Immune response to xenobiotics in the skin: from contact sensitivity to drug allergy

Skin is the most frequent target of adverse drug reactions. These cutaneous drug reactions (CDRs) show varied clinical manifestations ranging from mildly discomforting rashes to life-threatening Stevens-Johnson syndrome or toxic epidermal necrolysis. Most CDRs appear to be immune mediated, although the mechanism by which they are initiated remains unclear. In this review, current knowledge of the mechanisms by which xenobiotics provoke immune responses in the skin after epicutaneous administration and how similar reactions may occur after systemic routes are summarised. This review also discusses a variety of genetic or environmental factors that may determine the susceptibility of individuals towards immune responses in skin following drug exposure.     

Single-dose dexamethasone induces whole-body insulin resistance and alters both cardiac fatty acid and carbohydrate metabolism

Glucocorticoids impair insulin sensitivity. Because insulin resistance is closely linked to increased incidence of cardiovascular diseases and given that metabolic abnormalities have been linked to initiation of heart failure, we examined the acute effects of dexamethasone (DEX) on rat cardiac metabolism. Although injection of DEX for 4 h was not associated with hyperinsulinemia, the euglycemic-hyperinsulinemic clamp showed a decrease in glucose infusion rate. Rates of cardiac glycolysis were unaffected, whereas the rate of glucose oxidation following DEX was significantly decreased and could be associated with augmented expression of PDK4 mRNA and protein. Myocardial glycogen content in DEX hearts increased compared with control. Similar to hypoinsulinemia induced by streptozotocin (STZ), hearts from insulin-resistant DEX animals also demonstrated enlargement of the coronary lipoprotein lipase (LPL) pool. However, unlike STZ, DEX hearts showed greater basal release of LPL and were able to maintain their high heparin-releasable LPL in vitro. This effect could be explained by the enhanced LPL mRNA expression following DEX. Our data provide evidence that in a setting of insulin resistance, an increase in LPL could facilitate increased delivery of fatty acid to the heart, leading to excessive triglyceride storage. It has not been determined whether these acute effects of DEX on cardiac metabolism can be translated into increased cardiovascular risk.     

Prostaglandin E(2) promotes colorectal adenoma growth via transactivation of the nuclear peroxisome proliferator-activated receptor delta

Cyclooxygenase-derived prostaglandin E(2) (PGE(2)) is the predominant prostanoid found in most colorectal cancers (CRC) and is known to promote colon carcinoma growth and invasion. However, the key downstream signaling pathways necessary for PGE(2)-induced intestinal carcinogenesis are unclear. Here we report that PGE(2) indirectly transactivates PPARdelta through PI3K/Akt signaling, which promotes cell survival and intestinal adenoma formation. We also found that PGE(2) treatment of Apc(min) mice dramatically increased intestinal adenoma burden, which was negated in Apc(min) mice lacking PPARdelta. We demonstrate that PPARdelta is a focal point of crosstalk between the prostaglandin and Wnt signaling pathways which results in a shift from cell death to cell survival, leading to increased tumor growth.     

Value of Fentanyl in Flexible Sigmoidoscopy

Studies have recorded significant patient discomfort during flexible sigmoidoscopy when it is performed without sedation/analgesia. This study observed whether a single dose of 50 mcg intravenous fentanyl reduces pain, improving compliance, acceptability, and completion rates. In a prospective study, 109 consecutive patients were offered the option of 50 mcg intravenous fentanyl or no analgesia. Patients pre-procedure expectations, objective pain scores, and willingness to undergo a subsequent procedure using the same technique were recorded. Endoscopist recorded the success, complications, and objective pain scores for each patient. Of the 46 patients (42%) choosing fentanyl, 9 (20%) experienced moderate/severe pain as against 26(41%) of the 63 patients (58%) opting for no analgesia (p < 0.05). Further, 52% receiving fentanyl had a significantly better experience compared to their pre-procedure expectations as against 33% who received no analgesia (p < 0.05). No patient receiving fentanyl expressed unwillingness to undergo the procedure again using the same technique, whereas 16 (25%) of those receiving no analgesia indicated they would not (p < 0.01). Endoscopists recorded moderate/severe pain in 13 patients (12%), whereas 35 patients (32%) recorded moderate/severe pain (p < 0.001). Analgesia for endoscopy should involve patient choice. However, a single dose of 50 mcg fentanyl reduced patient discomfort and improved satisfaction. It appeared safe and likely to improve patient compliance and acceptability for flexible sigmoidoscopy.