Artemisinin: From Chinese Herbal Medicine to Modern Chemotherapy

Malaria is a disease that has blighted humankind since early times. The first antimalarial treatment available to Europeans was the dried bark of the cinchona tree from Peru. The main problem in its use was adulteration by other material. The ‘active principle’ was first extracted in 1820 and named quinine. It was found to be a more powerful and reliable drug than cinchona bark. Once its chemical structure had been determined, it was possible to synthesize substances chemically related to quinine that were equally powerful but could be manufactured industrially. Mepacrine (atabrine) was amongst the most successful, but had adverse side effects. To avoid these side effects, further chemical modification gave chloroquine, a highly successful drug. This sequence is a common way of converting an herbal remedy into a modern-style chemical drug. It parallels, to some extent, the process of potentiation common in traditional herbal medicine. By the 1970s, drug resistance had developed with chloroquine. To find and develop a new antimalarial drug that worked on an entirely different pharmacological principle, Chinese scientists turned to their herbal compendia (ben cao) and found that Artemisia annua (qing hao) was frequently mentioned as a treatment for intermittent fever. Whether, in view of the distinctive doctrines of Chinese medicine, it should be possible to extract an active principle as described above is discussed. After a very careful reading of the procedure given for the use of qing hao, an active substance, artemisinin, was extracted. Artemisinin has a truly remarkable chemical structure, and chemical modification produced artesunate, the drug of choice. To prevent the development of resistance, artesunate is used in combination with other antimalarial drugs. Modern pharmacology has largely ignored that other substances in artemisia and the cinchona bark may contribute to their therapeutic effect. This matter is also discussed

Artemisinin

Malaria is a disease that has blighted humankind since early times. The first antimalarial treatment available to Europeans was the dried bark of the cinchona tree from Peru. The main problem in its use was adulteration by other material. The ‘active principle’ was first extracted in 1820 and named quinine. It was found to be a more powerful and reliable drug than cinchona bark. Once its chemical structure had been determined, it was possible to synthesize substances chemically related to quinine that were equally powerful but could be manufactured industrially. Mepacrine (atabrine) was amongst the most successful, but had adverse side effects. To avoid these side effects, further chemical modification gave chloroquine, a highly successful drug. This sequence is a common way of converting an herbal remedy into a modern-style chemical drug. It parallels, to some extent, the process of potentiation common in traditional herbal medicine. By the 1970s, drug resistance had developed with chloroquine. To find and develop a new antimalarial drug that worked on an entirely different pharmacological principle, Chinese scientists turned to their herbal compendia (ben cao) and found that Artemisia annua (qing hao) was frequently mentioned as a treatment for intermittent fever. Whether, in view of the distinctive doctrines of Chinese medicine, it should be possible to extract an active principle as described above is discussed. After a very careful reading of the procedure given for the use of qing hao, an active substance, artemisinin, was extracted. Artemisinin has a truly remarkable chemical structure, and chemical modification produced artesunate, the drug of choice. To prevent the development of resistance, artesunate is used in combination with other antimalarial drugs. Modern pharmacology has largely ignored that other substances in artemisia and the cinchona bark may contribute to their therapeutic effect. This matter is also discussed

(η5-Cyclopentadienyl)(2-naphthylethynyl)(triphenylphosphine-κP)nickel(II)

The title compound, [Ni(C₅H₅)(C₁₂H₇)(C₁₈H₁₅P)], does not contain strong hydrogen-bond donors or acceptors and the primary interactions are limited to those of the weak C-H...π(arene) type and mainly involving the arene rings

Biosynthetic Studies of Natural Plant Products: The Biosynthesis of Petasin in Petasites hybridus (L) Compositae

