Dipeptide monoester ganciclovir prodrugs for transscleral drug delivery: targeting the oligopeptide transporter on rabbit retina.

PURPOSE: The overall aim of this research work was to evaluate a series of dipeptide monoester prodrugs of an antiviral agent, ganciclovir (GCV), for oligopeptide transporter-targeted transscleral drug delivery to rabbit retina. METHODS: The permeability and enzymatic hydrolysis of dipeptide monoester GCV prodrugs were evaluated using freshly excized rabbit retinal pigment epithelium (RPE)-choroidsclera (RCS) and sclera tissue preparations. Affinity and transport mechanism of these prodrugs and their translocation across RCS were investigated through competitive inhibition studies of [(3)H]glycylsarcosine with the prodrugs. RESULTS: The transport of glycylsarcosine was found to be saturable (K(m) = 1.21 +/- 0.41 mM, V(max) = 15.89 +/- 1.54 pmoles/min/cm(2)), pH, temperature, and energy dependant. Dipeptides, angiotensin converting enzyme inhibitors, and a beta-lactum antibiotic strongly inhibited the transport of glycylsarcosine indicating the functional presence of oligopeptide transport (OPT) system on the RPE. Dipeptide prodrugs (valine-valine-GCV, glycine-valine-GCV, and tyrosine-valine-GCV), and valine-GCV demonstrate a high enzymatic stability and affinity toward the retinal OPT system. The transport of the prodrugs was significantly inhibited ( approximately 50%) in the presence of glycylsarcosine. The rank order of scleral permeability was Gly-Val-GCV approximately GCV>Val-GCV>Tyr-Val-GCV approximately Val-Val-GCV. The RCS permeability values of Val-GCV (3.29 +/- 0.09 x 10(6)cm/s), Val-Val-GCV (4.14 +/- 0.33 x 10(6)cm/s), Gly-Val-GCV (3.40 +/- 0.47 x 10(6)cm/s) and Tyr-Val-GCV (3.08 +/- 0.29 x 10(6)cm/s) were two-fold higher than that of GCV (1.61 +/- 0.06 x 10(6)cm/s). CONCLUSIONS: The dipeptide monoester GCV prodrugs, owning to higher lipophilicity and OPT-mediated translocation across RPE, appear to be promising candidates in the treatment of ocular cytomegalovirus infections following an episcleral administration.     

Economic evaluation of vaccination programmes: a consensus statement focusing on viral hepatitis

The methods that have been used to estimate the clinical and economic impact of vaccination programmes are not always uniform, which makes it difficult to compare results between economic analyses. Furthermore, the relative efficiency of vaccination programmes can be sensitive to some of the more controversial aspects covered by general guidelines for the economic evaluation of healthcare programmes, such as discounting of health gains and the treatment of future unrelated costs. In view of this, we interpret some aspects of these guidelines with respect to vaccination and offer recommendations for future analyses. These recommendations include more transparency and validation, more careful choice of models (tailored to the infection and the target groups), more extensive sensitivity analyses, and for all economic evaluations (also nonvaccine related) to be in better accordance with general guidelines. We use these recommendations to interpret the evidence provided by economic evaluation applied to viral hepatitis vaccination. We conclude that universal hepatitis B vaccination (of neonates, infants or adolescents) seems to be the most optimal strategy worldwide, except in the few areas of very low endemicity, where the evidence to enable a choice between selective and universal vaccination remains inconclusive. While targeted hepatitis A vaccination seems economically unattractive, universal hepatitis A vaccination strategies have not yet been sufficiently investigated to draw general conclusions.     

Predicting the reduction of parasitaemia following exchange transfusion in severe Plasmodium falciparum malaria: comparison of two mathematical formulae

