A view on imaging in drug research and development for respiratory diseases

With the incidence of respiratory diseases increasing throughout the world, new therapies are needed. This review provides a short overview of different imaging techniques of interest for drug discovery and development within the pulmonary disease area. The focus is on studies performed in both animals and humans, which are of importance for understanding pathophysiological aspects and evaluating new drugs. Rather than emphasizing particular lung diseases, the noninvasive diagnosis and quantification of a number of characteristics related to several pathological conditions of the lung are addressed: inflammation, mucus secretion and clearance, emphysema, ventilation, perfusion, fibrosis, airway remodeling, and pulmonary arterial hypertension. Techniques are discussed based on their present use or potential future utilization in the context of drug studies.     

High-resolution resonant and nonresonant fiber-scanning confocal microscope

We present a novel, hand-held microscope probe for acquiring confocal images of biological tissue. This probe generates images by scanning a fiber-lens combination with a miniature electromagnetic actuator, which allows it to be operated in resonant and nonresonant scanning modes. In the resonant scanning mode, a circular field of view with a diameter of 190 μm and an angular frequency of 127 Hz can be achieved. In the nonresonant scanning mode, a maximum field of view with a width of 69 μm can be achieved. The measured transverse and axial resolutions are 0.60 and 7.4 μm, respectively. Images of biological tissue acquired in the resonant mode are presented, which demonstrate its potential for real-time tissue differentiation. With an outer diameter of 3 mm, the microscope probe could be utilized to visualize cellular microstructures in vivo across a broad range of minimally-invasive procedures.     

Improved pharmacokinetic and pharmacodynamic profile of rapid-acting insulin using needle-free jet injection technology

OBJECTIVE

Insulin administered by jet injectors is dispensed over a larger subcutaneous area than insulin injected with a syringe, which may facilitate a more rapid absorption. This study compared the pharmacologic profile of administration of insulin aspart by jet injection to that by conventional insulin pen.

RESEARCH DESIGN AND METHODS

Euglycemic glucose clamp tests were performed in 18 healthy volunteers after subcutaneous administration of 0.2 units/kg body wt of aspart, either administered by jet injection or by conventional pen, using a randomized, double-blind, double-dummy, cross over study design. Pharmacodynamic and pharmacokinetic profiles were derived from the glucose infusion rate (GIR) needed to maintain euglycemia and from plasma insulin levels, respectively.

RESULTS

The time to maximal GIR was significantly shorter when insulin was injected with the jet injector compared with conventional pen administration (51 ± 3 vs. 105 ± 11 min, P < 0.0001). The time to peak insulin concentration was similarly reduced (31 ± 3 vs. 64 ± 6 min, P < 0.0001) and peak insulin concentrations were increased (108 ± 13 vs. 79 ± 7 mU/L, P = 0.01) when insulin was injected by jet injection compared with conventional pen injection. Jet injector insulin administration reduced the time to 50% glucose disposal by ∼40 min (P < 0.0001). There were no differences in maximal GIR, total insulin absorption, or total insulin action between the two devices.

