Article

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

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

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.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... Opioides O Papiro Ebers (1550 a.C.) descreve uma mistura de substâncias, entre as quais o ópio, que era utilizada para a sedação de crianças, com bastante eficá-Figueirinha J. e Conceição J.cia, pois acreditava-se que a Deusa Ísis também sedava o seu filho Hórus, adquirindo assim um caráter espiritual e mágico31,32. Os registos mais antigos que revelam a extração do ópio da papoila são dos sumérios que habitavam no atual Iraque, e datam do final do terceiro milénio depois de Cristo, embora, anos antes, Cláudio Galeno (129-199) percebera os riscos do uso exagerado do ópio com um dos seus pacientes, o Imperador Antonino, que se tornou dependente deste composto, embora outras civilizações, como a grega, turca ou chinesa, já usassem o ópio há muitos anos[31][32][33][34][35] . São encontrados manuscritos na Turquia, Egito, Alemanha e Inglaterra com informações sobre o abuso e a tolerância a certas drogas que datam do século VI33 . ...
... Em 1806, o farmacêutico alemão Friedrich Sertürner (1783-1841) isolou a substância ativa do ópio a partir de Pa-paver somniferum, a morfina, em homenagem ao Deus grego do sono. Por sua vez, Robert Robinson (1886-1975) venceu o prémio Nobel da Química em 1947 pela descrição da fórmula química da morfina34 . Salienta-se que a morfina foi uma das descobertas mais importantes do século XIX, devido às suas propriedades analgésicas e sedativas31,34,35,37 . ...
... Por sua vez, Robert Robinson (1886-1975) venceu o prémio Nobel da Química em 1947 pela descrição da fórmula química da morfina34 . Salienta-se que a morfina foi uma das descobertas mais importantes do século XIX, devido às suas propriedades analgésicas e sedativas31,34,35,37 . Alexander Wood (1817-1884), em 1855, antes da guerra da Rebelião-Civil como ficou conhecida, afirmou ter administrado, com uma agulha oca, uma solução de morfina para o alívio de uma neuralgia. ...
Article
Full-text available
In one of the worst war times that humanity has ever experienced, such as the Second World War (1939-1945), there was a considerable development of the therapeutic arsenal and the Pharmaceutical Industry. It was during this period that penicillin, discovered by Alexander Fleming in 1928, was used; in which there was the creation of a rudimentary pharmacovigilance system and the need to assess the toxicity (safety) of the medicinal product before its commercialization. Additionally, it is noted that there were several personalities, from workers to distinguished politicians, who were dependent on substances such as morphine, heroin and methamphetamines that are still used today. This publication aims to analyse the main advances in pharmacological therapy and relate the topic, whenever possible, to important military and social events in the final outcome of the Second World War. The use of antibiotics (e.g., sulphonamides, penicillin, and streptomycin), opioids (e.g., morphine and heroin), and central nervous system stimulants (e.g., amphetamines and cocaine) will be discussed in greater detail. Regarding methodology, a literature review was carried out, giving priority to scientific articles. It was concluded that pharmacological advances and the discovery of new drugs during the Second World War were due to the enormous investment in research, on the part of governments and private investors, militarily favouring the bloc they supported, with the aim of increasing the state of alertness, energy, ability to concentrate and a sense of well-being, providing pain relief and treating soldiers' bacterial infections so that they could fight effectively until victory.
... The pharmacist Friedrich Sertürner isolated morphine from opium in the early 1800s, which represented the first time an alkaloid was isolated from a plant product (9), an event of noted significance in chemistry. He tested the new compound in rats, mice, cats, and dogs (10,11) and observed the effects to be similar to that of opium. It is said that when Serturner was suffering from a toothache that he took his purified product and noted the alleviation of his own pain (9). ...
... Of his own patients he noted that "they all find relief in the incessant use of the syringe and they all state that without the syringe life would be insupportable" (10). The dual advantage of morphine's increased potency relative to opium and the direct access to the systemic circulation to provide faster distribution to the active site (the opioid receptors as yet unidentified) further drove the increase in morphine use, particularly for use in the military during warfare (11). Appreciation of the risks of addiction and of infection were delayed for many years but were generally understood by 1885 (10). ...
... Appreciation of the risks of addiction and of infection were delayed for many years but were generally understood by 1885 (10). In the late 1800s and the early 1900s, the United States and other countries began the establishment of legislation and agreements to restrict the use, manufacture, imports, and sales of opium (11). ...
Article
Full-text available
Throughout history humanity has searched for an optimal approach to the use of opioids that maximizes analgesia while minimizing side effects. This review reflects upon the conceptualization of the opioid receptor and the critical role that the pharmaceutical sciences played in its revelation. Opium-containing formulations have been delivered by various routes of administration for analgesia and other therapeutic indications for millennia. The concept of a distinct site of opium action evolved as practitioners developed innovative delivery methods, such as intravenous administration, to improve therapeutic outcomes. The introduction of morphine and synthetic opioids engendered the prevalent assumption of a common opioid receptor. Through consideration of structure-activity relationships, spatial geometry, and pharmacological differences of known ligands, the idea of multiple opioid receptors emerged. By accessing the high-affinity property of naloxone, the opioid receptor was identified in central and peripheral nervous system tissue. The endogenous opioid neuropeptides were subsequently discovered. Application of mu-, delta-, and kappa- opioid receptor-selective ligands facilitated the pharmacological characterization and distinctions between the three receptors, which were later cloned and sequenced. Opioid receptor signal transduction pathways were described and attributed to specific physiological outcomes. The crystal structures of mu, delta, kappa, and nociceptin/orphanin FQ receptors bound to receptor-selective ligands have been elucidated. Comparison of these structures reveal locations of ligand binding and engagement of signal transduction pathways. Expanding knowledge regarding the structure and actions of the opioid receptor fuels contemporary strategies for driving the activity of opioid receptors toward maximizing therapeutic and minimizing adverse outcomes.
... It took several years until they realized that intravenous morphine injection led to addiction more rapidly than oral administration. In the 1860s, morphine addiction became a significant problem associated with the Civil War in the United States, to the point that it was known as "the soldier's disease" [15]. Some authors consider the Civil War-related opioid use the first opioid epidemic in the Americas. ...
... As a result, several countries signed the Hague International Opium Convention in 1912 to control opium production and commercialization. The signing of this treaty was propelled by problems associated with opium use in the Far East, specifically in China [15]. Two years later, with the support of the temperance movement, the United States enacted the Harrison Narcotics Tax Act, stating that this legislation was made: ...
... Another milestone in opioid history is the elucidation of morphine's chemical structure by Robert Robinson in 1925, an accomplishment that led to him being awarded the Nobel Prize in Chemistry in 1947 [15]. In the decades after Robinson's work, the search for "the holy grail," i.e., effective analgesics with fewer adverse side effects, led to the active synthesis and screening of hundreds of morphine's derivatives. ...
