Response surface methodology for the development of self-nanoemulsified drug delivery system (SNEDDS) of all-trans-retinol acetate

The purpose was to prepare, characterize, and optimize a self-nanoemulsified drug delivery system (SNEDDS) of a model lipophilic compound, all-trans-retinol acetate. As part of the optimization process, the main effects, interaction effects, and quadratic effects of the formulation ingredients were investigated. METHOD: A three-factor, three-level Box-Behnken design was used to explore the quadratic response surfaces and construct a second-order polynomial model in the form: Y = A + A1X1 + A2X2+ A3X3 + A4X1X2 + A5X2X3 + A6X1X3+ A7X1(2) + A8X2(2) + A9X3(2) + E. Amount of added oil (X1), surfactant (X2), and cosurfactant (X3) were selected as the factors. Particle size (Y1), turbidity (Y2), and cumulative amount of the active ingredient emulsified after 10 (Y3) and 30 (Y4) min were the observed variables. Response surface plots were used to demonstrate the effect of factors (X1), (X2), and (X3) on the response (Y4). Amount of added soybean oil (X1), Cremophor EL (X2), and Capmul MCM-C8 (X3) showed a significant effect on the emulsification rates, as well as on the physical properties of the resultant emulsion (particle size and turbidity). Observed and predicted values of Y4 obtained from the constructed equations were in close agreement. Response surface methodology was then used to predict the levels of factors X1, X2, and X3 under the constrained variables for an optimum response. Applied constraints were 0 < Y1 < 0.5, 1 < Y2 < 20, 60 < Y3 < 80, and 90 < Y4 < 100. The predicted values were 0.0704 microm for particle size (Y1), 18.95 NTU for turbidity (Y2), 88.88% for drug release after 10 min (Y3), and 110.7% drug release after 30 min (Y4). Two new formulations were prepared according to the predicted levels. The observed and predicted values were in close agreement.     

Oral delivery of mono-PEGylated sCT (Lys18) in rats: regional difference in stability and hypocalcemic effect

In the in vitro experiment using a luminal, mucosal, and fecal fluid/extract from jejunum and colon of a rat, Lys18-residue modified mono-PEG(2k)-sCT (Lys18-PEG(2K)-sCT) exhibited a longer half-life than salmon calcitonin (sCT) in a colonic fluid and its extract. A physical adsorption study showed that Lys18-PEG(2K)-sCT had lower adsorption in the feces than sCT over an 8-hr period. An absorption study of the sCT and Lys18-PEG(2K)-sCT from the jejunum and colon using an in situ closed-loop technique in anesthetized rats showed a dose-dependent reduction in the plasma Ca2+ level but to a certain limit. Furthermore, the hypocalcemic response by intracolonic administration was significantly higher than the intrajejunal one, demonstrating that the colon had better absorption. In particular, Lys18-PEG(2K)-sCT (5 microg/rats) produced the most pronounced hypocalcemia after the intracolonic administration, which resulted in a sustained reduction in the serum calcium level over an 8-hr period, with a maximum reduction (% max(d)) of 38% after 4 hr. The overall reduction in the serum calcium levels, which was expressed as the net change in the AUC relative to the control over an 8-hr period, was 25.51 +/- 3.38 for Lys18-PEG(2K)-sCT. The relative pharmacological bioavailability of the intracolonically administered Lys18-PEG(2K)-sCT was 2.1-fold higher than sCT and the absolute pharmacological bioavailability was 73.59% of i.v.-injected sCT in an 8-hr period. Overall, this study highlights the feasibility of the oral delivery of Lys18-PEG(2K)-sCT in achieving a sustained calcium-lowering effect.     

Two randomised phase II trials of subcutaneous interleukin-2 and histamine dihydrochloride in patients with metastatic renal cell carcinoma

Histamine inhibits formation and release of phagocyte-derived reactive oxygen species, and thereby protects natural killer and T cells against oxidative damage. Thus, the addition of histamine may potentially improve the efficacy of interleukin-2 (IL-2). Two randomised phase II trials of IL-2 with or without histamine dihydrochloride (HDC) in patients with metastatic renal cell carcinoma (mRCC) were run in parallel. A total of 41 patients were included in Manchester, UK and 63 in Aarhus, Denmark. The self-administered, outpatient regimen included IL-2 as a fixed dose, 18 MIU s.c. once daily, 5 days per week for 3 weeks followed by 2 weeks rest. Histamine dihydrochloride was added twice daily, 1.0 mg s.c., concomitantly with IL-2. A maximum of four cycles were given. The Danish study showed a statistically significant 1-year survival benefit (76 vs 47%, P = 0.03), a trend towards benefit in both median survival (18.3 vs 11.4 months, P = 0.07), time to PD (4.5 vs 2.2 months, P = 0.13) and clinical benefit (CR + PR + SD) (58 vs 37%, P = 0.10) in favour of IL-2/HDC, whereas the UK study was negative for all end points. Only three patients had grade 4 toxicity; however, two were fatal. A randomised phase III trial is warranted to clarify the potential role of adding histamine to IL-2 in mRCC.     

