistry. Literature indicates that compounds having amide pharmacophore have wide range of pharmacological activities, viz., anticonvulsant, antitubercular, antimicrobial, analgesic and anti-inflammatory, insecticidal, antitumor, fibrinolytic, and antiplatelet aggregatory. This chapter focuses on the anticonvulsant activity of substituted amides. The well-known and recent data on the preparation of amides used in the synthesis of these biologically active anticonvulsant compounds are summarized. The favorable amide derivatives possessing anticonvulsant activity will reignite the interest of medicinal chemists in amide and its derivatives.
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Pain is an important signal of almost all pathological processes. At the same time, in the presence of painful sensations, a person tried to eliminate them to improve the quality of life. Therefore, at all times, painkillers are played a very important role in the pharmaceutical market. The search for new molecules with analgesic properties and the development of dosage forms for already acting drugs are still important tasks in the pharmaceutical environment. In this review, we tried to show development path of the search for a new painkillers.
Thesis
Opioids are effectively used for the treatment of acute and chronic pain, however, serious problems such as fatal overdose due to respiratory depression and opioid addiction are associated with the use of these medications. A strong body of evidence suggests that the simultaneous targeting of mu opioid receptors and other opioid receptor types may be beneficial in improving mu opioid receptor-mediated side effects. This dissertation reports in vitro experiments designed to pharmacologically analyze opioid compounds that activate the mu opioid receptor and inhibit the delta opioid receptor to provide information that allows for assessment of their potential as novel analgesics. Such “bifunctional opioid peptidomimetics” were evaluated to define their structure-activity relationship (SAR) properties and improve our understanding of how such compounds bind to and activate the mu and delta opioid receptors and influence downstream signaling. Some key findings were that substitutions to the N1 position of the tetrahydroquinoline (THQ) core of the peptidomimetic improved delta opioid receptor affinity while maintaining an already high mu opioid receptor affinity. In addition, larger substituents at the C6 position of the THQ core, such as a 2-napthyl or 2-methyl-tetrahydroisoquinoline, were instrumental in achieving the desired mu opioid receptor agonist and delta opioid receptor antagonist pharmacological profile. These SAR insights provide valuable information to advance the design and development of these novel opioid compounds that exhibit a high binding affinity for both mu and delta opioid receptors. Several bifunctional opioid peptidomimetics demonstrate a greater degree of mu opioid receptor agonism than the prototypical opioid full agonist, DAMGO. The assessment of this “superagonism” was achieved by using multiple cell lines, performing G protein activation assays, and competition binding assays with or without sodium ions and guanine nucleotide. Several of these peptidomimetics also demonstrated a difference in the way they signal downstream of the mu opioid receptor, with some compounds preferring G protein activation and others preferring the recruitment of arrestin proteins. In addition to characterizing superagonism and biased agonism, interactions between the mu and delta opioid receptors at the single cell level were examined to further understand the mechanism of action of these bifunctional peptidomimetics in an attempt to explain the beneficial pharmacology generated by such compounds. In conclusion, these compounds may serve as valuable pharmacological tools to further define biased agonism at the opioid receptors and help drive the development of bifunctional opioid compounds as safe and non-addictive analgesics.
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Morphine is known as a pain reliever which frequently prescribed globally. However, genuine result such as, dependence, pain relieving resilience, immunosuppression, gastrointestinal (GI) manifestations limit their utilization (12). The word Opium comes from the ancient Greek OPOS which means means vegetable juice. It is also refer to the Opium Poppy (Papver somniferum) (1). In order to overcome tolerance, a higher dosage of morphine is commonly used, although this technique leads patients to a greater risk of having serious side effects, such as morphine reward and withdrawal symptoms (4).
Book
This book examines the origins, development, and rise of the opioid epidemic in the United States from the perspective of the public policy process. The book begins with a brief historical examination of the history of the problem of opioid addiction and crises in the United States and public policy responses to past crises. The major focus of the book is on the current opioid epidemic and explores the national, state, and local governments’ policy response to the opioid epidemic. The authors conclude with a discussion of how accurate problem definition, diagnosis, and appropriate and timely policy responses by policymakers could have helped minimized if not prevented the problem of opioid addiction and overdose deaths. The authors outline policy process tools that will be essential in fighting both the current crisis and the next one.