Chapter
This chapter provides an overview of the history of opioids and people’s different relationships with them across time and geography. It begins with the origins of the poppy flower, the recreational and medical use of opium in ancient cultures and Asia, and its pathway to European users. This chapter also reviews the different medicinal opium preparations (e.g., beverages, syrups, concoctions) used until the nineteenth century and the Opium Wars between England and China. Another section describes the discovery of morphine, the development of semisynthetic and synthetic opioids, the identification of endogenous opioid peptides, and the pharmacological characterization of opioid receptor subtypes. Finally, this chapter provides a brief description of the role of opioids in modern societies and reviews how basic concepts related to opioids and opioid use disorders (OUDs) have evolved through time.
... The development of opioids, a class of potent painkillers, has a rich and complex history spanning millennia. Originating from the opium poppy, opioids such as morphine were first identified and isolated for medical use in the 19th century [10]. These naturally occurring compounds, including morphine and codeine, were followed by a surge of synthetic opioids like heroin, hydrocodone, oxycodone, and fentanyl in the 20th century [10]. ...
... Originating from the opium poppy, opioids such as morphine were first identified and isolated for medical use in the 19th century [10]. These naturally occurring compounds, including morphine and codeine, were followed by a surge of synthetic opioids like heroin, hydrocodone, oxycodone, and fentanyl in the 20th century [10]. Opioid receptors are a large family of receptors including MORs, delta (δ)-opioid receptors (DORs), kappa (κ)-opioid receptors (KORs), and nociceptin receptors (NORs), also referred to as opioidreceptor-like receptor 1 (ORL1) [11]. ...
... Chemically, the basic backbone of morphine is a hydrogenated phenanthrene nucleus composed of the A, B, C, D rings, where the phenolic hydroxyl group at the 3-position carbon atom of the A ring, Frontiers in Molecular Biosciences frontiersin.org the alcohol hydroxyl group at the 6-position of the C ring and the tertiary amine nitrogen at the 17-position of the D ring are the substitutable groups of morphine (Christrup, 1997;Brook et al., 2017) ( Figure 1A). Compounds with phenolic hydroxyl group at position 3 and alcoholic hydroxyl group at position 6 substituted by other groups with similar or higher MOR affinity than morphine as well as better analgesic effect and higher addiction probability, such as oxymorphone with hydroxyl group at position 6 substituted by carbonyl group (Weiss, 1955;Kirby, 1967). ...
... Morphine, naloxone, and EM-1 are the three classes of MOR ligands, representing semi-synthetic agonists, antagonists, and endogenous peptide agonists, respectively, all three of which bind to the orthosteric pocket of MOR (Vizi et al., 1976;Brook et al., 2017;Toubia and Khalife, 2019). The design and synthesis of preferred ligands such as TRV130, PZM21, and SR-17018 also illustrate that subtle changes in the conformation of the MOR ...
Article
Full-text available
Morphine, the most widely used analgesic, relieves severe pain by activating the μ-opioid receptor (MOR), whereas naloxone, with only slight structural changes compared to morphine, exhibits inhibitory effect, and is used to treat opioid abuse. The mechanism by which the MOR distinguishes between the two is unclear. Molecular dynamics (MD) simulations on a 1-μs time scale and metadynamics-enhanced conformational sampling are used here to determine the different interactions of these two ligands with MOR: morphine adjusted its pose by continuously flipping deeper into the pocket, whereas naloxone failed to penetrate deeper because its allyl group conflicts with several residues of MOR. The endogenous peptide ligand endomorphin-1 (EM-1) underwent almost no significant conformational changes during the MD simulations. To validate these processes, we employed GIRK4 S143T , a MOR-activated G βγ -protein effector, in combination with mutagenesis and electrophysiological recordings. We verified the role of some key residues in the dynamic recognition of naloxone and morphine and identified the key residue I322, which leads to differential recognition of morphine and naloxone while assisting EM-1 in activating MOR. Reducing the side chain size of I322 (MOR I322A ) transformed naloxone from an inhibitor directly into an agonist of MOR, and I322A also significantly attenuated the potency of MOR on EM-1, confirming that binding deep in the pocket is critical for the agonistic effect of MOR. This finding reveals a dynamic mechanism for the response of MOR to different ligands and provides a basis for the discovery of new ligands for MOR at the atomic level.
... 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. ...
Thesis
Full-text available
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
Full-text available
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.
... In 1914, the United States government recognized the potential for opioid abuse and misuse and approved the Harrison Narcotics Act, which prohibited the use of prescription opioids for nonmedical use [78]. A century later, the so-called "opioid epidemic" was declared in the United States and has spread among high-income countries. ...
Article
Full-text available
Pain is one of the most common symptoms in patients with cancer. Pain not only negatively affects the quality of life of patients with cancer, but it has also been associated with reduced survival. Pain management is therefore a critical component of cancer care. Prescription opioids remain the first-line approach for the management of moderate-to-severe pain associated with cancer. However, there has been increasing interest in understanding whether these analgesics could impact cancer progression. Furthermore, epidemiological data link a possible association between prescription opioid usage and cancer development. Until more robust evidence is available, patients with cancer with moderate-to-severe pain may receive opioids to decrease suffering. However, future studies should be conducted to evaluate the role of opioids and opioid receptors in specific cancers.
... This effort has led to the discovery of new and promising therapeutic agents isolated from plants, which were later approved for use (Li and Weng, 2017). Some of these include morphine from Papaver somniferum (Brook et al., 2017) for pain relief, paclitaxel from Taxus brevifolia (Wani et al., 1971), vinblastine and vincristine from Catharanthus roseus (Neuss et al., 1959) as cancer therapeutic agents, and artemisinin from Artemisia annua for malaria treatment (Tu, 2011). However, only three (Vitex negundo, Momordica charantia, and Blumea balsamifera) of the ten medicinal plants endorsed by the Department of Health of the Philippines in 1997 through R.A. 8423, otherwise known as the Traditional and Alternative Medicine Act, became popular. ...
Preprint
Full-text available
Traditional medicinal plants are integral to the diverse ethnolinguistic cultures and biodiversity in the Philippines. In this synthesis, we performed a Philippine-wide analysis of the knowledge, extent, and interactions of traditional plant use among various ethnolinguistic groups. Our synthesis identified 796 plant species from 160 families and 65 orders utilised by 35 ethnolinguistic groups to treat 25 disease types. We found strong connections between linguistically similar groups, indicating that geographical proximity, linguistic background, shared cultural practices, and environmental factors collectively influence the patterns of medicinal plant usage among the different groups. We developed the Species Use Priority Importance ( SUPRIM ) indicator to assess the priority level of plant species based on their use among ethnolinguistic groups and disease types. Factors such as availability of healthcare facilities, proximity to roads, educational facilities, and tree density were significantly correlated with higher SUPRIM indicator values. We posit that environmental status shaped the values of medicinal plant species within ethnolinguistic communities. Understanding these dynamics is essential to effectively conserve ecosystems and indigenous peoples that rely on them. Continued research efforts and conservation initiatives dedicated to the integration of traditional knowledge into healthcare systems are essential for preserving this invaluable heritage and promoting sustainable healthcare practices in the Philippines.
