Heteroaryl ether analogues of an antileishmanial 7-substituted 2-nitroimidazooxazine lead afford attenuated hERG risk: In vitro and in vivo appraisal.

Previous investigation of the potent antileishmanial properties of antitubercular 7-substituted 2-nitroimidazo[2,1-b][1,3]oxazines with biaryl side chains led to our development of a new clinical candidate for visceral leishmaniasis (DNDI-0690). Within a collaborative backup program, a racemic monoaryl lead (3) possessing comparable activity in mice but a greater hERG liability formed the starting point for our pursuit of efficacious second generation analogues having good solubility and safety. Asymmetric synthesis and appraisal of its enantiomers first established that chiral preferences for in vivo efficacy were species dependent and that neither form afforded a reduced hERG risk. However, in line with our findings in a structurally related series, less lipophilic heteroaryl ethers provided significant solubility enhancements (up to 16-fold) and concomitantly attenuated hERG inhibition. One promising pyridine derivative (49) displayed 100% oral bioavailability in mice and delivered a 96% parasite burden reduction when dosed at 50 mg/kg in a Leishmania donovani mouse model of visceral leishmaniasis.

Cellulose ether treatment in vivo generates chronic wasting disease prions with reduced protease resistance and delayed disease progression.

Chronic wasting disease (CWD) is a prion disease of free-ranging and farmed cervids that is highly contagious because of extensive prion shedding and prion persistence in the environment. Previously, cellulose ether compounds (CEs) have been shown to significantly extend the survival of mice inoculated with mouse-adapted prion strains. In this study, we used CEs, TC-5RW, and 60SH-50, in vitro and in vivo to assess their efficacy to interfere with CWD prion propagation. In vitro, CEs inhibited CWD prion amplification in a dose-dependent manner. Transgenic mice over-expressing elk PrPC (tgElk) were injected subcutaneously with a single dose of either of the CEs, followed by intracerebral inoculation with different CWD isolates from white tailed deer, mule deer, or elk. All treated groups showed a prolonged survival of up to more than 30 % when compared to the control group regardless of the CWD isolate used for infection. The extended survival in the treated groups correlated with reduced proteinase K resistance of prions. Remarkably, passage of brain homogenates from treated or untreated animals in tgElk mice resulted in a prolonged life span of mice inoculated with homogenates from CE-treated mice (of + 17%) even in the absence of further treatment. Besides the delayed disease onset upon passage in TgElk mice, the reduced proteinase K resistance was maintained but less pronounced. Therefore, these compounds can be very useful in limiting the spread of CWD in captive and wild-ranging cervids.

Superior gallstone dissolubility and safety of tert-amyl ethyl ether over methyl-tertiary butyl ether.

BACKGROUND: The use of methyl-tertiary butyl ether (MTBE) to dissolve gallstones has been limited due to concerns over its toxicity and the widespread recognition of the safety of laparoscopic cholecystectomy. The adverse effects of MTBE are largely attributed to its low boiling point, resulting in a tendency to evaporate. Therefore, if there is a material with a higher boiling point and similar or higher dissolubility than MTBE, it is expected to be an attractive alternative to MTBE. AIM: To determine whether tert-amyl ethyl ether (TAEE), an MTBE analogue with a relatively higher boiling point (102 °C), could be used as an alternative to MTBE in terms of gallstone dissolubility and toxicity. METHODS: The in vitro dissolubility of MTBE and TAEE was determined by measuring the dry weights of human gallstones at predetermined time intervals after placing them in glass containers with either of the two solvents. The in vivo dissolubility was determined by comparing the weights of solvent-treated gallstones and control (dimethyl sulfoxide)-treated gallstones, after the direct infusion of each solvent into the gallbladder in both hamster models with cholesterol and pigmented gallstones. RESULTS: The in vitro results demonstrated a 24 h TAEE-dissolubility of 76.7%, 56.5% and 38.75% for cholesterol, mixed, and pigmented gallstones, respectively, which represented a 1.2-, 1.4-, and 1.3-fold increase in dissolubility compared to that of MTBE. In the in vitro experiment, the 24 h-dissolubility of TAEE was 71.7% and 63.0% for cholesterol and pigmented gallstones, respectively, which represented a 1.4- and 1.9-fold increase in dissolubility compared to that of MTBE. In addition, the results of the cell viability assay and western blot analysis indicated that TAEE had a lower toxicity towards gallbladder epithelial cells than MTBE. CONCLUSION: We demonstrated that TAEE has higher gallstone dissolubility properties and safety than those of MTBE. As such, TAEE could present an attractive alternative to MTBE if our findings regarding its efficacy and safety can be consistently reproduced in further subclinical and clinical studies.