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The dopaminergic system has been suggested to serve as a functional target for ketamine, especially with its addictive and antidepressant effects. In this work, intracellular vesicle impact electrochemical cytometry and single cell amperometry were applied to a model cell line to show that the intravesicular contents and number of exocytotic events increased and the fraction of release decreased after treatment by subanesthetic ketamine (1 μM for 15 min). In addition, time‐of‐flight secondary ion mass spectrometry was used to show that cellular lipids change following acute ketamine administration relative to control cells with an increased proportion of low‐curvature lipids and a decreased proportion of high‐curvature lipids. We propose that ketamine modulates dopaminergic function with a dose‐dependent pharmacologic action by dominantly interacting with different proteins and changing lipid composition. It might be helpful to better understand the relationship of the dopaminergic system and drug abuse, as well as anesthetic and antidepressant effects.
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The lack of satisfactory treatment for persistent pain profoundly impairs the quality of life for many patients. Stimulation of brainstem pain control systems can trigger powerful analgesia, but their complex network organi-zation frequently prevents separation of analgesia from side effects. To overcome this long-standing challenge, we developed a biocompatible gelatin-embedded cluster of ultrathin microelectrodes that enables fine-tuned, high-definition three-dimensional stimulation in periaqueductal gray/dorsal raphe nucleus in awake rats. Analgesia was assessed from both motor reactions and intracortical signals, corresponding to pain-related signals in humans. We could select an individual-specific subset of microelectrodes in each animal that reliably provided strong pain inhibition during normal and hyperalgesia conditions, without noticeable behavioral side effects. Gait, spontaneous cortical activity at rest, and cortical tactile responses were minimally affected, indicating a highly selective action. In conclusion, our developed biocompatible microelectrode cluster and stimulation paradigm reliably enabled powerful, fine-tuned, and selective analgesia without noticeable side effects.
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This comprehensive review on opioids summarizes the scope of the current opioid epidemic, the diagnosis and treatment of opioid use disorder, and the medical and psychiatric complications of opioid use.
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O controle da qualidade de drogas vegetais deve ser realizado em todas as etapas que envolvem a produção de um medicamento fitoterápico ou produto tradicional fitoterápico, iniciando-se com a identificação da espécie vegetal. Dentre as evidências utilizadas para esse fim, as características farmacobotânicas, como aspectos morfológicos externos e anatômicos, além de análise sensorial, são as mais acessíveis. Considerando que as plantas medicinais são comercializadas em grande parte sob a forma rasurada ou pulverizada, as descrições morfoanatômicas estão entre os primeiros parâmetros para o controle da qualidade. A descrição macroscópica, microscópica, microscópica do pó e microscópica de impurezas constam da Farmacopeia Brasileira, dada a importância dessas características no controle da qualidade de matérias-primas vegetais. Embora os métodos químicos analíticos sejam atualmente os mais aceitos como técnicas padrão de identificação para muitas drogas vegetais, a Farmacobotânica é particularmente aplicável na análise de misturas quando os marcadores anatômicos podem ser facilmente reconhecidos. Nos últimos anos, as análises moleculares (DNA barcoding) têm sido utilizadas em diversas áreas, surgindo como ferramentas promissoras para a identificação de plantas. No entanto, apesar do seu potencial indiscutível, as análises do material genético para fins de identificação rotineira de matérias-primas vegetais aplicadas ao controle da qualidade de drogas vegetais ainda não são viáveis do ponto de vista econômico.
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Gaseous molecules have been increasingly explored for therapeutic development. Here, following an analytical background introduction, a systematic review of medical gas research is presented, focusing on tissue protections, mechanisms, data tangibility, and translational challenges. The pharmacological efficacies of carbon monoxide (CO) and xenon (Xe) are further examined with emphasis on intracellular messengers associated with cytoprotection and functional improvement for the CNS, heart, retina, liver, kidneys, lungs, etc. Overall, the outcome supports the hypothesis that readily deliverable “biological gas” (CO, H2, H2S, NO, O2, O3, and N2O) or “noble gas” (He, Ar, and Xe) treatment may preserve cells against common pathologies by regulating oxidative, inflammatory, apoptotic, survival, and/or repair processes. Specifically, CO, in safe dosages, elicits neurorestoration via igniting sGC/cGMP/MAPK signaling and crosstalk between HO‐CO, HIF‐1α/VEGF, and NOS pathways. Xe rescues neurons through NMDA antagonism and PI3K/Akt/HIF‐1α/ERK activation. Primary findings also reveal that the need to utilize cutting‐edge molecular and genetic tactics to validate mechanistic targets and optimize outcome consistency remains urgent; the number of neurotherapeutic investigations is limited, without published results from large in vivo models. Lastly, the broad‐spectrum, concurrent multimodal homeostatic actions of medical gases may represent a novel pharmaceutical approach to treating critical organ failure and neurotrauma.