In recent years, the study of natural products has undergone a shift in emphasis from the classical, purely structural type of chemical investigation to consideration of the relationship of such compounds with the organism of origin. The widespread application of modern chromatographic and spectroscopic techniques has considerably simplified the isolation and characterisation of these compounds, permitting increasing attention to turn to wider biological issues as well as purely chemical aspects. Among these are the examination of biosynthetic processes and pathways, and the solution of mechanistic 1,2) problems. The investigation of biosynthesis has led to a greater understanding of the metabolic significance of many natural products, and to consideration of their biological function (3). In addition, the application of chemical characters to taxonomic (4) and phylogenetic (5) systematic has provided a valuable new source of evidence for the relationships between taxa. This thesis describes an investigation into the biosynthesis of the sesquiterpenoid, petasin (1), isolated from the plant Fetasites hybridus (L) Compositae. the structure of which was originally determined by Aebi and Waaler 6). The work was initiated as part of a long-term project by Dr. G. H. Draffan and Dr. J. A. Zabkiewicz, formerly of this department. Their preliminary findings have already been described (7). Petasin has been chosen for this study because it possesses the eremophilane (2) carbon skeleton, which cannot be directly derived by the Biogenetic Isoprene Rule proposed by Ruzicka 8). It has been suggested 9), 10) that eremophilanes are derived from the eudesmane (3) skeleton by a methyl shift across the ring Junction (3A). Another factor influencing the choice of petasin has been the easy availability of P. hybridus in the wild state. Finally, the chemotaxonomic studies of the Czech group of Sorm 11, 12) into various Petasites species have provided valuable background information on the chemistry of the sesquiterpenoids of this genus. Chemical studies of P. hybridus leaves from a number of sources thoughout Britain have demonstrated the consistent nature of the sesquiterpenoid constituents, the petasin esters being the principal components in each case. A more detailed examination, using the highly sensitive techniques of gas-liquid chromatography (GLC) and gas chromatography coupled to mass spectrometry (GC-MS), has revealed a number of other, non-esterified sescuiteruenoids, in particular, the hydrocarbon eremophilene (4) 13, 14). Many of these compounds may be significant as intermediates in the biosynthetic pathway. Using the available evidence of the sesouiterpenoid constituents, coupled with chemotaxonomic information, a rationalisation has been made of the probable biosynthetic pathway leading to petasin. This places eremophilene as the first fully cyclised component of the sequence. Stereoelectronic considerations of the cyclisation of trans,trans-farnesyl pyrophosphate (5) to eremophilene have led to a detailed proposition for the mechanism of these reactions, and for the mode of action of the enzymes responsible. This approach may also be applied to the biosynthesis of other classes of terpenoids, and is consistent with currently available experimental results. A series of conventional biochemical reactions is then postulated to derive the oxidised products, including petasin. Radioactive tracer methods have been employed in this investigation of petasin biosynthesis. (2-14C)Mevalonic acid (6k) was fed to growing leaves of P. hybridus via a cotton wick inserted through the petiole. Radioactive petasin was isolated, and selective chemical degradation was carried out to determine the location of the labelled carbon atoms. Radioactivity was found in petasin as shown in structure (1A) confirming the origin of the eremophilane skeleton from mevalonic acid in the manner originally proposed by Robinson However, 14C-labelling on its own gives no information as to the mechanism of cyclisation, and the crucial point concerning the origin of the methyl group at C-15 of eremophilane remains unanswered. The main difficulty encountered in this work concerns the ineffective penetration of externally fed mevalonic acid to the site of synthesis in the plant. The level of incorporation (0.003-0.03% of total radioactivity) might appear to imply that mevalonic acid was not directly involved in the biosynthesis, but for the specific location of the label in the molecule of petasin. This type of result is consistent with work covering other isoprenoid classes from higher plants

St. John of the Cross : the poetics of heroism and the heroism of poetics

In Chapter 1, I demonstrate a dialectical circularity between St. John's early years through the year 1568 and his theological, vocational and literary achievements. Chapter 2 offers a verbal and nominal analysis of the "Cántico espiritual" from which I show three new strains of interpretation: First, a personal dialogue on the attainment of true love; second, the inclusion of sacramental imagery; and third, a heroic trajectory of the poetic soul. In Chapter 3, I present an analysis of "Noche oscura" and "Llama de amor viva," whereby I demonstrate that both poems belong to the same poetics. All in all, this paper shows that St. John's biography, vocation and mystical heights merge, only later to emerge, as lyrical expressions of life, theology and divine experience

Motion Correction via Locally Linear Embedding for Helical Photon-counting CT

X-ray photon-counting detector (PCD) offers low noise, high resolution, and spectral characterization, representing a next generation of CT and enabling new biomedical applications. It is well known that involuntary patient motion may induce image artifacts with conventional CT scanning, and this problem becomes more serious with PCD due to its high detector pitch and extended scan time. Furthermore, PCD often comes with a substantial number of bad pixels, making analytic image reconstruction challenging and ruling out state-of-the-art motion correction methods that are based on analytical reconstruction. In this paper, we extend our previous locally linear embedding (LLE) cone-beam motion correction method to the helical scanning geometry, which is especially desirable given the high cost of large-area PCD. In addition to our adaption of LLE-based parametric searching to helical cone-beam photon-counting CT geometry, we introduce an unreliable-volume mask to improve the motion estimation accuracy and perform incremental updating on gradually refined sampling grids for optimization of both accuracy and efficiency. Our numerical results demonstrate that our method reduces the estimation errors near the two longitudinal ends of the reconstructed volume and overall image quality. The experimental results on clinical photon-counting scans of the patient extremities show significant resolution improvement after motion correction using our method, which reveals subtle fine structures previously hidden under motion blurring and artifacts

A Conversation With a Cinematograher: Bill Butler

On the evening of November 15, Bill Butler met with the film and television students at Columbia College. Butler is one of the major cinematographers workign today, with credits such as One Flew Over the Cuckoo\u27s Nest, Jaws, and Grease.The discussion was moderated by Thaine Lyman, chair of the Television Department and Anthony Loeb, chair of the Film Department. Photographer: Joy Caniglia. 29 pages.https://digitalcommons.colum.edu/conversations/1004/thumbnail.jp