Ester und Stereoisomere

This review discusses concepts of isomers, stereoisomers, chirality, and enantiomers as applied to drugs used in anaesthesia. The inhalational anaesthetics enflurane and isoflurane are examples of stereoisomers. A chiral centre is formed when a carbon or quaternary nitrogen atom is connected to four different atoms. A molecule with one chiral centre is then present in one of two possible configurations termed enantiomers. A racemate is a mixture of both enantiomers in equal proportions. Many of the drugs used in anaesthesia are racemic mixtures (the inhalational anaesthestics, local anaesthetics, ketamine, and others). The shape of the atracurium molecule is comparable to that of a dumb-bell: the two isoquinoline groups representing the two bulky ends connected by an aliphatic chain. In each isoquinoline group there are two chiral centres, one formed by a carbon and the other by a quaternary nitrogen atom. From a geometric point of view, the connections from the carbon atom to a substituted benzene ring and from the quaternary nitrogen to the aliphatic chain may point in the same direction (cis configuration) or in opposite directions (trans configuration). The two isoquinoline groups in atracurium are paired in three geometric configurations: cis-cis, trans-trans, or cis-trans. However, the two chiral centres allow each isoquinoline group to exist in one of four stereoisomeric configurations. In the symmetrical atracurium molecule, the number of possible stereoisomers is limited to ten. Among these, 1 R-cis, 1′ R-cis atracurium was isolated and its pharmacologic properties studied. This isomer, named cis-atracurium, offers clinical advantages over the atracurium mixture, principally due to the lack of histamine-releasing propensity and the higher neuromuscular blocking potency. The ester groups appear in one of two steric configurations true and reverse esters. In the true esters, oxygen is positioned between the nitrogen atom and the carbonyl group, while in the reverse esters it is positioned on the other side of the carbonyl group. True esters, suxamethonium and mivacurium, are hydrolysed by the enzyme plasma cholinesterase (butyrylcholinesterase), albeit at different rates. The more rapid degradation of suxamethonium is responsible for its fast onset and short duration of action in comparison with mivacurium. The reverse esters, atracurium, cisatracurium, and remifentanil, are hydrolysed by nonspecific esterases in plasma (carboxyesterases). Remifentanil is hydrolysed rapidly; the degradation leads to its inactivation and short duration of action. Cis-atracurium is preferentially degraded and inactivated by a process known as Hofmann elimination. In a second step, one of the degradation products, the monoester acrylate, is hydrolysed by a nonspecific esterase.     

Glomus vagale presenting as a supraclavicular mass: Magnetic resonance imaging findings

Glomus vagale are rare vascular tumours of the paraganglion cells of the vagus nerve, and they usually occur in the carotid space. Tumours can be familial, multicentric, malignant but rarely hormonally active. A rare case is reported of glomus vagale presenting as a supraclavicular mass.     

Conjoint bicondylar Hoffa fracture in an adult

Conjoint bicondylar Hoffa fracture is an extremely rare injury. Only one case has been reported previously in the pediatric age group. We describe this injury in a 17-year-old male who presented following a fall with direct impact on his semiflexed right knee. Plain radiographs were inadequate to define the exact pattern of injury. Computed tomographic (CT) scans demonstrated the coronal fracture involving both the femoral condyles which were joined by a bridge of intact bone. The patient was treated with open reduction and internal fixation using swashbuckler (modified anterior) approach. Union occurred within 3 months and at final followup (at 18 months) the patient had a good clinical outcome. The possible mechanism of injury is discussed.     

The emergence of resistance to targeted cancer therapeutics

Drug resistance has always been a concern in cancer treatment, often blamed on the genetic complexity and instability of tumor cells. While studies of cancer cell lines have implicated an array of potential mechanisms, it has been difficult to translate these insights into clinically meaningful improvements in cancer treatment. The successful deployment of molecularly targeted therapeutics in some cancers has led to widespread optimism that this approach will become broadly applicable. Despite their early promise in the clinic, the novel therapeutics are often plagued with the age old problem of acquired drug resistance. Progress in understanding why certain patients respond and why some develop resistance can be made rapidly through studies of the drug target in tumor tissue from patient. One important lesson is that many cancers, even in the most advanced stages, continue to rely on a limited number of critical oncogenic signals for maintenance of the malignant phenotype. This article reviews the mechanisms of drug resistance to a variety of cancer therapeutics and provides an approach for how measures of drug target activity can be incorporated into clinical trial design.     

Cardiac MRI in Congenital Heart Disease – Our Experience

A significant recent advance that has occurred world over in the continuously evolving field of Magnetic Resonance Imaging (MRI) practice is the introduction of Cardiac applications. Cardiac MRI has moved to the centre stage of clinical management strategy by non-invasively imaging the structure as well as function of the heart. It has a wide range of specific applications such as delineation of morphological anatomy, quantification of flow and pressure across cardiac valve dysfunction, evaluation of myocardial function, assessment of infarcts, mapping coronary arteries and so on. Evaluation of congenital heart disease (CHD) is an important application of Cardiac MRI since the morphological details of chambers, septum, defects and anomalous connections are depicted accurately. Besides, flow information across valves, chambers, outflow tracts and shunts are also provided. This article describes our experience in the use of cardiac MRI in congenital heart disease.Key Words: Cardiac MRI, Congenital heart disease, Cyanotic and Acyanotic heart disease     