Thesis
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This master thesis aims at examining the binary distinction between licit and illicit global production networks of (dual-use) controlled substances. It is hypothesized that licit trade of controlled substances is subject to regulation which prevents diversion from occurring. Most studies focus on illegal trafficking, but rarely on licit trade. When they do, their scope is restricted to a location and one controlled substance, either plant-based or synthetic. No studies have conducted this from the perspective of global production networks on opiates, the base for many pharmaceutical medicines. I argue that there are junctions in which illicit practices penetrate the licit trade, which are located in what I refer to as critical nodes. My results show that these critical nodes are part of the global production network, from the cultivation of poppy fields to the consumption of opiate-based medicine. At a time of questioning supply-chains, the opioid crisis, and international drug control regime dissensus, this study aims to address the gap in the existing literature. It does so by analyzing one controlled substance, with eclectic theorizing evaluating international regulation and the possibility of compliance in practice. This study follows a qualitative and inductive methodology completed by additional quantitative data. My findings show that there are critical nodes and for most, they are structural and dependent on their cultural and geographical roots. The efforts made by key actors in critical nodes are considered sufficient both internationally and domestically speaking. Three reasons for this attitude are outlined: 1) that enough is already being done, 2) that in agenda-setting other matters are prioritized, such as the issue of the counterfeit medicines-a battle of ideologies and values, i.e., access and availability of medicines-and 3) that more regulations would be difficult to set and implement in the context of a free-trade globalized market.
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This review covers recent developments in the area of morphine synthesis and biosynthesis. Literature is reviewed since the publication of the last major review. The first part of the chapter discusses recent advancements in biosynthesis of morphine alkaloids. Total syntheses published since 1996 are reviewed next and the third section discusses all published approaches to morphine skeleton. At the end of the of the chapter, an additional reference list is provided for synthesis of medicinally important derivatives, improvements in alkoloid interconversion, as well as a list of all dissertations dealing with morphine synthesis.
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This review summarizes recent developments in the total synthesis of morphine alkaloids and some of the semisynthetic derivatives. The literature is covered for the period of 5 years after the publication of the last review in 2005. The syntheses that appeared in this period are covered in detail and are placed in the context of all syntheses of opiate alkaloids since the original one published by Gates in 1952. The introduction covers the historical aspects of total synthesis of these alkaloids. The synthesis of some of the medicinally useful derivatives is reviewed in the last section along with some of the methodology required for their preparation. Graphical Abstract
Book
Continuing in the tradition of the acclaimed first edition, Pharmacodynamic Basis of Herbal Medicine, Second Edition examines in extensive detail the physiologic effects of complimentary and alternative therapies, foods, supplements, vitamins, and traditional herbal remedies. The author considers the site, mode, and mechanism of action to explain the desired and adverse effects and interactions of each herb, drug, and food in an encyclopedic volume. Today's Questions Devoting entire chapters to the most influential herbal remedies, the text either endorses or debunks popular conceptions with pure scientific data. The author provides answers to today's naturopathic questions by paying particular attention to the chronic diseases engendered by obesity, as well as Alzheimer's, cancer, imbalances of neurotransmitters such as Parkinson's, and depression. The Latest Research Incorporating current research on the devastating role of chronic systemic inflammation and the cumulative effect of poor oxygen metabolism and free radicals on changes in mitochondrial DNA, enzyme activity, and accelerations in the aging process, the text bridges the gap between ancient remedies and modern knowledge Effective Treatment Deconstructing the molecular mystery that is the interaction among herbal properties, physiology, and disease, Pharmacodynamic Basis of Herbal Medicine, Second Edition opens the door to successful herbal treatment.