... L a evolución en el conocimiento se sustenta en el descubrimiento de nuevas sustancias, moléculas, técnicas, maniobras y acciones que logran demostrar su utilidad o validez a través de la práctica, el sentido común y la experiencia. Los opioides son un ejemplo de este proceso, su uso puede remontarse a los inicios de la civilización, en lugares tan remotos como Sumeria y Egipto (1) , inicialmente como alucinógenos o euforizantes en rituales religiosos y posteriormente como uso medicinal para aliviar el dolor en enfermedades y procedimientos quirúrgicos. Sin embargo, fue hasta el inicio del siglo XIX cuando Sertürner logra aislar el ingrediente activo del opio, nombrándolo «morfina», en honor al dios griego del sueño. ...
Article
Full-text available
Introducción: los opioides forman parte del manejo anestésico desde tiempos remotos. El desarrollo de nuevos fármacos a partir del fentanilo dio como resultado opioides más potentes y específicos. El sufentanyl se presenta como una opción más para el manejo anestésico perioperatorio, en diferentes escenarios clínicos, como anestesia general, sedación o adyuvante; el margen terapéutico amplio, la potencia analgésica y los efectos adversos predecibles lo presentan como una opción equiparable y en algunos casos superior a otros opioides como el fentanilo. Las dosis referidas por la Food and Drug Administration (FDA) y algunos artículos son amplias, en una gran variedad de situaciones la orientación a la dosificación mínima efectiva es la más recomendada. Objetivo: presentar una revisión de los aspectos farmacocinéticos y farmacodinámicos del sufentanyl, sus propiedades farmacológicas, aplicaciones y recomendaciones basadas en la literatura y la práctica clínica. Aportar difusión del conocimiento y uso del sufentanyl para fomentar un cambio en el paradigma clásico del uso de opioides en anestesia. Conclusiones: El sufentanil es una de las mejores opciones para el manejo del dolor en distintos escenarios clínicos, desde procedimientos de corta duración como las sedaciones hasta cirugías de gran complejidad, su perfil farmacocinético muy similar al fentanilo, con un amplio margen terapéutico y mayor potencia analgésica, lo convierten en una opción más que adecuada para la práctica anestésica contemporánea.
... New technological developments enable plants to be transformed into "factories" that create natural medical compounds for use in the production of biotech pharmaceuticals, medications, and treatments [10]. The application of plants as drugs has recently required the separation of active ingredients, starting with the early-19th-century isolation of morphine from Papaver somniferum [11,12]. The identification of early pharmaceuticals, such as digitoxin, cocaine, pilocarpine, codeine, and quinine, that are derived from medicinal plants marked a remarkable achievement in the field of medicine [13]. ...
Article
Full-text available
For thousands of years, nature has been a source of medical substances, and an astounding numeral of contemporary remedies have been identified from natural origins. Plants have long been used as folk herbal medicines to treat various disorders, and their different natural products have inspired the design, discovery, and development of new drugs. With the invention of recent molecular targets based on proteins, there is a growing need for fresh chemical diversification in screening. Natural products will play a vital part in supplying this need via the continuous exploration of global biodiversity, the majority of which remains unexplored. Even though drug discovery from medicinal plants remains an important source of novel therapeutic leads, various hurdles exist, including identifying and executing suitable high-throughput screening bioassays, scaling up the supply of bioactive molecules, and acquiring plant materials. Investigating these natural resources takes multidisciplinary , nationwide, and global partnerships in design, synthesis, discovery, and drug development techniques. This review article discusses current advancements and future approaches for discovering natural items such as health-and wellness-promoting remedies. It also summarizes strategies to unify the therapeutic use of plant-derived natural products worldwide to support future drug discoveries derived from plant sources.
... (Brookmeyer et al. 2007;Brook et al. 2017). The air pollutants may negatively affect some biochemical factors, which would therefore slow down the development and growth of plants as a whole (Farooqui et al. 1995). ...
Chapter
In the current Anthropocene era of rapid urbanization and industrialization, air pollution is one of the major issues the world is currently facing. Particulate matter pollution, in particular, poses a risk both to the environment and public health. The biochemical, morphological, and biological status of green plants, as well as their responses, have been significantly influenced by the altered ambient environment caused by the particulate matter pollutant in urban areas. It turns out to be a useful indicator of the overall impact of particulate matter pollution as well as the detrimental effects of this pollution on vegetation when considering the context of the plants (wide distribution, increases the contact area, etc.). The chapter discusses how particulate matter pollution affects morphological characteristics like stomata structure, leaf area, flowering, growth, leaf number, as well as reproduction, along with biochemical parameters like pigment content, protein, enzymes, and sugar as physiological aspects like pH as well as relative water content. A brief overview of the effects of this matter on species diversity as well as climate change is also provided in the chapter. Additionally, the review highlights the genotoxic effects of particulate matter on plants.
... Medicinal plants have remained an important resource for discovery of lead compounds and novel drugs with potent anti-inflammatory, analgesic, and antioxidant activities. These include salicylic acid from the Willows plant, morphine from the poppy opium and resveratrol from several plants [8][9][10] . Ethnobotanical studies indicate that plant parts of the genus Fagaropsis are widely used to treat various illnesses by various communities in the East African region [11] . ...
Article
Full-text available
Background: Fagaropsis hildebrandtii has been widely used in African traditional medicine to treat various illnesses, particularly those associated with inflammation, pain and oxidative stress. However, experimental data on the anti-inflammatory, anti-nociceptive and antioxidant of the different parts of F. hildebrandtii is still limited. Objectives: The objectives of this study were to determine the phytochemical composition, anti-inflammatory, antinociceptive and antioxidant activities of stem bark extract of F. hildebrandtii from Makueni County, Kenya. Materials and Methods: The stem bark of F. hildebrandtii was extracted by maceration using water and methanol. Standard qualitative methods were then used to determine the presence or absence of various phytochemicals in the extracts. Total phenolic and flavonoid contents were determined by Folin-Ciocalteu and aluminium chloride calorimetric methods, respectively. Anti-inflammatory and anti-nociceptive activities of increasing water and methanol extracts doses (2-250mg/Kg) were tested using carrageenan-induced paw edema and acetic acid-induced writhing animal models, respectively in comparison with dexamethasone and aspirin as standard. Antioxidant activities of plant extracts were assayed by 2,2-Diphenyl-1-picrylhydrazyl (DPPH) method, with ascorbic acid as the standard. Data analysis was conducted by two-way ANOVA with appropriate post hoc tests. Statistical significance level was set at p ≤ 0.05. Results: Phenols, flavonoids, alkaloids, saponins, tannins, terpenoids and coumarin were detected in the extracts. However, anthocyanins and anthraquinones were absent in both water and methanolic extracts. Notably, methanol extract had a high total phenolic level compared to water extract (34.590 ± 2.490 mgGAE/g vs. 7.893 ± 1.619 mgGAE/g; p<0.05). Total flavonoid content of F. hildebrandtii methanol extract was also higher in comparison to water extract (132.18 ± 0.26 mgCE/g vs. 42.68 ± 0.93mgCE/g; p<0.05). F. hildebrandtii water and methanol extracts had a radical scavenging activity IC50 of 0.98 µg/ml and 0.987 µg/ml respectively, which was significantly lower than 5.674 µg/ml for ascorbic acid, indicating a higher antioxidant potency. The percentage inhibition of carrageenan-induced hind paw edema by F. hildebrandtii extracts was not significantly different in comparison with 10 mg/Kg of dexamethsone standard over a 5-hour test period (p>0.05). F. hildebrandtii water and methanol extracts exhibited a dose-dependent inhibition of acetic acid-induced writhing in mice, reaching a maximum of 53.1 ± 6.1% and 80.24 ± 12.59%, respectively, at 250 mg/Kg. Notably, the percentage inhibition of acetic acid-induced writhing by 50 mg/kg and 250 mg/kg of F. hildebrandtii methanolic extract was similar to that of aspirin standard at 150 mg/kg (77.75 ± 19.64% vs. 80.24 ± 12.59% vs. 84.99 ± 3.26%, p>0.05, two-way ANOVA). Conclusion: F. hildebrandtii has anti-inflammatory, antinociceptive and antioxidant activities. These findings validate the use of F. hildebrandtii crude extracts among Kenyan ethnic groups in management of diseases associated with inflammation, pain, and oxidative stress.
