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.

The role of viscosity on skin penetration from cellulose ether-based hydrogels.

BACKGROUND: The rheological properties of dermal drug delivery systems are of importance when designing new formulations. Viscosity not only affects features such as spreadability and skin feel, but may also affect the skin penetration of incorporated actives. Data on the latter aspect are controversial. Our objective was to elucidate the relation between viscosity and drug delivery performance of different model hydrogels assuming that enhanced microviscosity might delay drug release and penetration. MATERIALS AND METHODS: Hydrogels covering a broad viscosity range were prepared by adding either HPMC or HEC as gelling agents in different concentrations. To investigate the ability of the gels to deliver a model drug into the skin, sulphadiazine sodium was incorporated and its in vitro skin penetration was monitored using tape stripping/HPLC analysis and non-invasive confocal Raman spectroscopy. RESULTS: The trends observed with the two different experimental setups were comparable. Drug penetration depths decreased slightly with increasing viscosity, suggesting slower drug release due to the increasingly dense gel networks. However, the total penetrated drug amounts were independent of the exact formulation viscosity. CONCLUSION: Drug penetration was largely unaffected by hydrogel viscosity. Moderately enhanced viscosity is advisable when designing cellulose ether hydrogels to allow for convenient application.

Dr Snow killed a bird: The genesis of pharmacokinetics and pharmacodynamics in anaesthesia.

This essay presents a pharmacologist's perspective of what would be now called 'preclinical research' and 'uncontrolled clinical trials' surrounding the first public demonstration by William Thomas Green Morton of painless surgery achieved by the inhalation of ether in a patient at the Massachusetts General Hospital on 16 October 1846. Of the many people who made history in those earliest days of surgical anaesthesia in both the United States and Great Britain, John Snow stands out for his personal research that spanned basic science and clinical medicine. Primarily, Snow used the relationship between the vapour pressure of a volatile liquid and temperature to design a vaporiser. This allowed control of the inspired concentration of the volatile liquid epitomised by diethyl ether, and thus the time-course and depth of anaesthesia. In an era when developments in anaesthesia were almost exclusively based on empirical modifications to apparatus and technique, Snow, and to a lesser extent his contemporary Andrew Buchanan, stood out from all others in advancing the quantitative basis of anaesthesia. Both described the physiological basis of control over gas uptake whereby they related that gas moved across concentration gradients in the body: alveolar to arterial to tissue to venous gas tensions, and Snow devised a progressional semi-quantitative scale of five 'stages' of ether anaesthesia. They thereby introduced the elements of what would be referred to 'pharmacokinetics' and 'pharmacodynamics', a century later. This essay attempts to place them and their scientific insights into context with contemporaneous principal personae and knowledge.

Ventilation/perfusion ratios measured by multiple inert gas elimination during experimental cardiopulmonary resuscitation.

BACKGROUND: During cardiopulmonary resuscitation (CPR) the ventilation/perfusion distribution (VA /Q) within the lung is difficult to assess. This experimental study examines the capability of multiple inert gas elimination (MIGET) to determine VA /Q under CPR conditions in a pig model. METHODS: Twenty-one anaesthetised pigs were randomised to three fractions of inspired oxygen (1.0, 0.7 or 0.21). VA/ Q by micropore membrane inlet mass spectrometry-derived MIGET was determined at baseline and during CPR following induction of ventricular fibrillation. Haemodynamics, blood gases, ventilation distribution by electrical impedance tomography and return of spontaneous circulation were assessed. Intergroup differences were analysed by non-parametric testing. RESULTS: MIGET measurements were feasible in all animals with an excellent correlation of measured and predicted arterial oxygen partial pressure (R(2) = 0.96, n = 21 for baseline; R(2) = 0.82, n = 21 for CPR). CPR induces a significant shift from normal VA /Q ratios to the high VA /Q range. Electrical impedance tomography indicates a dorsal to ventral shift of the ventilation distribution. Diverging pulmonary shunt fractions induced by the three inspired oxygen levels considerably increased during CPR and were traceable by MIGET, while 100% oxygen most negatively influenced the VA /Q. Return of spontaneous circulation were achieved in 52% of the animals. CONCLUSIONS: VA /Q assessment by MIGET is feasible during CPR and provides a novel tool for experimental purposes. Changes in VA /Q caused by different oxygen fractions are traceable during CPR. Beyond pulmonary perfusion deficits, these data imply an influence of the inspired oxygen level on VA /Q. Higher oxygen levels significantly increase shunt fractions and impair the normal VA /Q ratio.