Ether Anesthesia in the Austere Environment: An Exposure and Education.

Medical services in the austere and limited environment often require therapeutics and practices uncommon in modern times due to a lack of availability, affordability, or expertise in remote areas. In this setting, diethyl ether, or simply ether anesthesia, still serves a role today as an effective inhalation agent. An understanding of ether as an anesthetic not only illustrates the evolution in surgical anesthesia but also demonstrates ether's surviving function and durable use as a practical agent in developing nations. Although uncommon, it is not unseen, so a working knowledge should be understood if observation and advocacy for patients receiving this method of anesthesia are experienced.

Intrarectal Anesthesia in Neurosurgery.

In the early days of modern neurologic surgery, the inconveniences and potential dangers of general anesthesia by chloroform and ether using the so-called "open-drop technique" led to the quest for alternative methods of anesthesia. This became all the more necessary, since patient positioning and the surgical arrangements often hindered the use of a drop bottle. One approach to solve this problem was intrarectal ether application. The present article aims to shed light on this original, less well-known anesthesia technique in the neurosurgical field.

Obstetric and Other Uses of Ether Before Ether Day, According to the Boston Medical and Surgical Journal of 1828-1846.

From the inception of the Boston Medical and Surgical Journal in 1828 until the prominent public demonstration of surgical anesthesia on Ether Day of 1846, ether was often mentioned in the journal. Many of the examples were related to obstetrics. Because molecular structures were not available in the early 1800s, diverse volatile liquids were termed ethers. In addition to sulphuric ether, so-called ethers included cyanide-releasing propionitrile and ethanolic solutions of chloroform and of the potent vasodilator ethyl nitrite. Familiarity with anesthetically unsuitable ethers may have long deterred consideration of inhaled sulphuric ether for analgesia and anesthesia.

Impact of a Multimodal Approach in Prevention of Surgical Site Infection in Hepatic Transplant Recipients.

INTRODUCTION: In liver transplant (LT) recipients, surgical site infection (SSI) represents an important cause of morbidity and mortality. OBJECTIVE: This study measures the impact of a multimodal approach to the incidence of surgical site infection in LT recipients. MATERIALS AND METHODS: All of the LT recipients in our department were registered on the national database in solid organ transplant. A study was performed in two analytical-interventional phases. Phase 1 took place between July 14, 2009, and February 20, 2014. Phase 2 took place between February 21, 2014, and July 15, 2015. The multimodal change implemented during phase 1 was that 0.5% alcoholic chlorhexidine and ether were applied to the surgical field; surgical prophylaxis was primarily with ampicillin/sulbactam plus cefazolin. In phase 2, 2% alcoholic chlorhexidine alone was applied to the surgical field. The prior standard prophylaxis was changed to piperacillin tazobactam administered during surgery as a continuous infusion of 13.5 g over 8 hours with a pre-incision loading dose of 4.5 g. The loading dose of piperacillin tazobactam was combined with a single dose of gentamicin of 5 mg/kg. RESULTS: One hundred eight patients have received transplants since the start of the program: 82 patients during phase one and 26 patients during phase two. During phase 1, 13 cases of SSI were recorded, representing a rate of 15.85 per 100 transplants. Sixteen micro-organisms were isolated during phase 1, of which 12 corresponded to gram-negative bacilli. With regard to resistance profiles, 13 showed multidrug resistant and extensively drug resistant profiles. During phase 2, no cases of SSI were recorded (relative risk = 0.158 [95% confidence interval 0.0873-0.255], P = .0352]. CONCLUSION: A multimodal approach allowed for the reduction of the incidence of SSI in LTs and offered a protective strategy.

Ether in the developing world: rethinking an abandoned agent.

BACKGROUND: The first true demonstration of ether as an inhalation anesthetic was on October 16, 1846 by William T.G. Morton, a Boston dentist. Ether has been replaced completely by newer inhalation agents and open drop delivery systems have been exchanged for complicated vaporizers and monitoring systems. Anesthesia in the developing world, however, where lack of financial stability has halted the development of the field, still closely resembles primitive anesthetics. DISCUSSION: In areas where resources are scarce, patients are often not given supplemental intraoperative analgesia. While halothane provides little analgesia, ether provides excellent intra-operative pain control that can extend for several hours into the postoperative period. An important barrier to the widespread use of ether is availability. With decreasing demand, production of the inexpensive inhalation agent has fallen. Ether is inexpensive to manufacture, and encouraging increased production at a local level would help developing nations to cut costs and become more self-sufficient.