... Taking higher doses of morphine than prescribed or combining it with other central nervous system depressants (such as alcohol) can lead to respiratory depression, coma, or even death. Overdose requires immediate medical (Benyhe, 1994;Brook et al., 2017). ...
... Morphine is one of the oldest known drugs [116]. It shows a strong binding to the µ receptor, while its binding to the δ and κ receptors is weaker [117]. ...
Article
Full-text available
Pain is an unpleasant sensory and emotional experience that affects every aspect of a patient's life and which may be treated through different pharmacological and non-pharmacological approaches. Analgesics are the drugs most commonly used to treat pain, and in specific situations, the use of opioids may be considered with caution. These drugs, in fact, do not always induce optimal analgesia in patients, and several problems are associated with their use. The purpose of this narrative review is to describe the pharmacological approaches currently used for the management of chronic pain. We review several aspects, from the pain-scale-based methods currently available to assess the type and intensity of pain, to the most frequently administered drugs (non-narcotic analgesics and narcotic analgesics), whose pharmacological characteristics are briefly reported. Overall, we attempt to provide an overview of different pharmacological treatments while also illustrating the relevant guidelines and indications. We then report the strategies that may be used to reduce problems related to opioid use. Specifically, we focus our attention on therapeutic drug monitoring (TDM), a tool that could help clinicians select the most suitable drug and dose to be used for each patient. The actual potential of using TDM to optimize and personalize opioid-based pain treatments is finally discussed based on recent scientific reports.
... Entre los efectos que sintió fue la somnolencia, por lo que decidió bautizar a esta sustancia como morfium, recordando que en la mitología griega existía el dios de las ensoñaciones llamado Morfeo. Más tarde, el nombre fue cambiado a morfina, por Joseph Louis Gay-Lussac (1778-1850), mejor conocido por sus trabajos sobre la física de los gases 22 . A partir de 1853, el uso de la morfina se popularizó, en gran medida a consecuencia de la invención de la aguja hipodérmica. ...
Article
Full-text available
Opium and its derivatives, and recently the opioids have ac companied the humankind since the ancient civilizations to the present day. Its analgesic, hypnotic and pleasant effects did not go unnoticed by ancient people, which considered most of these effects of medical utility and noticed that they had remarkable mood benefits. Currently, there are no other kind of drugs that can palliate intense pain as efficiently as these powerful analgesics. However, the medical and rec reational use of opiates and opioids may carry health risks such as tolerance, hyperalgesia, and addiction. Nowadays, in addition to being indisputably the most powerful medical treatment to alleviate the suffering caused by pain, it has also become a public health problem due to the high number of people with opioid use disorder that have facilitated deaths caused by opioids overdose. In this review we will discuss the medical benefits of opiates and opioids, as much as the unwanted effects they produce. Keywords: Opioids; opiates; medical utility; health risks; addiction; abuse.
... Menthol ( Fig. 2.5j) is an ancient natural drug that belongs to the alkaloid group isolated from Papaver somniferum (Brook et al. 2017). Morphine is a powerful opiate analgesic psychoactive pain-relieving drug that operates directly on the central nervous system (CNS). ...
Chapter
The diversity of bioactive phytochemicals in plants of medicinal importance is the most precious gift of nature. The floral and phytochemical diversity of earth has been exploited as a primary source of life-supporting plant-derived bioactive phytochemicals to fight against common ailments and disorders in traditional-, herbal-, and ethnomedicine since the beginning of human civilization. Despite certain challenges associated with plant-derived drugs, modern medicine also is keenly interested in exploring this phytochemical diversity for the discovery of new bioactive molecules or unique templates or scaffolds for the development of novel synthetic or semi-synthetic drugs due to the inability of alternative drug discovery strategies, the huge structural diversity of plant-based therapeutic phytochemicals, their superior quality, higher curative properties with fewer adverse side effects, safety, affordability and acceptance across multiple cultures, and ethnicities in contrast to synthetic chemical drugs. Nations with a wealth of biodiversity have been an eagle’s eye for the global pharmaceutical sector to identify new therapeutic agents or develop new drugs to manage specific chronic diseases throughout the last two centuries. The discovery of new phytochemicals from medicinal plants is a complicated, challenging, and/or time-consuming scientific task, usually involving the selection and collection of biota, extraction of phytochemicals, isolation, and purification of each or targeted compound, structure elucidation and identification of innovative phytochemicals, bioactivity tests (biochemical and pharmacological tests) using various techniques according to the structural variety, and stability. A comprehensive and in-depth systematic phytoanalysis and phytopharmacological investigation of the full spectrum of phytochemical diversity of medicinal plants should be performed to achieve the dreams of plant-derived drug discovery via exploration of recent advances in technologies, instruments, and integration of different disciplines, such as ethnobotany, phytochemistry, analytical chemistry, biotechnology, genomics, transcriptomics, proteomics, metabolomics, and pharmacology. These will help to overcome challenges associated with phytochemical discovery, screening, isolation, separation, purification, detection, identification, and structural characterization in the realm of phytochemicals. Simplification in comprehensive and effective regulatory governing systems of biodiversity-rich countries for the accessibility of plant resources and techniques and conservation of threatened, endangered plants may motivate phytochemical-based drug research programs and many pharmaceutical and biotechnology companies.KeywordsMedicinal plantPhytochemical diversityAlkaloidTerpeneModern medicineEthnomedicine
... In addition to its potent antimalarial properties, chloroquine has also been shown to regulate inflammatory autoimmune responses (Park et al., 2019) and is effective as an antitumour agent (Goel and Gerriets, 2019). Another alkaloid (morphine) that is isolated from Papaver somniferum L. is widely used as a potent analgesic agent (Brook et al., 2017). More commonly it is converted to the less addictive codeine and is widely used to treat pain (Van Wyk and Wink, 2017). ...