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.

Distribution of ether in two postmortem cases.

Diethyl ether (ether) is a volatile liquid that was used in the 1800s as an anesthetic agent; however, it is no longer used for this purpose, partly because of its odor and flammability. Two postmortem cases in which ether was detected are presented. The first case was an 18-year-old male found hanging from a basement ceiling brace in a semi-sitting position with a gas mask covering his face. A container of Prestone starting fluid and a bong were found on the floor close to the body. The second case was a 20-year-old male found unresponsive in his dormitory room with two black plastic trash bags secured over his head. Two saturated rags and a resealable bag containing a clear liquid were contained within these trash bags. An almost empty can of Tradco starting fluid was also found at the scene. Ether concentrations were determined by headspace gas chromatography-mass spectrometry in the selective ion monitoring mode. In case #1, the medical examiner ruled that the cause of death was asphyxia due to hanging; the manner of death was undetermined. In case #2, the medical examiner ruled that the cause of death was asphyxia and the manner of death was suicide.

Synthesis and evaluation of ether containing 99mTc-nitrido dithiocarbamate complexes as brain perfusion imaging agent.

In the present study, a series of (99m)Tc-nitrido dithiocarbamate complexes containing ether linkages have been prepared and their brain perfusion characteristics studied. Two primary dithiocarbamates and two secondary dithiocarbamates were synthesized in >80% yield and were characterized by elemental analyses. The ligands were then labeled using a (99m)Tc-nitrido intermediate, prepared from sodium pertechnetate using commercially available nitrido kit-vials, at a low ligand concentration of 0.1 mg. The prepared complexes were obtained in more than 95% yield and were characterized by paper electrophoresis and HPLC. All the complexes were found to be neutral and eluted out as a single species in HPLC. Biodistribution studies were carried out in normal Swiss mice. All the complexes showed uptake in the brain. (99m)TcN complexes of secondary dithiocarbamates showed higher initial brain uptake (5 min p.i.) than their primary amine counterparts. However, all the complexes exhibited rapid washout from the brain.

Correlation of bispectral index and Guedel's stages of ether anesthesia.

UNLABELLED: Bispectral index (BIS) analysis is a method of electroencephalograph (EEG) analysis based on the interfrequency phase relationships of the EEG, designed to quantify anesthetic hypnosis. The BIS was created after concurrent collection of EEG and clinical data from a large number of patients anesthetized with various drugs over a prolonged period and then performing a Fourier analysis followed by a bispectral calculation. The clinical stages of anesthetic depth are very well demonstrated in etherized patients. In this study, we studied the BIS changes during various stages of ether anesthesia and quantified the hypnotic depth during the surgical stage of ether anesthesia. The values for BIS under various stages and planes of ether anesthesia were recorded in 21 patients listed for short surgical procedures. During diethyl ether anesthesia, BIS initially increased and subsequently decreased. During surgical anesthesia, a BIS value of 30 was observed. IMPLICATIONS: For the first time, bispectral index (BIS) has been studied in patients being anesthetized solely with ether. Ether both causes an increase and decrease in BIS during induction and emergence. The index observed during the surgical stage of ether anesthesia is probably the correct value for the depth of hypnosis because no other volatile anesthetic can produce the true anesthetic state when used alone. This value could be taken as the value to be attained when balanced anesthesia is being practiced.