L-arginine supplementation enhances exhaled NO, breath condensate VEGF, and headache at 4,342 m

We examined the effect of dietary supplementation with L-arginine on breath condensate VEGF, exhaled nitric oxide (NO), plasma erythropoietin, symptoms of acute mountain sickness, and respiratory related sensations at 4,342 m through the course of 24 h in seven healthy male subjects. Serum L-arginine levels increased in treated subjects at time 0, 8, and 24 h compared with placebo, indicating the effectiveness of our treatment. L-arginine had no significant effect on overall Lake Louise scores compared with placebo. However, there was a significant increase in headache within the L-arginine treatment group at 12 h compared with time 0, a change not seen in the placebo condition between these two time points. There was a trend (p = 0.087) toward greater exhaled NO and significant increases in breath condensate VEGF with L-arginine treatment, but no L-arginine effect on serum EPO. These results suggest that L-arginine supplementation increases HIF-1 stabilization in the lung, possibly through a NO-dependent pathway. In total, our observations indicate that L-arginine supplementation is not beneficial in the prophylactic treatment of AMS.     

Management of difficult intubation in a patient with ankylosing spondylitis--a case report

We describe a case of difficult intubation in a patient suffering from ankylosing spondylitis undergoing total hip replacement surgery. The anesthetic management of 42 year old patient with difficult airway is discussed. Failure of epidural anesthesia procedure necessitated general anesthesia. The problems of performing awake fibreoptic intubation and other alternative techniques to secure the airway are described. Cervical spine involvement in ankylosing spondylitis is of great concern for the anesthetist. Longstanding progressive course of this disease leads to fibrosis, ossification and ankylosis of entire spine and sacroiliac joints. Cervical spine mobility is decreased and in severe cases total fixity occurs in a flexed position. Patient may also have atlanto-occipital and temporo-mandibular joint involvement as well. Cricoarytenoid cartilages involvement may result in upper airway compromise. Furthermore cervical spine vertebrae are prone to fractures, especially on hyperextension and may lead to spinal cord transection and quadriplegia. In this case report we describe the airway management of such patient with fixed rigidity of cervical spine and thoracolumbar kyphosis.     

Acquired hepatocerebral degeneration in hepatitis C infection

Patients with chronic liver disease (CLD) often have neurological sequelae, of which hepatic encephalopathy is the most frequent and reversible. Rare irreversible complications of CLD are acquired (non Wilsonian) hepatocerebral degeneration (AHCD) and hepatic myelopathy (HM). To our knowledge, AHCD has rarely been reported in patients with hepatitis C virus (HCV) infection. We report a patient with HCV infection who developed AHCD and resulted in serious complications.     

Gossypiboma in the early postoperative period: computed tomography appearance

Recognition of postoperatively retained foreign body, referred euphemistically as gossypiboma, is essential but is very often considerably delayed. Legal implications as well as confusing configuration patterns cause considerable dilemma in the accurate diagnosis. A good understanding of the radiological appearances of this foreign body helps in appropriate early management of such patients. We present computed tomographic features of gossypiboma in patient who presented with symptoms of fever and pain in the immediate postoperative period.     

Surgical skill is predicted by the ability to detect errors

BACKGROUND: Objective analysis methods of surgical performance are now available so comparison between surgeons is available. One such method is by direct observation using the Objective Structured Assessment of Technical Skills (OSATS), but this is a time-consuming process; therefore, a simple screening tool for the ability to detect errors (previously validated) was analyzed and considered as a predictor of qualitative performance. METHODS: Thirty-eight volunteer surgeons were recruited to the skills laboratory to undertake 3 exercises. Two were bench-top surgical tasks that were scored using the global rating of the OSATS technique. The third task was the ability to detect simple errors in 22 synthetic models of common surgical procedures, some of which contained purposefully made errors. P<.05 was deemed to be statistically significant. RESULTS: The scores (interquartile ranges in parentheses) for the 3 sections were excision of sebaceous cyst=21 (19,24), closure of small bowel enterotomy=23 (21,27), and identification of errors=31 (27,34). Three scorers blinded to the operative models exhibited an interobserver reliability of .9 and .91 for the video tasks, respectively. Spearman's rank correlations between the error examination and performance on the 2 tasks were both statistically significant at .69 (cystectomy) and .54 (enterotomy). CONCLUSIONS: The ability to detect simple surgical errors is a predictor of technical skill and performance of bench tasks. What must be answered is whether the use of such models and principles can shorten the qualitative surgical learning curve.