Article
Full-text available
The harmful side effects associated with conventional anti-inflammatory pharmaceuticals has focussed attention on medicinal plants as alternative therapeutics. However, the use of medicinal plants is predominantly based on ethnobotanical knowledge and often lacks toxicity data and safety validation. A comprehensive review of the toxicity and phytochemical properties of southern African medicinal plants used for inflammation and pain-related ailments was undertaken. Various ethnobotanical books and search engines including Science direct, Sci-Finder, Google Scholar and Scopus were used to determine which medicinal plants have been screened for toxicity. A total of 117 medicinal plants have previously been evaluated by toxicity screening. The predominant toxicity test used was the MTT reduction assay (109 species), followed by the brine shrimp lethality assay (57 species), and the XTT assay (24 species). The Ames test, which was used to screen 20 species, was the most frequently used assay to determine mutagenic properties of the plant extracts. The top five most commonly screened cell lines were Vero monkey kidney cells (46 plant extracts), RAW 264.7 macrophages (23 extracts), human breast cancer cells (MCF-7, 12) (21 extracts), mouse fibroblast (3T3) (18 extracts) and Graham cells (HEK-293) (17 extracts). Over 80% of the tested medicinal plant extracts were found to be non-toxic. Although many species have been evaluated for their toxicity properties, plant extracts are often tested using one or two assays and also lack diversity in terms of choice of cell lines used for screening. Phytochemical studies remain scarce and substantial further work is required.
... Morphine remains a first line treatment for severe acute pain 200 years after its first commercial production (Brook et al., 2017). However, its long-term use is compromised by tolerance and morphine-induced hypersensitivity (MIH) (Colvin et al., 2019). ...
Article
Full-text available
Morphine diminishes pain, but its long‐term use is compromised by tolerance and hyperalgesia. Studies implicate δ receptors, β‐arrestin2 and Src kinase in tolerance. We examined whether these proteins are also involved in morphine‐induced hypersensitivity (MIH). A common pathway for tolerance and hypersensitivity may provide a single target to guide improved analgesic approaches. We examined mechanical sensitivity using automated von Frey in wild‐type (WT) and transgenic male and female C57Bl/6 mice before and after hind paw inflammation by complete Freund's adjuvant (CFA). CFA‐evoked hypersensitivity ceased on day 7 in WT but persisted for the 15‐day testing period in μ−/−. Recovery was delayed until day 13 in δ−/−. We explored the expression of opioid genes in the spinal cord using quantitative RT‐PCR. Restoration to basal sensitivity in WT occurred with increased δ expression. By contrast, κ expression was reduced, while μ remained unchanged. Daily morphine reduced hypersensitivity in WT on day 3 compared to controls; however, hypersensitivity recurred on day 9 and beyond. By contrast, WT had no recurrence of hypersensitivity in the absence of daily morphine. We used β‐arrestin2−/−, δ−/− and Src inhibition by dasatinib in WT to establish whether these approaches, which diminish tolerance, also attenuate MIH. While none of these approaches affected CFA‐evoked inflammation or acute hypersensitivity, all caused sustained morphine anti‐hypersensitivity, abolishing MIH. Like morphine tolerance, MIH in this model requires δ receptors, β‐arrestin2 and Src activity. Our findings suggest that MIH is caused by a tolerance‐induced reduction in endogenous opioid signalling. image Key points Morphine is effective for treating severe acute pain, but tolerance and hypersensitivity often develop during its use in treating chronic pain. It is unclear whether these detrimental effects share similar mechanisms; if so, it might be possible to develop a single approach to minimise both phenomena. Mice deficient in μ receptors, δ receptors or β‐arrestin2 and wild type mice treated with the Src inhibitor dasatinib exhibit negligible morphine tolerance. We show that these same approaches also prevent the development of morphine‐induced hypersensitivity during persistent inflammation. This knowledge identifies strategies, such as the use of Src inhibitors, which may mitigate tolerance and morphine induced hyperalgesia.
... [2][3][4] However, it was not until the nineteenth century that the plant's natural alkaloids and active ingredients started to be systematically isolated and analysed, leading to the discovery of morphine (1805), codeine (1832) and thebaine (1835). [5][6][7] This was followed by the development of more potent and efficacious semi-synthetic opioid medications (synthesised in the laboratory from naturally occurring opium compounds), which included diamorphine (heroin) (1874), oxymorphone (1914), oxycodone (1916) and hydrocodone (1920). [8][9][10][11][12][13] Although first developed as an antitussive, the euphoric and well-being effects associated with heroin soon became sought after for non-medical purposes, leading to concerns from the early 20th century about dependence. ...
Article
Full-text available
The term ‘opioids’ refers to both the natural compounds (‘opiates’) which are extracted from the opium poppy plant ( Papaver somniferum) and their semi-synthetic and synthetic derivatives. They all possess relatively similar biochemical profiles and interact with the opioid receptors within the human body to produce a wide range of physiological effects. They have historically been used for medicinal purposes, their analgesic and sedative effects, and in the management of chronic and severe pain. They have also been used for non-medicinal and recreational purposes to produce feelings of relaxation, euphoria and well-being. Over the last decade, the emergence of an illegal market in new synthetic opioids has become a major global public health issue, associated with a substantial increase in unintentional overdoses and drug-related deaths. Synthetic opioids include fentanyl, its analogues and emerging non-fentanyl opioids. Their popularity relates to changes in criminal markets, pricing, potency, availability compared to classic opioids, ease of transport and use, rapid effect and lack of detection by conventional testing technologies. This article expands on our previous review on new psychoactive substances. We now provide a more in-depth review on synthetic opioids and explore the current challenges faced by people who use drugs, healthcare professionals, and global public health systems.
... Historically, solvent extract procedures have been described since the 17th century. Scientists used solvent extraction techniques to isolated morphine from the milk of poppies (Brook et al., 2017), quinine from the bark of the Cinchona tree, and cocaine from coca leaves (Goldstein et al., 2009;Achan et al., 2011). In addition to extraction methods, further complexity arises when the compound of interest requires separation from other constituents present in the tissues of the natural source. ...
Article
Full-text available
Natural products, those molecules derived from nature, have been used by humans for thousands of years to treat ailments and diseases. More recently, these compounds have inspired chemists to use natural products as structural templates in the development of new drug molecules. One such compound is leonurine, a molecule isolated and characterized in the tissues of Herb leonuri. This molecule has received attention from scientists in recent years due to its potent anti-oxidant, anti-apoptotic, and anti-inflammatory properties. More recently researchers have shown leonurine to be useful in the treatment of cardiovascular and nervous system diseases. Like other natural products such as paclitaxel and artemisinin, the historical development of leonurine as a therapeutic is very interesting. Therefore, this review provided an overview of natural product discovery, through to the development of a potential new drug. Content will summarize known plant sources, the pathway used in the synthesis of leonurine, and descriptions of leonurine’s pharmacological properties in mammalian systems.
... Morphine is believed to be one of the most common alkaloids with multiple functions. Morphine was first isolated from opium poppy by Germen chemist Serturner in 1805 though the history of using opium poppy can date back to 600 BCE (Brook et al., 2017). For the opium plant, morphine defends the plant host against predators. ...