Diät als Regulativ des Energiehaushaltes

Zusammenfassung Von allen Eingriffen in die Energiebilanz ist die Beschränkung der Kalorienzufuhr am wirksamsten. Die Möglichkeiten einer Voraussage über die mutmaßliche Gewichtsabnahme bei brennwertbeschränkten Diäten werden diskutiert. In der Praxis sind Berechnungen dieser Art so unübersehbar mit unvermeidlichen Fehlern behaftet, daß ihre Anwendung gegenstandslos ist. Brauchbare Statistiken über die Auswirkung kalorienknapper Kostformen sind spärlich, untereinander kaum vergleichbar. Hochgradiger Kalorienentzug über längere Zeit kann Fettsucht fast immer zum Schwinden bringen. Nur in Einzelfällen ist der Zwang zur Fetteinlagerung und Fixierung in den Depots so stark, daß jede Beeinflussung durch Herabsetzung der Nahrungszufuhr entfällt. Der gesundheitliche Nutzen einer erzwungenen Gewichtsabnahme kann durch erhebliche subjektive oder objektive Nachteile weit übertroffen werden. Die Minimalquoten der lebenswichtigen Nährstoffe müssen bei jeder Reduktionsdiät sichergestellt sein. Die Möglichkeiten, durch eine bestimmte Zusammensetzung der Kost Einfluß auf den Energiehaushalt zu nehmen, werden erörtert. Diäten, die eine spezifische Einwirkung auf den Energiestoffwechsel ausüben, sind nicht bekannt. Indirekte Einflüsse werden durch Dämpfung des Nahrungsdranges ausgeübt. Sehr verschiedene Kostformen können erfolgreich sein. Es wird begründet, daß relativ eiweißreiche, nicht zu fettarme, kohlenhydratbeschränkte Reduktionsdiäten zweckmäßig sind. Bestimmte Diätschemata haben in diesem weitgesteckten Rahmen keine speziellen Vorteile; die Kalorienzufuhr bleibt entscheidend. Die Regelung der Diät ist eine unersetzliche Voraussetzung zur Behandlung der Fettsucht. Sie ist aber nur ein Teilstück des Therapieplanes.

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Summary Of all the interventions in the balance of energy, the restriction of the supply of calories is the most efficacious one. The possibility of a prediction on the presumable decrease of weight on diets with a restricted combustion value is discussed. In practice, calculations of this kind are so much affected with inevitable faults that their application is of no use. Useful statistics on the effects of diets with a small proportion of calories are scarce and hardly comparable with one another. Extensive withdrawal of calories through a sufficiently long period of time may almost always cause obesity to disappear. Only in a few cases the pressure to store fat and to fix it in deposits is so strong that any influence by a decrease of the food supply fails to take place. The advantage to health of a forced decrease of weight may be by far exceeded by considerable subjective or objective disadvantages. The minimum quotas of vital nutritive material must be secured with every reductive diet. The possibilities of influencing the metabolism of energy by a certain composition of the diet are discussed. Diets which have a specific effect on the metabolism of energy are unknown. Direct influence is exercised by reducing the impulse to supply the body with food. Very different diets can be successful. It is reasonable to believe that reductive diets with a relatively large proportion of albumen, a not too small proportion of fat, and a restricted proportion of carbohydrates are useful. Certain dietary schemes are of no special advantage within this wide frame; the supply of calories is deciding. The regulation of the diet is an absolute supposition of the treatment of obesity. It is, however, only a part of the therapeutic plan.

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Résumé De toutes les interventions dans le bilan d'énergie, la restriction de la fourniture de calories est la plus efficace. La possibilité d'une prédiction concernant l'amaigrissement probable dans une diète restreinte en valeur de combustion est discutée. Dans la pratique, de tels calculs sont attachés, de manière incontrôlable, de fautes inévitables; donc leur application n'est pas importante. Des statistiques utilisables sur les effets de diètes pauvres en calories sont rares et à peine comparables entre elles. Le retrait de calories d'un haut degré pendant un temps assez long peut, presque toujours, faire disparaître l'obésité. Seulement dans quelques cas particuliers la pression d'accumuler de la graisse et de la fixer dans les dépôts est ainsi forte que toute influence par une diminution de la fourniture de nourriture manque d'avoir lieu. L'avantage pour la santé d'un amaigrissement forcé peut, de beaucoup, être excédé par des désavantages subjectifs et objectifs considérables. Les cotes minimum de matériel nutritif vital doivent être mises en sûreté dans toutes les diètes réduisantes. Les possibilités d'influencer le métabolisme d'énergie par une certaine composition de la diète sont discutées. Des diètes ayant un effet spécifique sur le métabolisme d'énergie sont inconnues. Il y a une influence directe par la réduction de l'impulsion du corps de se pourvoir d'aliment. Des diètes très différentes peuvent être couronnées de succès: C'est raisonnable de croire que des diètes réduisantes relativement riches en albumine, pas trop pauvres en graisse et restreintes en carbohydrates sont utiles. De certains schémas de diètes ne sont pas particulièrement avantageux au dedans de ce cadre large; la fourniture de calories est décidante. Le réglement de la diète est une supposition absolue du traitment de l'obésité. Pourtant, c'est seulement une partie du plan thérapeutique.