CONCLUSIONS

Administration of insulin aspart by jet injection enhances insulin absorption and reduces the duration of glucose-lowering action. This profile resembles more closely the pattern of endogenous insulin secretion and may help to achieve better meal insulin coverage and correction of postprandial glucose excursions.Administration of insulin by jet injection is a needle-free alternative to conventional insulin administration with syringes or insulin pens. Jet injectors deliver insulin at a high velocity (typically >100 m/s) across the skin in the subcutaneous tissue and may dispense the insulin over a larger area than insulin injected with a syringe (1). This may enhance the efficiency with which insulin is absorbed from the subcutaneous compartment into the circulation so that the insulin peak can be advanced and the duration of (glucose-lowering) action reduced. Studies on jet injection technology for insulin administration date back to the 1960s (2). Most have suggested faster absorption of regular and NPH insulin when injected with a jet injector rather than with a syringe (3–8). Data on the use of jet injectors for the administration of rapid-acting insulin analogs are limited to one open-label study. In that study, peak insulin levels were reached in about half the time when lispro insulin was injected with a jet injector instead of a syringe. However, the glucose-lowering time-action profiles were not significantly different, the number of subjects examined was low (n = 4), and the dose of insulin tested was relatively high (30 units for all) (9).Although rapid-acting insulin analogs have clearly advanced glycemic treatment of type 1 and insulin-requiring type 2 diabetes, their pharmacological profile is still far from mimicking the profile of endogenous insulin release. Indeed, the time until insulin’s maximal glucose-lowering effect generally amounts to >90 min, and the duration of significant hyperinsulinemia often exceeds 3 hours (10–12). As a consequence, risks of (immediate) postprandial hyperglycemia and (late) postprandial hypoglycemia remain relatively high in many patients treated with rapid-acting insulin analogs. Faster absorption of insulin may reduce these risks and may provide a more physiological meal-time substitution of insulin. The aim of this study was therefore to compare the pharmacodynamic and pharmacokinetic profile of subcutaneous administration of the rapid-acting insulin analog aspart by jet injection to that of administration by conventional insulin pen in healthy individuals using the euglycemic glucose clamp technique (13). We chose to use an insulin pen as comparator because insulin pens may be more accurate than syringes (14) and are currently used by the vast majority of insulin-treated patients with diabetes in western Europe (15).     

A systemic framework for the progress test: Strengths, constraints and issues: AMEE Guide No. 71

There has been increasing use and significance of progress testing in medical education. It is used in many ways and with several formats to reflect the variety of curricula and assessment purposes. These developments have occurred alongside a recognised sensitivity for error variance inherent in multiple choice tests from which challenges to its validity and reliability have arisen. This Guide presents a generic, systemic framework to help identify and explore improvements in the quality and defensibility of progress test data. The framework draws on the combined experience of the Dutch consortium, an individual medical school in the United Kingdom, and the bulk of the progress test literature to date. It embeds progress testing as a quality-controlled assessment tool for improving learning, teaching and the demonstration of educational standards. The paper describes strengths, highlights constraints and explores issues for improvement. These may assist in the establishment of potential or new progress testing in medical education programmes. They can also guide the evaluation and improvement of existing programmes.     

Weight loss induced by tyrosine kinase inhibitors of the vascular endothelial growth factor pathway

Weight loss, cachexia and sarcopenia are profound problems in the frail oncologic patients. With the development and increasing use of angiogenesis inhibitors in metastatic cancer patients, the question arises as to their influence on body weight and composition. Angiogenesis is not only important for the growth, development and metastatic potential of tumors but also for physiological processes in adipogenesis. A less known approach of angiogenesis inhibitors is their experimental use in obese models. This review focuses on the effects on the body weight and composition of angiogenesis inhibitors, especially of those targeting the vascular endothelial growth factor pathway.     

To pee or not to pee: ammonia hypothesis of hepatic encephalopathy revisited

Hepatic encephalopathy is a neuropsychiatric syndrome associated with liver failure. Its aetiology has been debated for the past 100 years. Nevertheless, elevated ammonia levels are still believed to play a central role in its pathogenesis. After intestinal production, ammonia is detoxified by the liver. In liver failure, skeletal muscle and brain have been proposed to be alternative, although temporary, ammonia detoxifying organs. However, there is an increasing body of evidence that the kidney, in addition to the gut, is a pivotal organ determining systemic ammonia levels. In the last 20 years, it has been shown that the kidney can switch from an organ of systemic net ammonia production to a net ammonia excretion organ. The kidney plays a central role in the determination of ammonia levels. It is at least as important as the gut and could therefore serve as a target for new treatments for hepatic encephalopathy.     

Tenosynovitis caused by a pseudallescheria boydii infection and symptoms of reflex sympathetic dystrophy after a dog bite

Tenosynovitis caused by a Pseudallescheria boydii infection is an extremely rare complication after a dog bite and is easily misdiagnosed, leading to a delay in treatment. Careful history taking and adequate cultures can lead to a timely diagnosis, and longstanding antimycotic treatment can successfully eradicate the fungus.