Chapter
Full-text available
Plant secondary metabolites (PSMs) play key roles in plant survival by regulating plant physiological processes, helping plants adapt to their habitats, and protecting plants against pathogenic attacks and environmental stress. In addition, these valuable natural compounds have potential pharmacological and toxicological effects on humans. Understanding the complex biosynthetic processes of PSMs is crucial for sustainable bioeconomy and accomplishing sustainable development goals (SDGs). However, because of the complexity of plant secondary metabolic systems, identifying the function of related enzyme-encoding genes is not sufficient for this purpose. To study these sophisticated processes holistically, it is imperative to implement an integrative approach combining multiomics data to highlight the relationships between the underlying biological activities and their functions. In this chapter, we provide an overview of PSMs, including their classification, biosynthetic pathways, and functions, as well as relevant omics-based approaches, multiomics data integration tools and methods, and applications. Conversely, with advancements in multiomics technologies and research, selecting appropriate multiomics research methods and storage, management, and comparison of different types of datasets obtained from different platforms will be the major challenge in the future.
... Although the vasodepressive impacts during hemorrhagic shock and respiratory effects of morphine have been long known, morphine has been a mainstay of military analgesia since the Crimean War (in the United States since the Civil War) and remained so through much of the most recent conflicts in Iraq and Afghanistan. [1][2][3] As a result of emerging research, the Tactical Combat Casualty Care guidelines (TCCC) were modified in 2014 to formalize what had been ad hoc use of oral transmucosal fentanyl lozenges as well as intravenous ketamine (for those in shock or at risk for shock), in addition to morphine (IV and intraosseous routes only); these guidelines cover analgesia administered near the point of injury as well as during en-route care. 4 Previous work has been done to explore trends in the use of these medications in combat, and concern has been raised that the TCCC guidelines have not been consistently followed. ...
Article
Introduction Battlefield pain management changed markedly during the first 20 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. Materials and Methods Using Department of Defense Trauma Registry data for the Afghanistan conflict from 2005 to 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 an indication with minimal contraindication for analgesia. We further employed frequency matching to explore the presence of disparities in analgesia by casualty affiliation. Results 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 U.S. military (31.9%), civilian/other (23.3%), and non-U.S. military (19.3%). Fentanyl surpassed morphine in the frequency of administration in 2012. The median age of those receiving ketamine was higher (30 years) than those receiving fentanyl (26 years) or nonsteroidal anti-inflammatory drugs (23 years). Among the frequency-matched subanalysis, the odds ratio for ketamine administration with Afghan casualties was 1.84 (95% CI, 1.30-2.61). Conclusions 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.
... Ancient examples include herbal remedies, alcohol, and opium poppies. The earliest written evidence of opium and alcohol being used for their sedative properties comes from Mesopotamia (Al Ansari et al., 2019;Brook et al., 2017). Ancient Egyptian doctors used surgical equipment and are thought to have used the mandrake fruit to produce a tonic to cause a state of anesthesia (Pahor, 1992;Sullivan, 1996). ...
Article
General anesthetics are a class of drugs with diverse molecular mechanisms that cause a state of unconsciousness. Generally, anesthetics are thought to exert this effect by co- opting endogenous sleep pathways within the brain, and activity patterns recorded during anesthesia resemble those recorded during natural sleep. Monitors of anesthetic depth take advantage of the relationship between brain activity patterns and anesthetic concentration to define a depth of exposure. Recovery from anesthetic-induced unconsciousness is typically assumed to be a passive, linear process that relies upon elimination of drug from the body. However, it has been shown that activity patterns undergo discrete transitions between several distinct brain states under anesthesia. Furthermore, the brain exhibits a resistance to recovery of consciousness during emergence from anesthesia. Together, these results show that emergence cannot be explained by drug elimination alone. In this dissertation, we present evidence to suggest that stochastic fluctuations between distinct brain states account for this resistance to emergence. Furthermore, we show evidence to suggest that local cortical interactions are the principal organizing mechanism that gives rise to the brain states and state transitions recorded under general anesthesia. This mechanism is distinct from those known to drive state transitions during natural sleep. During sleep, broadly projecting modulatory pathways engage neurons throughout the thalamocortical network in coherent activity patterns and state transitions. Here, we demonstrate local heterogeneity in activity patterns and transition times within the cortex. Furthermore, our results indicate that, despite there being only weak coupling between activity patterns and transition times between different cortical regions, this coupling is sufficient to give rise to global brain states. Altogether, the work presented in this dissertation indicates that the nature of oscillations within the cortex is strongly influenced by local interactions. This finding suggests that the mechanisms thought to give rise to state transitions during sleep are not the same as those that give rise to transitions under anesthesia. This finding that local interactions are potentially a stronger organizing mechanism for cortical activity than previously appreciated has important implications for anesthetic monitoring, clinical sleep disorders, and our basic understanding of thalamocortical activity patterns.
... The majority of evidence suggests that Daniel Ludwig (1625-1680), Robert Boyle (1627-1691), Jean-François Derosne (1774-1855), and Armand Séquin (1767-1835) were the first to extract morphine, but no one was able to identify or publish the results. [30,31]. In 1806 Fredrich Sertürner reported separating the active narcotic ingredient from opium, indicating that this active compound's molecular structure contains nitrogen, carbon, hydrogen, and oxygen. ...
Article
Poppy (Papaver somniferous L.) is a member of the Papaveraceous family. It is indigenous ofsouth east of Europe and Asia. It is cultivated all over the world and there is not any wild type of this species. It is widely grown as an ornamental flower throughout Europe, North America, South America, and Asia. Until now more than 40 different alkaloids have been known in thisspecies which the most important ones are morphine, codeine, thebaine, papaverine and noscapine. Alkaloids are affected with genetical characteristics and environmental conditions. Poppy seeds are an important food item and the source of poppy seed oil, healthy edible oilthat has many uses. The most important application of papaver alkaloids is due to their analgesic properties. Use of opium poppy (Papaver somniferum L.) as a medicinal plant hasbeen described in the ancient literature of Indian system of medicine (Ayurveda). Keyword: - Opium, Alkaloids, Morphine, Codeine, Medicinal plants
... 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). ...
Article
Full-text available
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.
Chapter
According to tradition, natural materials have been utilized to treat various diseases and illnesses since ancient times. For millennia, humans have used natural materials obtained from plants as medicine. These natural goods have yet to reach their full potential. Natural goods have a wide structural variety and specific pharmacological or biological activities resulting from thousands of years of natural selection and evolution. Under lab conditions, the capabilities of the synthetic organic chemist are subdued by the structural variety of natural products, which result in the use of natural products in both modern and traditional medicine for the treatment of various ailments.
