Tolerability of N-chlorotaurine plus ammonium chloride in the rabbit and human eye - a phase 1 clinical study

Background  N-chlorotaurine (NCT), an endogenous mild antiseptic, is well-tolerated by application to the human conjunctiva and has been shown to offer beneficial effects in infectious conjunctivitis. Animal tests revealed improved efficacy of a combination of NCT with ammonium chloride in adenoviral conjunctivitis. The aim of this study was to evaluate the tolerability of NCT plus ammonium chloride in the healthy rabbit and human eye. Methods  First, a tolerability study was performed in rabbits. In a blinded and randomized fashion, one eye was treated with the test medication, the other one with 0.9% saline. Twenty-one animals (three per concentration) were treated with one drop every 2 hours for 6 days. Second, in two volunteers one drop of a defined concentration was applied to one eye every 15 min for 1 hour, saline to the control eye. Four different concentrations were tested on different days. Third, a double-blind, randomized phase 1 study in 13 healthy volunteers was performed. One drop of 0.1% NCT plus 0.1% NH₄Cl versus saline was applied every 15 min within the first hour, followed by four drops every 2 hours. This regimen was done daily for 5 days. Results  In rabbits, no side effects were seen with 0.1% NCT plus 0.1% NH₄Cl, while higher concentrations sometimes caused short-time and minimal conjunctival injection and secretion after dosing. By 1% NCT plus 1% NH₄Cl, these effects were moderate, but disappeared again without any detectable residues. In the pilot study with two volunteers, treatment with 0.5% NCT plus 0.1% NH₄Cl caused medium-scale eye burning for 30 seconds, while 0.1% NCT plus 0.1% NH₄Cl was very well-tolerated, with no or minimal burning for a few seconds. In the subsequent phase 1 study, 0.1% NCT plus 0.1% NH₄Cl was well-tolerated by all subjects except for minimal eye burning for a few seconds after dropping. No objective signs of eye changes could be detected in the human beings. Conclusion  The results of this study clearly demonstrate the good tolerability of a promising NCT formulation with improved activity.     

Voiding cystourethrography using the suprapubic versus transurethral route in infants and children: results of a prospective pain scale oriented study

PURPOSE: We determined the advantages and disadvantages of different types of contrast medium injection into the bladder for imaging children during evaluation for urinary tract infection in regard to child behavior and distress during urethral catheterization or suprapubic puncture. MATERIALS AND METHODS: From December 2000 to September 2001 we prospectively compared transurethral catheter and suprapubic voiding cystourethrography in children with a history of urinary tract infection. A total of 65 children with a mean age of 33.8 months were entered into the study, of whom 32 underwent transurethral catheterization and 33 underwent suprapubic puncture with topical anesthesia. Each child was evaluated, particularly in regard to discomfort and pain using an objective pain score that measures stress and pain during a medical procedure. RESULTS: Objective pain score recording showed a mean pain score plus or minus SD of 4.25 +/- 1.3 in the transurethral catheterization and 3.03 +/- 1.21 in the suprapubic puncture groups. Correlation studies of age in the 2 groups also showed a significant impact of age on the objective pain score. In the transurethral group the score increased with age (p <0.001), whereas in the suprapubic group it decreased with age (p <0.001). CONCLUSIONS: The current study shows that the suprapubic puncture technique with topical anesthesia was well tolerated and associated with a low pain score independent of patient age. Transurethral catheterization was also tolerated but it was associated with a low pain score only in the younger age group. Thus, we recommend that voiding cystourethrography in children older than 24 months should be done via the suprapubic route.     

Repeated transurethral resection of recurrent superficial bladder tumors--does it affect the spread and stage of the tumor?

OBJECTIVES: This prospective study was done to demonstrate the effect of repeated resection of superficial bladder tumors (TURT) on deep malignant cell infiltration in bladder wall. MATERIAL AND METHODS: Thirty-six patients underwent radical cystectomy for invasive bladder cancer, 16 patients originally had superficial cancer that became invasive after repeated TURT (group I) and the other 20 patients (group II) presented with invasive bladder cancer from the start. Each cystectomy specimen was subjected to a thorough histopathological study. RESULTS: There was a statistically significant difference in pattern of local spread of malignant cells between the two groups. Isolated clusters of malignant cells in-between normal bladder muscle fibers, isolated subserosal malignant deposits as well as cells reaching the adjacent cervix uteri were found only in group I. Intravesical pressure was measured in another 10 patients during TURT and was found to be high reaching up to 80 cm H2O. CONCLUSIONS: We conclude that some malignant cells penetrate through the denuded urothelium during TURT by the effect of high intravesical pressure. This may be responsible, among other factors, for tumor recurrence with deeper stages.     