Two mathematical models to predict the level of parasitaemia after exchange transfusion in severe malaria have been described. One formula, described by Wilkinson and colleagues, calculates the level from the total volume of blood exchanged whereas the other, derived by Van den Ende and colleagues, is recursive and gives estimates of the reduction in parasitaemia after each aliquot of exchange. The accuracies of predictions based on these two formulae were compared using data collected from 20 patients undergoing partial exchange transfusion (40 ml blood/kg body weight). The transfusions led to significant changes in the mean (S.D.) haemoglobin concentrations, which rose from 8.9 (2.4) to 10.1 (1.5) g/dl, and in the median levels of parasitaemia, which fell from 16.5% (interquartile range = 12.8%-28.8%) to 4.5% (interquartile range = 1.2%-9.3%). The median level of post-transfusion parasitaemia predicted by the Van den Ende formula (6.6%, with an interquartile range of 4.5%-10.2%) was similar to that observed, whereas that predicted by the Wilkinson formula (7.2%, with an interquartile range of 5.6%-12.4%) was significantly higher (P = 0.018). However, the median difference between the predictions based on the two formulae was represented by a parasitaemia of only 1.0% (interquartile range = 0.6%-1.85%). Thus, although the Van den Ende formula is more accurate than the Wilkinson, the difference is unlikely to be clinically significant.     

Lap-band failures: conversion to gastric bypass and their preliminary outcomes

BACKGROUND: The LAP-BAND is designed to be an adjustable laparoscopically placed gastric restriction device for the treatment of severe obesity. The purpose of this study was to assess the outcome in patients who had failed to effectively lose weight with this device and were converted to a gastric bypass. METHODS: A retrospective chart review was performed of all LAP-BANDS placed in patients at our institution from March 1996 to June 1998. RESULTS: 36 LAP-BANDS were placed. To date, 18 of 36 (50%) have been removed. Fourteen of 18 were simultaneously converted to a gastric bypass. Indications for conversion included: failed weight loss (5), failed weight loss with esophageal dilatation (5), failed weight loss with leaking band (2), and symptomatic esophageal dilatation (1). Median time to conversion after LAP-BAND placement was 38.2 months. Median follow-up after conversion to gastric bypass was 8.3 months. Nineteen percent excess weight loss occurred after LAP-BAND placement. Forty-three percent excess weight loss occurred after conversion to gastric bypass (P =.025). CONCLUSIONS: In our experience, the LAP-BAND is associated with a high frequency of inadequate weight loss. Conversion to gastric bypass in this subset of patients is technically challenging but results in superior weight loss in a shorter time period.     

Training in laparoscopic suturing skills using a new computer-based virtual reality simulator (MIST-VR) provides results comparable to those with an established pelvic trainer system

BACKGROUND: We hypothesized that the Minimally Invasive Surgery Trainer (MIST-VR; VP Medical R, London, U.K.) would be as effective as the Yale Laparoscopic Skills Course in improving laparoscopic intracorporeal suturing skills. MATERIALS AND METHODS: Each student made six attempts to tie a knot laparoscopically. Students were then randomized to train on the MIST-VR for five sessions (six skills/session) or the Yale Skills for five sessions (three skills/session) over 5 days. On completion of training, all students were evaluated by a test consisting of six attempts to tie a laparoscopic knot. RESULTS: The percentage improvement in knot tying time did not differ significantly in the pelvic trainer group (30 +/- 21%) (from 443 +/- 135 to 311 +/- 137 seconds) and the MIST-VR group (39 +/- 21%) (from 409 +/- 109 to 256 +/- 140 seconds) (P = 0.308). CONCLUSIONS: The MIST-VR is equivalent to the Yale Skills Course for training in the advanced laparoscopic skill of intracorporeal suturing.     

Pigmented villonodular synovitis: magnetic resonance features of an unusual case of bilateral hip joint involvement

Pigmented villonodular synovitis (PVNS) is usually a mono-articular disorder. Bilateral symmetrical affection of this disease process is exceptional. A case is reported of a patient with PVNS with bilateral, symmetrical hip joint involvement.     

Antiemetic efficacy of prophylactic dimenhydrinate (Dramamine) vs ondansetron (Zofran)