Article
Full-text available
الطب العربي و الأمراض المستحدثة: ترجمة و قراءة تحليلية لرسالة في «مرض الانفلونزا (الگريپ)» الطب العربي بجانب الطبّيّن الصيني و الهندي «الآيورڤدا» Ayurveda من ابرز المناهج الطبية عالمياً، و يعود عمر الجذور المكتوبة للطب العربي مثل البرديات المصرية او الألواح البابلية ما يزيد على العشرة آلاف سنة؛ و مع انه يمتاز بأكبر قدرٍ من التراث المدون بالحرف العربي دائماً و اللغة العربية غالباً، إلا أن الإهتمام به من مختلف الجوانب التاريخية والأجتماعية والإقتصادية والتطبيقية لا يزال متواضعاً على الرغم من جداوه وأهميته. مع بروز جائحة كرونا «كوڤيد 19» اضطر المجتمع العلمي مجدداً للإهتمام بمناهج الطب المختلفة عن الطب الرائج لأسباب عدة أهمها:1) تجربة الصين في علاج جائحة كورونا «كوڤيد 19» بالطب الصيني؛ 2) الإذعان العلمي بن مناهج الطب الشعبي كانت و لا تزال مصدر لإكتشاف الإدوية. تتناول هذه الدراسة رؤية ومنهجية الطب العربي في التعامل مع الإمراض المستحدثة عبر ترجمة وقراءة تحليلية لرسالة وثقت أول بروز لمرض الانفلونزا في الشرق الأوسط قبل حوالي قرن. Arabic Medicine and Emerging Diseases: Translation and Analytical Reading of a Treatise on “Influenza Disease (Grip)” Arabic medicine, along with Indian medicine (Ayurveda) and Chinese medicine, is one of the most prominent medical school worldwide. The written roots of Arabic medicine, such as Egyptian papyri or Babylonian tablets, are more than ten thousand years old; Although it is characterized by the greatest amount of heritage recorded in the Arabic letter and often the Arabic language, the interest in it from the various historical, social, economic and applied aspects is still inadequate despite its seriousness and importance. With the emergence of the “Covid 19” pandemic, the scientific community was again forced to pay attention to different medical approaches from convention medicine for several reasons, the most important are: 1) China’s experience in treating the Corona pandemic “Covid 19” with Chinese medicine; 2) Scientific compliance among the methods of traditional medicine was and still is a source for the drug discovery. This study shows the approach and methodology of Arabic medicine in dealing with emerging diseases through translation and analytical reading of a letter documenting the first emergence of influenza in the Middle East about a century ago.
Chapter
Opioids are the prototypical analgesics, antitussives, and antidiarrheal drug class and are used extensively in veterinary medicine. This chapter provides an overview of the history of opioid use in veterinary practice and the current impact of the opioid crisis. Basic and clinical opioid pharmacology is presented including receptor classification, location, and regulation, pharmacokinetics, and pharmacodynamic effects. Considerations regarding route of administration as well as descriptions of selected full opioid agonists, partial opioid agonists, mixed opioid agonist–antagonists, and antagonists relevant to veterinary anesthesia and pain management are provided.
Article
The rates of opioid use and opioid related deaths are escalating in the United States. Despite this, evidence-based treatments for Opioid Use Disorder are underutilized. There are three medications FDA approved for treatment of Opioid Use Disorder: Methadone, Buprenorphine, and Naltrexone. This article reviews the history, criteria, and mechanisms associated with Opioid Use Disorder. Pertinent pharmacology considerations, treatment strategies, efficacy, safety, and challenges of Methadone, Buprenorphine, and Naltrexone are outlined. Lastly, a practical decision making algorithm is discussed to address pertinent psychiatric and medical comorbidities when prescribing pharmacology for Opioid Use Disorder.
Chapter
The incidence and prevalence of various viral infections have risen tremendously and remain a life-threatening risk to people over the past century. Viral outbreaks and reemerging of viral infection are constantly challenging the global healthcare system. To combat crises, vaccines, antibiotics, and broad-spectrum antiviral agents are used and have often shown limited efficacy with unsatisfactory clinical outcomes. The world is looking for a promising alternative medicine that will be more effective with high safety profile. Traditional medicine gained much interest recently with the increase in people’s usage after the recent outbreak of COVID-19. In the current chapter, we have tried to cover the role of herbal drugs and their respective formulations in treating various viral diseases. A brief introduction to viral classification, epidemiology, and types of viral infections was provided to understand the topic and its relevance better. Various plant-based materials, including extracts and pure active constituents that are studied by multiple researchers in treating different viral infections, were reported. A discussion on the antiviral formulations currently under various phases of clinical trials, e.g., Kovir, Xagrotin, COVIDEX™, Septilin®, and Sho-Saiko-to (SST) and patents related to herbal antiviral molecules were also discussed with their merits. A comprehensive list of antiviral medications was given for the readers’ reference. Finally, the regulatory guidelines related to herbal products and regulatory bodies of India and other countries were enlisted for the complete understanding of the research stage to the marketing of herbal systems with particular emphasis on viral therapy.
Chapter
The overview is done to determine whether the era of natural products for drug discovery is over or not over. Though the drug discovery process is considered scientific, the study reveals that it may be considered highly inefficient in the infant stage, and it is hard to distinguish between natural products and systematically prepared synthetic compounds. The inference is that the era of natural products is not over. A few decades ago, it was speculated that the number of new natural product-derived drugs could go to zero. However, this analysis has proved a fact contrary to the speculation. It shows that the era of natural product drug discovery is not over, but it is with an endless frontier.
Article
Full-text available
Morroniside (MOR) is an iridoid glycoside and the main active principle of the medicinal plant, Cornus officinalis Sieb. This phytochemical is associated with numerous health benefits due to its antioxidant properties. The primary objective of the present study was to assess the pharmacological effects and underlying mechanisms of MOR, utilizing published data obtained from literature databases. Data collection involved accessing various sources, including PubMed/Medline, Scopus, Science Direct, Google Scholar, Web of Science, and SpringerLink. Our findings demonstrate that MOR can be utilized for the treatment of several diseases and disorders, as numerous studies have revealed its significant therapeutic activities. These activities encompass anti-inflammatory, antidiabetic, lipid-lowering capability, anticancer, trichogenic, hepatoprotective, gastroprotective, osteoprotective, renoprotective, and cardioprotective effects. MOR has also shown promising benefits against various neurological ailments, including Alzheimer's disease, Parkinson's disease, spinal cord injury, cerebral ischemia, and neuropathic pain. Considering these therapeutic features, MOR holds promise as a lead compound for the treatment of various ailments and disorders. However, further comprehensive preclinical and clinical trials are required to establish MOR as an effective and reliable therapeutic agent.
Chapter
Mass spectrometry is one of the most versatile analytical techniques due to the vast range of analytes that it can detect and quantify and, as such, for its contribution to a significant number of life science fields. The legal and forensics community has certainly benefited from this technique, which has been able to provide reliable evidence in court cases. Liquid Chromatography/Gas Chromatography–Mass Spectrometry (LC/GC–MS) still have a dominant role in the provision of forensic intelligence. However, in the past decade new and exciting MS-based techniques have emerged and are or have evolved to be at an operational deployment maturity, enabling either fast, ambient, non-destructive, or portable screening (or encompass all of these features). In this book, developments of LC–MS and GC–MS based techniques are covered with respect to operational practice and new applications, accompanied by other MS-based techniques that are increasing forensic opportunities and that operate on a variety of evidence types. Whilst the underpinning working principles of each relevant mass spectrometry technique are summarised, each chapter primarily focuses on its implementation in criminal investigation and court cases. In the last chapters, this book additionally covers emerging MS technologies that are at the beginning of their operational implementation journey as well as niche applications outside the fields of traditional forensic science but with a clear potential to impact future investigations (forensics beyond the courtroom). This book provides an up-to-date reference for the mass spectrometry-based tools that are currently available both as established and as emerging methods within forensic practice. It will help casework commissioning managers and forensic providers worldwide to make more informed decisions as to the forensic strategy and workflow when examining exhibits. It is also recommended to postgraduates and early career investigators with reference to the contribution that these techniques and methods could make if applied to classic forensic science practice.