The outlook of physician histories: J. Marion Sims and 'The Discovery of Anaesthesia'.

The fact that doctors have a long tradition of writing medical history to interpret and direct their profession is well established. But readers (particularly modern physician readers) can also understand physician-authored histories as offering commentary and analysis of the world beyond medicine. In this essay, we offer a reading (perhaps a modern one) of J. Marion Sims's 1877 article, 'The Discovery of Anaesthesia' which exemplifies the stance of looking both inward and outward from the medical field. We begin by discussing Sims, including the complicated legacy he left as a physician. Next, we review late 19th-century history with a focus on Reconstruction. Finally, we show how the modern reader can use Sims's article both to trace the first use of ether and nitrous oxide for surgical anaesthesia and to provide a window into the 19th-century medical profession and the post-Civil War period. Through this study, we hope to show how to read both medicine and the world around it in physician histories.

Uptake and efflux of rhenium in cells exposed to rhenium diseleno-ether and tissue distribution of rhenium and selenium after rhenium diseleno-ether treatment in mice.

UNLABELLED: We proposed a new water-soluble rhenium diseleno-ether compound (with one atom of Re and two atoms of Se) and investigated the uptake of Re into the nucleus of malignant cells in culture exposed to the compound for 48 h and its efflux from the nucleus after a post-exposure period of 48 h, as DNA is the main target of Re. We also studied the distribution of both Re and Se in the main organs after an oral administration of 10 or 40 mg/kg Re diseleno-ether to mice for four weeks, five days-a-week. MATERIALS AND METHODS: Re and Se concentrations were assayed by inductively coupled plasma mass spectrometry (ICP-MS). Statistical analysis was performed using the Wilcoxon signed-rank test, comparing two related groups. RESULTS: We observed that Re was well incorporated into the nucleus of malignant cells in the most sensitive cells MCF-7, derived from human breast cancer, and that there was no efflux of Re. In contrast, in MCF-7 resistant cells (MCF-7 Mdr and MCF-7 R), A549 and HeLa cells, there was significant efflux of Re from the nucleus after the wash-out period. In mice, an important and dose-dependent uptake of both Re and Se was observed in the liver, with lower concentrations in kidneys. The lowest concentrations were observed in blood, lung, spleen and bones. There was a significant increase of Re concentrations in the blood, liver and kidney in mice treated with Re diseleno-ether at the dose of 40 mg/kg/24 h versus those treated at the dose of 10 mg/kg/24 h. There was a significant increase of Se concentrations in all tissues with the dose of Re diseleno-ether of 10 mg/kg/24 h versus controls, and a significant increase in the liver in mice treated with dose of Re diseleno-ether of 40 mg/kg/24h versus those treated with 10 mg/kg/24 h. CONCLUSION: We are the first to demonstrate that a compound combining Re and Se in a single molecule, is able to deliver Re and Se to the organism via an oral route, for cancer treatment.

Researches regarding the Morton ether inhaler at Massachusetts General Hospital, Boston.

The Morton ether inhaler in the possession of Massachusetts General Hospital, Boston, MA, was traced back to 1906 when the earliest known photograph of it was published. The authors believe that the inhaler was given by William T. G. Morton, MD, to J. Mason Warren, MD, in January 1847. The inhaler was acquired by the Warren Anatomical Museum at an unknown date, loaned to Massachusetts General Hospital in October 1946, and placed on permanent loan to Massachusetts General Hospital in April 1948. Many documents relating to the inhaler have disappeared, and it was only identified in 2009 as the inhaler that probably belonged to J. Mason Warren, MD. The inhaler is not believed to be the one that Morton used on October 16, 1846, at Massachusetts General Hospital. It is the only known example of a Morton ether inhaler with valves (excluding replicas or reproduction inhalers) and is probably of similar design to the inhaler that Morton used on October 16, 1846.

Correspondence by Charles T. Jackson containing the earliest known illustrations of a Morton ether inhaler.

A letter, dated December 1, 1846, from Charles T. Jackson, MD, to Josiah D. Whitney contains a previously unreported description of a Morton ether inhaler and the only known contemporaneous hand-drawn illustrations of this type of ether inhaler. This letter and 2 other known letters on ether anesthesia were probably carried from Boston, MA, to Liverpool, United Kingdom, on the same paddle steamer (Acadia) that carried the well-known letter from Jacob Bigelow, MD, to Francis Boott, MD.

In vitro and in vivo efficacy of ether lipid edelfosine against Leishmania spp. and SbV-resistant parasites.