Impact of cardiac surgery using cardiopulmonary bypass on course of chronic lymphatic leukemia: a case-control study

BACKGROUND: Chronic lymphatic leukemia (CLL) is a common disease among elderly individuals. The number of older patients undergoing operations with cardiopulmonary bypass (CPB) is increasing. The aim of the present study was to evaluate the impact of cardiac surgery using CPB on the long-term course of CLL. METHODS: From 1992 to 2000, a total of 28 patients with CLL underwent heart surgery using CPB at our institution (group I). These patients were compared with 25 patients from the CLL register who were retrospectively matched with regard to preoperative administration of chemotherapy, Binet classification, age, and sex (group II). A time-point was selected for each patient in group II so that the variables for the two groups corresponded in relation to the time of operation of the patients in group I. Midterm follow-up data in both groups were analyzed. RESULTS: There were no differences between groups regarding matched variables. The mean follow-up time was similar in both groups (2.6 +/- 2.2 vs 2.3 +/- 1.3 years, p > 0.5). The 30-day mortality in group I was 14.3%. The mean stay in the intensive care unit was 4.2 +/- 7.5 days; the median number of units of packed red blood cells transfused was three (range 0 to 17). Compared with group II, in group I significantly fewer patients (11 vs 17, p = 0.049) required chemotherapy significantly later (1.98 +/- 2.06 vs 0.84 +/- 1.18 years, p = 0.018). During follow-up, no difference was found between groups regarding severe infections (10 vs 14, p = 0.14). Despite postoperative mortality in group I, the long-term mortality was similar in both groups (p = 0.3). CONCLUSIONS: Cardiac surgery using CPB did not have a negative impact on the natural course of CLL. Moreover, this procedure seems to be associated with a decrease in the number of postoperative chemotherapy administrations and with an increase of chemotherapy-free survival time. Although CLL may be a risk factor in the early postoperative period, it is not a contraindication for cardiac surgery using CPB.     

Hepatic metastases in patients with colorectal cancer: relationship between size of metastases,standard of reference,and detection rates

PURPOSE: To determine the relationship between the size of hepatic metastases, the standard of reference, and the reported detection rate in patients with colorectal cancer. MATERIALS AND METHODS: With use of a MEDLINE search (January 1994 to January 2001), articles were selected that contained original results on detection of hepatic metastases of colorectal cancer, categorized for size in at least two categories, with use of helical computed tomography (CT), helical CT at arterial portography, or magnetic resonance imaging. Results were compared with the size distribution of hepatic metastases in 47 consecutive patients with colorectal carcinoma, which were detected by using a combination of intraoperative ultrasonography (US) and palpation. RESULTS: Seven studies met all predefined criteria. Four studies involved intraoperative US in all patients and demonstrated a significant negative correlation (-0.988) between detection rate and fraction of small metastases. These studies had a higher fraction and lower detection rate of small metastases and a lower overall detection rate. A majority (58% [145 of 252]) of metastases in the study population were smaller than 20 mm. CONCLUSION: Few articles adequately describe the standard of reference and size distribution of hepatic lesions. Hepatic metastases of colorectal cancer are frequently smaller than 20 mm. When the standard of reference is suboptimal, many small metastases are excluded from analysis, and detection rates are therefore inflated.     

Assessment of transport rates of proteins and peptides across primary human alveolar epithelial cell monolayers.

In this study, we investigated bi-directional fluxes (i.e., in absorptive and secretive directions) of human serum proteins [albumin (HSA), transferrin (TF), and immunoglobulin G (IgG)] and peptides/proteins of potential therapeutic relevance [insulin (INS), glucagon-like peptide-1 (GLP-1), growth hormone (GH), and parathyroid hormone (PTH)] across tight monolayers of human alveolar epithelial cells (hAEpC) in primary culture. Apparent permeability coefficients (P(app); x10(-7)cm/s, mean+/-S.D.) for GLP-1 (6.13+/-0.87 (absorptive) versus 1.91+/-0.51 (secretive)), HSA (2.45+/-1.02 versus 0.21+/-0.31), TF (0.88+/-0.15 versus 0.30+/-0.03), and IgG (0.36+/-0.22 versus 0.15+/-0.16) were all strongly direction-dependent, i.e., net absorptive, while PTH (2.20+/-0.30 versus 1.80+/-0.77), GH (8.33+/-1.24 versus 9.02+/-3.43), and INS (0.77+/-0.15 versus 0.72+/-0.36) showed no directionality. Trichloroacetic acid precipitation analysis of tested molecules collected from donor and receiver fluids exhibited very little degradation. This is the first study on permeability data for a range of peptides and proteins across an in vitro model of the human alveolar epithelial barrier. These data indicate that there is no apparent size-dependent transport conforming to passive restricted diffusion for the tested substances across human alveolar barrier, in part confirming net absorptive transcytosis. The obtained data differ significantly from previously published reports utilising monolayers from different species. It can be concluded that the use of homologous tissue should be preferred to avoid species differences.     

Preservation of periprostatic autonomic nerves during total perineal prostatectomy by intrafascial dissection

A modification of Young's total perineal prostatectomy technique is described to prevent damage to the apical branches of the cavernous nerves. Based on anatomic relationships between investing prostatic fascial layers and the neurovascular bundle, emphasis is placed on division of the apical prostatic urethra between the anterolateral endopelvic fascia and Denonvilliers fascia (intrafascial dissection) in avoidance of the apical nerves. Vertical incision in the fused distal portion of Denonvilliers fascia is necessary to make this dissection atraumatic regarding the adjacent paraprostatic neurovascular bundle. Clinical application of this completely intrafascial prostatic dissection is exemplified. It is concluded that careful modification of Young's technique of total perineal prostatectomy may result in increased postoperative potency rates.