Article
It is shown that in the last century mankind has made significant progress in the search and study of new pain-relieving drugs through the targeted synthesis of chemical analogs of natural opioids, cannabinoids, cocaine and amphetamines. Experience with the medical use of new synthetic opioids, cannabinoids and amphetamines has shown not only their high analgesic efficacy in disease, but also their high danger due to the risks of drug dependence and addiction that have caused drug epidemics. The history of relevant drug epidemics is described, and the pharmacodynamics and pharmacokinetics of the most dangerous drugs, as well as the risks associated with drug epidemics, are outlined. In particular, it is pointed out that the risk of drug dependence to opioids, cannabinoids, amphetamine and cocaine was not recognized until too late. The drug crisis was therefore initially largely iatrogenic in nature. In recent decades, however, controls on the prescription of narcotic drugs have tightened, so drug addiction as iatrogeny occurs less frequently. But criminal elements of society were able to establish clandestine production of drugs and their realization in the youth and LGBT community under the guise of new, fashionable designer drugs and devices for their use. Moreover, the new synthetic drugs differ from natural drugs in their stronger psychostimulant effects, their ability to cause addiction after the first use and their high risk of fatal poisoning. It has been reported that there are no approved drugs for the treatment of drug abusers of opioids, cannabinoids, amphetamines and cocaine. However, the development of specific vaccines for these drugs has begun in recent years. Active immunization of drug abusers with specially created vaccines is expected to assist doctors in treating drug abusers in the future.
Article
Morphine is the most common opioid analgesic administered to treat pain in patients undergoing cancer chemotherapy. This study aimed to evaluate the cytotoxic and mutagenic effects of morphine alone and in combination with doxorubicin (Dox), an antineoplastic agent largely used in patients with solid cancers. Cytotoxicity was evaluated in neuroblastoma (SH-SY5Y) and fibroblast (V79) cells using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) colorimetric assay while mutagenicity was assessed using the Salmonella/microsome assay in the absence and in the presence of S9 mix. Morphine showed a cytotoxic effect mainly on SH-SY5Y cells and reduced the cytotoxic effects of Dox when evaluated in a co-treatment procedure. In the Salmonella/microsome assay, it was observed that morphine did not induce mutations and, in fact, decreased the mutagenic effects induced by Dox in TA98 and TA102 strains in the absence of metabolic activation. Furthermore, in the presence of metabolic activation, no induction of mutations was observed with morphine. In conclusion, morphine decreased Dox cytotoxicity in both neuronal and non-neuronal cells and showed antimutagenic effects in the TA102 strain which detects mutagens inducing DNA oxidative damages. However, morphine decreased frameshift mutations induced by Dox in non-cytotoxic concentrations, an effect suggesting interference of Dox intercalation activity that could decrease its chemotherapeutic efficacy. These compelling findings highlight the importance of conducting further studies to explore the potential implications of co-administering morphine and Dox during cancer chemotherapy.
Article
Cannabis, cocaine, 3,4-methylenedioxymethamphetamine, and lysergic acid diethylamide are psychoactive substances with a significant increase in consumption during the 21st century due to their popularity in medicinal and recreational use. New psychoactive substances (NPSs) mimic established psychoactive substances. NPSs are known as being natural and safe to consumers; however, they are neither natural nor safe, causing severe adverse reactions, including seizures, nephrotoxicity, and sometimes death. Synthetic cannabinoids, synthetic cathinones, phenethylamines, and piperazines are all examples of NPSs. As of January 2020, nearly 1000 NPSs have become documented. Due to their low cost, ease of availability, and difficulty of detection, misuse of NPSs has become a familiar and growing problem, especially in adolescents and young adults in the past decade. The use of NPSs is associated with higher risks of unplanned sexual intercourse and pregnancy. As many as 4 in 100 women seeking treatment for substance abuse are pregnant or nursing. Animal studies and human clinical case reports have shown that exposure to certain NPSs during lactation periods has toxic effects on neonates, increasing various risks, including brain damage. Nevertheless, neonatal toxicity effects of NPSs are usually unrecognized and overlooked by healthcare professionals. In this review article, we introduce and discuss the potential neonatal toxicity of NPSs, emphasizing synthetic cannabinoids. Utilizing the established prediction models, we identify synthetic cannabinoids and their highly accumulative metabolites in breast milk.
Preprint
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.
Article
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.
Article
Although μ-opioid peptide (MOP) receptor agonists are effective analgesics available in clinical settings, their serious adverse effects put limits on their use. The marked increase in abuse and misuse of prescription opioids for pain relief and opioid overdose mortality in the past decade has seriously impacted society. Therefore, safe analgesics that produce potent analgesic effects without causing MOP receptor-related adverse effects are needed. This review highlights the potential therapeutic targets for the treatment of opioid abuse and pain based on available evidence generated through preclinical studies and clinical trials. To ameliorate the abuse-related effects of opioids, orexin-1 receptor antagonists and mixed nociceptin/MOP partial agonists have shown promising results in translational aspects of animal models. There are several promising non-opioid targets for selectively inhibiting pain-related responses, including nerve growth factor inhibitors, voltage-gated sodium channel inhibitors, and cannabinoid- and nociceptin-related ligands. We have also discussed several emerging and novel targets. The current medications for opioid abuse are opioid receptor-based ligands. Although neurobiological studies in rodents have discovered several non-opioid targets, there is a translational gap between rodents and primates. Given that the neuroanatomical aspects underlying opioid abuse and pain are different between rodents and primates, it is pivotal to investigate the functional profiles of these non-opioid compounds compared to those of clinically used drugs in non-human primate models before initiating clinical trials. More pharmacological studies of the functional efficacy, selectivity, and tolerability of these newly discovered compounds in non-human primates will accelerate the development of effective medications for opioid abuse and pain.
Article
Full-text available
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.
Chapter
Endogenous opioids and opioid receptors play key neuroendocrinological roles in regulating the body’s response to stress and pain. As part of this function, endogenous opioids regulate the hypothalamo–pituitary–adrenal (HPA), hypothalamo—pituitary–gonadal axes (HPG) axes and posterior pituitary function. Exogenous opioids have been used from ancient times as analgesics but have a well-known addictive potential. Opiate dependency is now a widespread global problem, driven by the easy availability of both prescribed and illegal opiates. As a consequence, the endocrine complications from opiates are becoming more common and chronic opiate users are at high risk of developing hypoadrenalism and hypogonadism. A robust screening protocol for these endocrinopathies, in collaboration between pain specialists and endocrinologists, is essential for appropriate replacement treatment and the prevention of morbidities and possibly mortality, especially from hypoadrenalism.
Article
Full-text available
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.
Article
Full-text available
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.
Article
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.
Article
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.