Effect of prostaglandin E1 infusion on leukocyte traffic and fibrosis in acute lung injury induced by bleomycin in hamsters.

OBJECTIVE: To determine whether the iv infusion of prostaglandin E1 (PGE1) could modify the early influx of neutrophils into bleomycin-injured lungs and if that would affect subsequent development of inflammation and fibrosis. BACKGROUND AND METHODS: In vivo controlled animal study performed in a university hospital pulmonary research laboratory. Male Syrian golden hamsters (100- to 110-g body weight) were divided into four treatment groups: a) No treatment; b) intratracheal bleomycin plus PGE1 infusion; c) bleomycin plus saline infusion; d) PGE1 infusion only. PGE1 (180 ng/hr.100 g) or saline were infused iv 3 to 25 hr after intratracheal instillation of bleomycin sulfate (0.5 U/0.5 mL.100 g). Total and differential counts of cells recovered by lavage, lavage fluid protein, and lung total protein and hydroxyproline levels were measured from 6 hr to 30 days later. RESULTS: PGE1 infusion reduced the influx of neutrophils 6 hr after bleomycin injury by 53% compared with saline infusion (p less than .0001), but increased inflammatory cell traffic after 24 hr for 15 days. At 4 days, protein recovered in lung lavage fluid was also decreased in PGE1-treated, bleomycin-injured animals, reflecting reduced injury to lung permeability barriers. Accumulation of lung collagen in the PGE1-treated, bleomycin-instilled hamsters tended to be lower than in the bleomycin-injured, saline-infused group at 15 and 30 days, although these differences did not achieve statistical significance. Despite this fact, greater than 33% of the animals in the PGE1-treated group died, possibly indicating an increased risk of sepsis in these animals. CONCLUSIONS: PGE1 infusion can decrease early neutrophil traffic and reduce injury to the lung permeability barriers. However, this treatment augments late inflammatory events and does not significantly alter the development of fibrosis.     

Exenatide.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and dosage and administration of exenatide are discussed. SUMMARY: Exenatide, derived from a compound found in the saliva of the Gila monster, is an incretin mimetic agent that enhances glucose-dependent insulin secretion and has several other antihyperglycemic actions. The drug is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus who are taking metformin, a sulfonylurea, or both but who have not achieved adequate glycemic control. Peak plasma concentration following subcutaneous administration of exenatide is attained in 2.1 hours. The mean apparent volume of distribution after administration of a single subcutaneous dose is 28.3 L. The terminal half-life of the drug is 2.4 hours. Based on animal studies, the bioavailability of exenatide after subcutaneous injection has been estimated to be between 65% and 75%. The drug is predominantly eliminated by glomerular filtration followed by proteolytic degradation. Clinical trials have shown that exenatide given subcutaneously twice daily significantly reduced glycosylated hemoglobin values when maximum doses of a sulfonylurea, metformin, or both were ineffective. The most common adverse effects are nausea, vomiting, diarrhea, jitteriness, dizziness, headache, and dyspepsia. Drug-drug interactions with digoxin, lovastatin, lisinopril, and acetaminophen have been documented. The recommended starting dosage is 5 microg subcutaneously twice daily within one hour before the morning and evening meals. CONCLUSION: Exenatide offers a novel treatment option for patients with type 2 diabetes mellitus who are refractory to metformin or sulfonylurea therapy or both.     

The dietary lysine requirement of juvenile hybrid striped bass.