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Crystals of morphine hydriodide dihydrate have been examined by quantitative X-ray analysis. They are orthorhombic, space group P2 12121 with four molecules, C17H 19O3N,HI,2H2O per unit cell. Parameters for all the atoms in the crystal unit have been derived from calculation of the electron-density distribution projected down the b and c axes. The molecule is found to be approximately T shaped; the atoms of rings I and II and the oxide ring lie near one plane, while atoms of ring III and the ethanamine ring lie close to a second plane at right angles to the first; this is a consequence of the cis-fusion of rings II and III. Details of the stereochemical form of the different rings present are established.
Article
The products of hydrolysis of β-dihydrothebaine methine (I; R=R′=Me) with mineral acid, and of dihydrothebaine-φ methiodide (cf. VIII; R=H) with sulphurous acid, originally thought to be the same substance (III; R=Me) (Bentley, Robinson, and Wain, J., 1952, 958) have been shown to be two isomers (III and V; R=Me). A third isomer (VI; R=Me) has been prepared by Hofmann degradation of thebainone-B methiodide. Structures have been allotted to the isomers on the basis of infrared and ultraviolet absorptions. Catalytic hydrogenation of both (III; R=Me) and (V; R=Me) gives β-dihydrothebainone dihydromethine (XII). All three methines are converted into highly coloured substances by aerial oxidation. The structure allotted by Bentley and Wain (Part I, J., 1952, 967) to thebainone-C has been disproved. This base has been shown to be a cyclic base with the ethanamine chain bridging positions 13 and 8. The steric arrangement of groups at C(14) in thebainone-C has been proved to be the same as in morphine by reduction, degradation, and further reduction to dihydrothebainone dihydromethine.
Article
The completion of the first synthesis of morphine is described.
Article
Previous work2,3 has established the relative configuration at carbons 5, 6 and 13 in morphine. The present work relates the configuration at carbon 14 to 13, and thus completes the stereochemistry of the molecule. As starting material, dihydrothebainone (V) was chosen since its epimer at carbon 14, epi-dihydrothebainone (β-dihydrothebainone), was also available. Dihydrothebainone was degraded to thebenone (VIII) which on treating with isoamyl nitrite and potassium t-butoxide formed the dioximino compound. Rearrangement with p-toluenesulfonyl chloride in pyridine gave the dinitrile with loss of the carbonyl carbon, and hydrolysis to the acid amide and sublimation resulted in the imide, XV. When the same sequence was applied to epi-dihydrothebainone, the results were parallel except in the last cyclization, where polymeric material was formed rather than imide. This leads to the conclusion that in morphine the hydrogen at carbon 14 is cis to the ethanamine chain (confirming a previous assignment based on hydrogenation studies5) as are the hydrogens at carbons 5 and 6. The morphine molecule may thus be represented by Ib.
Article
Thebaine (VII) has been degraded to (−)-cis-[2-methyl-2-carboxy-cyclohexyl-(1)]-acetic acid (III), thus providing experimental proof of the absolute configuration of morphine, thebaine and related alkaloids.
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Friedrich Wilhelm Sertürner was born near Paderborn in 1783. At the age of twenty he passed examinations as a pharmacist's assistant in Paderborn. In a letter to the editor of Trommsdorffs Journal der Pharmacie Vol 13 (1805) he reported on the isolation of a substance from opium which showed alkaline character and was later called by him "morphine". In 1806, Sertürner moved to Einbeck where he first worked as assistant to the tenant of the magistrate's pharmacy. In 1809, he became pharmacist and, since the tenant was already 75 years old, he intended to take charge of the pharmacy. However,he was not successful. During the invasion of Napoleon Bonaparte's troops into Europe, French legislation became valid in those parts which fell under French government. According to French law, Sertürner was allowed to open a second pharmacy. In Einbeck, Sertürner continued research work on morphine and published the results in two papers. In one of these (1817), he introduced observations made with the drug in humans and for the first time called it "morphine". The French chemist Gay-Lussac showed interest in that publication and ordered a translation into French which earned Sertürner the scientific break-through. His was the first achievement in alkaloid research, and for that he received a doctor degree from the university of Jena in 1817.When Napoleon was finally defeated, Sertürner had to close his pharmacy in Einbeck and found another one in Hameln. When asiatic cholera spread in Germany in 1831, he postulated that cholera is caused by a poisonous,animated reproducing organism and made suggestions to avoid infection which are still valid today.Sertürner was honoured by many institutions but still felt not properly esteemed. His behavior become odd and he debilitated. He died in 1841 and was buried in Einbeck.