BACKGROUND: The leishmaniases are a complex of neglected tropical diseases caused by more than 20 Leishmania parasite species, for which available therapeutic arsenal is scarce and unsatisfactory. Pentavalent antimonials (SbV) are currently the first-line pharmacologic therapy for leishmaniasis worldwide, but resistance to these compounds is increasingly reported. Alkyl-lysophospoholipid analogs (ALPs) constitute a family of compounds with antileishmanial activity, and one of its members, miltefosine, has been approved as the first oral treatment for visceral and cutaneous leishmaniasis. However, its clinical use can be challenged by less impressive efficiency in patients infected with some Leishmania species, including L. braziliensis and L. mexicana, and by proneness to develop drug resistance in vitro. METHODOLOGY/PRINCIPAL FINDINGS: We found that ALPs ranked edelfosine>perifosine>miltefosine>erucylphosphocholine for their antileishmanial activity and capacity to promote apoptosis-like parasitic cell death in promastigote and amastigote forms of distinct Leishmania spp., as assessed by proliferation and flow cytometry assays. Effective antileishmanial ALP concentrations were dependent on both the parasite species and their development stage. Edelfosine accumulated in and killed intracellular Leishmania parasites within macrophages. In vivo antileishmanial activity was demonstrated following oral treatment with edelfosine of mice and hamsters infected with L. major, L. panamensis or L. braziliensis, without any significant side-effect. Edelfosine also killed SbV-resistant Leishmania parasites in in vitro and in vivo assays, and required longer incubation times than miltefosine to generate drug resistance. CONCLUSIONS/SIGNIFICANCE: Our data reveal that edelfosine is the most potent ALP in killing different Leishmania spp., and it is less prone to lead to drug resistance development than miltefosine. Edelfosine is effective in killing Leishmania in culture and within macrophages, as well as in animal models infected with different Leishmania spp. and SbV-resistant parasites. Our results indicate that edelfosine is a promising orally administered antileishmanial drug for clinical evaluation.

Equipamento para anestesia inalatória em ratos com oferta simultânea de anestésico e oxigênio / Inhalation anesthesia equipment for rats with provision of simultaneous anesthetic and oxygen

PURPOSE: To introduce a model of equipment for inhalation anesthesia in rats that offers better control of both flow and losses of ether during induction, maintenance, and recuperation. METHODS: The equipment consists of an air compressor with two outlets, a closed glass induction chamber, a glass reservoir for the anesthetic agent, a pediatric inhalation mask, a three-way stopcock, a Y-connector, and urinary catheters. Three hundred Wistar rats (Rattus norvegicus albinus) were given inhalation anesthesia. The evaluated parameters were equipment operation, duration of each phase of anesthesia, corneal reflex, muscular tonus, respiration during induction and maintenance, and volume of anesthesia. RESULTS: The average time taken for induction was 7.3 minutes; the average anesthetic recuperation time was 6.4 minutes. The amount of anesthetic used varied according to the weight of the animal, with the average volume of ether used being 6.5ml/hour. The availability of oxygen (room air) decreased the recuperation time and averted both respiratory depression and insufficient depth of anesthesia. CONCLUSION: The proposed equipment is practical, inexpensive, and allows for satisfactory control of anesthetic parameters during the entire procedure, making inhalation anesthesia in rats safe and essentially complication free.

OBJETIVO: Apresentar modelo de equipamento para anestesia inalatória em ratos, com melhor controle do fluxo, das perdas de anestésico na indução, da manutenção e da recuperação anestésica. MÉTODOS: O equipamento é constituído por compressor de ar com saída dupla, câmara de vidro fechada para indução, reservatório de vidro para o agente anestésico, máscara de inalação pediátrica, torneira de três vias, conexão em "Y" e sondas uretrais. Trezentos ratos Wistar (Rattus norvegicus albinus) foram anestesiados por via inalatória. Os parâmetros avaliados foram: viabilidade do equipamento, tempo de cada fase, reflexo corneano, tônus muscular e movimentos respiratórios na indução e na manutenção anestésica, além do volume de anestésico. RESULTADOS: A média do tempo gasto na indução anestésica foi de 7,3 minutos. A média do tempo de recuperação anestésica foi de 6,4 minutos. A média do volume de éter utilizado foi de 6,5 ml/h. Não foram observadas neste experimento morte dos animais, aumento excessivo de secreção traqueobrônquica ou interrupção da operação por superficialização anestésica. CONCLUSÃO: O equipamento proposto é prático, possui baixo custo e permite o controle adequado dos parâmetros de controle da anestesia durante todo o procedimento, tornando a anestesia inalatória em ratos segura e praticamente isenta de complicações.