Two experiments were conducted to determine the dietary lysine requirement of juvenile hybrid striped bass (Morone saxatilis x M. chrysops). In both experiments the diets contained 35 g crude protein/100 g diet (10 g crude protein supplied by casein and gelatin and 25 g crude protein supplied by crystalline L-amino acids) and contained graded levels of L-lysine.HCl resulting in eight dietary treatments. Diets were fed to triplicate groups of fish and ranged in dietary lysine concentration from 1.2 to 2.6 g/100 g of the dry diet in Experiment 1 and from 0.8 to 2.2 g/100 g of the dry diet in Experiment 2. Weight gain and food efficiency data from Experiment 1 indicated the dietary lysine requirement to be between 1.2 and 1.4 g/100 g of the dry diet. Weight gain, food efficiency and serum lysine data from Experiment 2 confirmed the requirement to be between 1.2 and 1.4 g/100 g of the dry diet. Broken-line analysis of weight gain and food efficiency data from Experiment 2 indicated the dietary lysine requirement to be 1.4 +/- 0.2% of the dry diet, or 4.0 g/100 g of the dietary protein. Changes in the relative proportions of dietary lipid and carbohydrate between the two experiments, although maintaining similar gross energy levels, did not alter the lysine requirement estimate of juvenile hybrid striped bass.     

Photodynamic therapy of normal rat arteries after photosensitisation using disulphonated aluminium phthalocyanine and 5-aminolaevulinic acid.

Photodynamic therapy of cancer exposes adjacent arteries to the risk of injury and the possibility of haemorrhage and thrombosis. The nature of photodynamic injury to normal arteries has not been satisfactorily defined, and the ability of arteries to recover with time is unclear. To clarify these issues, we have investigated the effects of PDT on rat femoral arteries, using a second-generation photosensitiser, disulphonated aluminium phthalocyanine, and a new method of photosensitisation, using endogenous synthesis of protoporphyrin IX following systemic administration of 5-aminolaevulinic acid (ALA). Pharmacokinetic studies of sensitiser fluorescence were carried out to determine peak levels of sensitiser. Subsequently photodynamic therapy at times corresponding to maximal fluorescence was performed using two light doses, 100 and 250 J cm-2. The nature of injury sustained and recovery over a 6 month period was investigated. Three days following PDT, all vessels treated showed complete loss of endothelium, with death of all medial smooth muscle cells, leaving an acellular flaccid artery wall. No vascular occlusion, haemorrhage or thrombosis was found. A striking feature was the lack of inflammatory response in the vessel wall at any time studied. Re-endothelialisation occurred in all vessels by 2 weeks. The phthalocyanine group showed repopulation of the media with smooth muscle cells to be almost complete by 3 months. However, the ALA group failed to redevelop a muscular wall and remained dilated at 6 months. Luminal cross-sectional area of the ALA-treated group was significantly greater than both control and phthalocyanine groups at 6 months. All vessels remained patent. This study indicates that arteries exposed to PDT are not at risk of catastrophic haemorrhage or occlusion, a finding that is of significance for both the local treatment of tumours and the use of PDT as an intraoperative adjunct to surgery for the ablation of microscopic residual malignant disease.     

Symptoms, diagnosis and endoscopic management of common bile duct stones

Symptomatic BDS commonly cause significant morbidity and attempt at stone removal should be attempted if possible. Complications of CBDS include biliary colic, jaundice, cholangitis and pancreatitis. Investigations aimed to predict the presence of stones within the bile duct include serum bilirubin, AST, ALP, common bile duct diameter and age as independent predictors of choledocholithiasis. TUS is a sensitive test in detecting bile duct dilatation but the sensitivity is reduced in its ability to detect choledocholithiasis. A NIH consensus statement found that ERC, MRC and EUS were comparable in their sensitivities, specificities and accuracy rates for detection of choledocholithiasis. ERC and stone removal using a balloon or basket is often performed following EST. EBD may be performed if patients have uncorrected coagulopathies but the risk of pancreatitis is higher than for EST (although the risk of bleeding complications is lower for EBD). ML is often required in difficult to remove CBDS and using this device, CBDS can be removed in 90–95% of cases. Other forms of lithotripsy including laser lithotripsy and EHL are confined to specialised centres and the evidence for their use is based on small studies. ESWL may clear stones from the bile duct in up to 93% of patients but frequently ERC and stone fragment removal is required post ESWL. The role of medical therapy in difficult to remove CBDS (or in CBDS in patients with severe co-morbid illness preventing ERC + stone removal) is still currently uncertain due to a lack of large randomised control trials.