Avaliação experimental de técnica utilizada por enfermeiros no tratamento de equimoses / Experimental assesment on the technique utilizes by nurses on the treatment against ecchymosis

Este trabalho consiste em estudo experimental de processos técnicos utilizados como apoio à regressão de equimoses. Buscou-se a resposta em laboratório através da indução de equimose traumática em 72 ratos, testados em grupos de oito, sendo cada grupo tratado respectivamente por aplicação tópica de: 1§ solução fisiológica; 2§ bolsa de gelo; 3§ bolsa de água quente; 4§ agar-agar; 5§ éter etílico; 6§ óleo mineral; 7§ fenoftaleína, 8§ associação-A entre o éter+Agar+óleo+fenoftaleína e 9§ associção-B, aplicação de gelo nas primeiras 24 h após a lesão e depois bolsa de água quente. Os dados obtidos foram tratados e comparados entre si e com o grupo controle usando-se análise de variância (ANOVA) paramétrica de Student-Newman-Keuls. Os resultados revelaram que o uso da associação-A mostrou atividade terapêutica extremamente significativa quando comparada com o grupo controle e associação-B, podendo-se concluir que o uso tópico da associação-A é eficaz para o tratamento das equimoses traumáticas induzidas em ratos

Effect of CGS 19755, a competitive N-methyl-D-aspartate antagonist, on general anesthetic potency.

CGS 19755 is a competitive N-methyl-D-aspartate (NMDA) receptor antagonist which penetrates the blood-brain barrier. The effect of pretreatment with subanesthetic doses of CGS 19755 on general anesthetic potency was determined in mice. Mice were pretreated with saline or CGS 19755 by intraperitoneal (IP) administration 30 min before IP administration of an anesthetic dose of ethanol or pentobarbital or measurement of the volatile anesthetic minimum alveolar concentration (MAC). CGS 19755 increased the duration of ethanol- and pentobarbital-induced loss of righting reflex in a dose-dependent manner. The highest dose of CGS 19755 tested, 50 mg/kg, increased duration of loss of righting reflex by about four- and twofold for ethanol and pentobarbital, respectively. CGS 19755 also decreased the MAC for halothane. However, CGS 19755 pretreatment had no effect on the MAC for diethyl ether. These results suggest that the potency of certain general anesthetic agents can be increased by antagonism of brain NMDA receptors.

Mechanism of transport and distribution of organic solvents in blood.

Little is known about the mechanism of transport and distribution of volatile organic compounds in blood. Studies were conducted on five typical organic solvents to investigate how these compounds are transported and distributed in blood. Groups of four to five rats were exposed for 2 hr to 500 ppm of n-hexane, toluene, chloroform, methyl isobutyl ketone (MIBK), or diethyl ether vapor; 94, 66, 90, 51, or 49%, respectively, of these solvents in the blood were found in the red blood cells (RBCs). Very similar results were obtained in vitro when aqueous solutions of these solvents were added to rat blood. In vitro studies were also conducted on human blood with these solvents; 66, 43, 65, 49, or 46%, respectively, of the added solvent was taken up by the RBCs. These results indicate that RBCs from humans and rats exhibited substantial differences in affinity for the three more hydrophobic solvents studied. When solutions of these solvents were added to human plasma and RBC samples, large fractions (51-96%) of the solvents were recovered from ammonium sulfate-precipitated plasma proteins and hemoglobin. Smaller fractions were recovered from plasma water and red cell water. Less than 10% of each of the added solvents in RBC samples was found in the red cell membrane ghosts. These results indicate that RBCs play an important role in the uptake and transport of these solvents. Proteins, chiefly hemoglobin, are the major carriers of these compounds in blood. It can be inferred from the results of the present study that volatile lipophilic organic solvents are probably taken up by the hydrophobic sites of blood proteins.