BACKGROUND: The prophylactic administration of dimenhydrinate (Dramamine) is as effective as the use of ondansetron (Zofran) in preventing postoperative nausea and vomiting (PONV) in patients undergoing elective laparoscopic cholecystectomy. A prospective double-blind randomized study was performed in a tertiary care referral center. METHODS: For this study, 128 American Society of Anesthesiology (ASA) physical statuses I, II, and III patients were randomly assigned to receive either ondansetron 4 mg intravenously (IV) at $17 per dose (group 1) or dimenhydrinate 50 mg IV at $2.50 per dose (group 2) before induction of anesthesia. The end points evaluated were frequency of PONV, need for rescue antiemetics, need for overnight hospitalization secondary to persistent nausea and vomiting, and frequency PONV 24 h after discharge. RESULTS: Chi-square tests and student's t-test were used to determine the significance of differences among groups. Of the 128 patients enrolled in this study, 20 were excluded: 15 patients received an additional antiemetic preoperative; 4 were converted to open cholecystectomies; and 1 procedure was aborted due to carcinomatosis. Of the 108 remaining participants, 50 received ondansetron (group 1) and 58 received dimenhydrinate (group 2). Both groups were well matched for demographics including gender, ASA class, and history of motion sickness. The need for rescue antiemetics occurred in 34% of group 1 and 29% of Group 2 (p = 0.376), postoperative vomiting in 6% of group 1 and 12% of group 2 (p = 0.228), and postoperative nausea in 42% of group 1 and 34% of group 2 (p = 0.422). One group 1 patient and two group 2 patients required overnight hospitalization for persistent nausea, a difference that was not significant. Rates of PONV 24 h after discharge were similar between groups 1 and 2 (10% vs 14%, p = 0.397 and 2% vs 5%, p = 0.375, respectively). CONCLUSIONS: Prophylactic administration of dimenhydrinate is as effective as the use of ondansetron in preventing PONV in patients undergoing elective laparoscopic cholecystectomy. Dimenhydrinate is the preferred drug because it is less expensive. With more than 500, 000 laparoscopic cholecystectomies performed in the United States each year, the potential drug cost savings from the prophylactic administration of dimenhydrinate instead of ondansetron exceed $7.25 million per year.     

Human sperm immobilization effect of Carica papaya seed extracts： an in vitro study

AIM: To examine if the seed extracts of Carica papaya, which showed antispermatogenic/sperm immobilization properties in animal models, could cause human sperm immobilization in vitro. METHODS: Chloroform extract, benzene chromatographic fraction of the chloroform extract, its methanol and ethyl acetate sub-fractions and the isolated compounds from the sub-fractions i.e., ECP 1 & 2 and MCP 1 &2, of the seeds of Carica papaya were used at concentrations of 0.1%, 0.5%, 1% and 2%. Sperm motility was assessed immediately after addition of extracts and every 5 minutes thereafter for 30 minutes. RESULTS: There were dose-dependent spermicidal effects showing an instant fall in the sperm motility to less than 20% at 2% concentration. Isolated compounds ECP 1 & 2 were more effective inducing a motility of less than 10%. Many of the spermatozoa became vibratory on the spot. Total inhibition of motility was observed within 20-25 min at all concentrations of all products. Scanning and transmission electron microscopy revealed deleterious changes in the plasma membrane of the head and mid-piece of spermatozoa. Sperm viability test and the number of abnormal spermatozoa after completion of incubation suggested that the spermatozoa were infertile. The effects were spermicidal but not spermiostatic as revealed by the sperm revival test. CONCLUSION: The results reveal spermicidal activity in vitro of the seed extracts of Carica papaya.     

Tc-99m and Re-186 complexes of tetraphosphonate ligands and their biodistribution pattern in animal models

The syntheses of four alpha-aminomethyl phosphonates and their complexation studies with (99m)Tc and (186/188)Re are reported. Complexation conditions were standardized to give maximum yields, which ranged from 90-97%. The yields of complexation were estimated by paper chromatography. The (99m)Tc complexes were stable for more than 4 h, while the (186/188)Re complexes were stable for 3-8 days when stored at 4 degrees C. Biodistribution of these complexes in Wistar rats were carried out, and the uptake in bone and other soft tissue are detailed. Bone uptake of the (99m)Tc complexes varied from 40-60% at 30 min postinjection depending on the ligands. The uptake in soft tissue was minimum with all the complexes. A comparison of the biodistribution studies of the (99m)Tc complexes with that of the well-established radiopharmaceutical (99m)Tc-MDP was carried out for the purpose of evaluating the efficacy of the radiopharmaceutical preparation with the complexes of these ligands. The bone uptake of the (186/188)Re complexes varied from 19-28% corresponding to 1.6-3% per g at 3 h postinjection. The residual activity in both (99m)Tc and (186/188)Re complexes showed renal clearance.