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Anesthesia and analgesia and the curse of Eve
Published in Michael J. O’Dowd, The History of Medications for Women, 2020
Ethylene, a gas first prepared by Becher in 1669, was reintroduced by Luckhardt and Carter of Chicago in 1923. It was widely used in obstetrics in America but was a highly explosive gas and was replaced by safer products. Cyclopropane, an expensive gas used in a completely closed-circuit apparatus, was also employed in obstetric analgesia. It was first prepared by the chemist Freund in 1882 and was introduced into clinical anesthesia in 1933. Trichlorethylene (Trilene), introduced in 1934, and methoxyflurane (Pentrane), first used in 1959, were both popular for a while.
The Twentieth Century
Published in Arturo Castiglioni, A History of Medicine, 2019
Among the general anesthetics, ethylene, which has had a fluctuating history since first used as an anesthetic by T. nunnely (1809–70) in 1849, was established (1922, 1923) by A. B. luckhardt (b. 1885) and his colleagues, and independently in 1923 by William E. brown (b. 1891). From this grew C. D. leake’s (b. 1896) production (1930) of the useful divinyl ether. Cyclopropane, an impurity of propylene, was found (1928) by G. H. W. lucas (b. 1894) and V. E. henderson(1877–1945) to be a more potent anesthetic than propylene. Laughing gas (nitrous oxide) was mixed with oxygen for anesthesia in 1868 by E. W. andrews. It was brought into the domain of practical anesthesia in the 1880’s by Sir Frederic hewitt, who was the first to construct a practical apparatus. With further improvements by the Cleveland dentist C. K. teter and by E. I. mckesson, J. gwathmey (1863–1944), J. S. lundy, and others, the method has obtained widespread favour.
The advent of anaesthesia and antisepsis
Published in Harold Ellis, Sala Abdalla, A History of Surgery, 2018
Of course, the early anaesthetic agents had their disadvantages, even though their use was widespread well into the second half of the 20th century. The senior author, for example, as a young doctor, became quite expert in the administration of both nitrous oxide and ether. Nitrous oxide is only suitable for a short anaesthetic, for example, dental extraction. Ether requires a long time to induce the patient, produces a good deal of nausea and is highly inflammable when mixed with oxygen. Chloroform, although easy to use, is associated with occasional incidents of sudden death from cardiac irregularity. Numerous inhalation agents, used alone or in combination, were developed in the 20th century: cyclopropane and halothane, for example, were safer and more pleasant for the patient. Intravenous anaesthetic drugs, such as pentothal and ketamine, make the induction of anaesthesia rapid and reasonably pleasant.
Bioactivation of cyclopropyl rings by P450: an observation encountered during the optimisation of a series of hepatitis C virus NS5B inhibitors
Published in Xenobiotica, 2018
Xiaoliang Zhuo, Ying-Zi Wang, Kap-Sun Yeung, Juliang Zhu, Xiaohua Stella Huang, Kyle E. Parcella, Kyle J. Eastman, John F. Kadow, Nicholas A. Meanwell, Yue-Zhong Shu, Benjamin M. Johnson
As a commonly used functional group in medicinal chemistry, the cyclopropane ring possesses unique bonding and conformational characteristics. The triangular structure of the cyclopropane, where the C–C–C bond angle (60°) is much less than that of an sp3-hybridised tetrahedral C–C–C bond angle (109.5°), confers inherent ring strain (de Meijere, 1979). In addition, the coplanarity of the cyclopropyl carbon atoms favours an eclipsed conformation for the adjacent CH2 groups, resulting in torsional strain (de Meijere, 1979). As a result, cyclopropyl C–C bonds (61 kcal/mol) are considerably weaker than straight-chain C–C bonds (e.g. CH3CH3, 91 kcal/mol) (van Leeuwen et al., 1995). On the other hand, the C–H bonds (109 kcal/mol) of a cyclopropyl ring are shorter and stronger than those of an acyclic hydrocarbon (e.g. CH3CH3, 102 kcal/mol), raising the energy needed to carry out hydrogen atom abstraction, the initial rate-limiting step in many cytochrome P450-mediated reactions (Blanksby & Ellison, 2003; Tian et al., 2006).
Evaluation of a tiered in vitro testing strategy for assessing the ocular and dermal irritation/corrosion potential of pharmaceutical compounds for worker safety
Published in Cutaneous and Ocular Toxicology, 2018
Jessica C. Graham, Nathan Wilt, Gertrude-Emilia Costin, Caren Villano, Jackie Bader, Lindsay Krawiec, Elizabeth Sly, Janet Gould
Besides PCs D-E (see above), 19 PCs were evaluated in the BCOP assay. Both the neat PC and a 20% (w/v) dilution were tested, and the higher IVIS was used to determine the hazard category. A higher IVIS was obtained for five neat PCs (Table 2, PC-F, -K, -M, -O and -P). The BCOP assay indicated that four compounds were severe eye irritants (IVIS >55) and eight were non-irritants (IVIS <3). There were eight PCs with IVIS between 3 and 25, which were ascribed a mild irritant potential, and one with an IVIS between 25 and 55 which was ascribed a moderate irritant potential. PCs regarded as activated cyclopropanes were generally predicted to be eye irritants in BCOP studies (4/4), with those also consisting of sulphonamide structural groups predicted to be severely irritating.
Drug metabolic stability in early drug discovery to develop potential lead compounds
Published in Drug Metabolism Reviews, 2021
Siva Nageswara Rao Gajula, Nimisha Nadimpalli, Rajesh Sonti
Change in the attached ring size and chirality can affect the metabolic stability of the drug. Reducing the ring size and changing the chirality improves metabolic stability. For example, switching from cyclohexane to cyclopropane improved the metabolic stability significantly from a half-life of 14 to 120 min. On the other hand, the change in the chirality from S to R increased the half-life from 14 to 84 min (MacKenzie et al. 2002). Cyclization is another approach to enhance the metabolic stability of drugs. Introducing the labile groups into the cyclic structure reduces the metabolism. For instance, incorporating the methyl group into cyclic structure blocked the metabolism of N-demethylation (MacKenzie et al. 2002).