Comparison of narrow band imaging versus white light imaging in detecting non muscle invasive bladder cancer.

BACKGROUND: In the present study, we compared Narrow Band Imaging (NBI) and White Light Cystoscopy (WLC) in Non-muscle invasive bladder cancer (NMIBC) for detection and its impact on recurrence. MATERIALS AND METHODS: This prospective study was conducted in the department of Urology at a tertiary institution from August 2021 to April 2023. The main aim was to determine the benefit of addition of NBI during TURBT in NMIBC. All patients with Urinary Bladder Mass (size less than 5 cm on USG/CT) aged >18 years of age planned for TURBT were included. RESULTS: Amongst 63 patients, the mean age was 59.84 ± 11.3 years; 80% were males. Sixty percent of patients had history of Tobacco consumption and Type II DM was the most common comorbidity (59%). Commonest symptom was gross haematuria. Posterior wall was most commonly involved and papillary lesions were commonest. A total of 125 lesions were identified on WLI, with mean 1.98 ± 1.75 and 78 additional lesions were identified only on NBI with mean 1.24 ± 1.63 lesions. Four patients had intra-operative complications. Five patients had recurrence at 6 weeks and eight patients had recurrence at 3 months. NBI had detected more lesions in patients who developed recurrence at 6 weeks and 3 months (mean: 1.41 and 1.43). CONCLUSION: NBI has additive role in detecting NMIBC lesions missed on WLI. NBI has significant role in preventing recurrence at 3 months and more so by detecting high grade tumours.

Toxicity assessment of molindone hydrochloride, a dopamine D2/D5 receptor antagonist in juvenile and adult rats.

Neuroleptic drug molindone hydrochloride is a dopamine D2/D5 receptor antagonist and it is in late stage development for the treatment of impulsive aggression in children and adolescents who have attention deficient/hyperactivity disorder (ADHD). This new indication for this drug would expand the target population to include younger patients, and therefore, toxicity assessments in juvenile animals were undertaken in order to determine susceptibility differences, if any, between this age group and the adult rats. Adult rats were administered molindone by oral gavage for 13 weeks at dose levels of 0, 5, 20, or 60 mg/kg-bw/day. Juvenile rats were dosed for 8 weeks by oral gavage at dose levels of 0, 5, 25, 50, or 75 mg/kg-bw/day. Standard toxicological assessments were made using relevant study designs in consultation with FDA. Treatment-related elevation in serum cholesterol and triglycerides and decreases in glucose levels were observed in both the age groups. Organ weight changes included increases in liver, adrenal gland and seminal vesicles/prostate weights. Decreases in uterine weights were also observed in adult females exposed to the top two doses with sufficient exposure. In juveniles, sexual maturity parameters secondary to decreased body weights were observed, but, were reversed. In conclusion, the adverse effects noted in reproductive tissues of adults were attributed to hyperprolactinemia and these changes were not considered to be relevant to humans due to species differences in hormonal regulation of reproduction. On the whole, there were no remarkable differences in the toxicity profile of the drug between the two age groups.

In vitro and in vivo genotoxicity assessment of the dopamine receptor antagonist molindone hydrochloride.

Molindone hydrochloride is a dihydroindolone neuroleptic with dopamine D2 and D5 receptor antagonist activity. As an integral component of its preclinical safety evaluation, molindone hydrochloride was evaluated in a series of in vitro and in vivo genetic toxicology assays. In the bacterial reverse gene mutation assays employing four Salmonella tester strains (TA98, TA100, TA1535, and TA1537) and the E. coli tester strain WP2uvrA, molindone hydrochloride was negative in all strains, except TA100, in which it induced a positive response (up to 3-fold) in the presence of rat liver S9. With human S9, a small (2-fold), but nonreproducible, increase in revertants was observed in TA100 at the highest concentration of molindone tested (5,000 µg/plate). The mutagenicity was completely abrogated by the addition of glutathione and UDP-glucuronic acid to rat liver S9, suggesting detoxification of the mutagenic metabolite(s) by Phase II conjugation reactions, pathways commonly operational in humans. Molindone hydrochloride did not induce chromosomal aberrations in human lymphocyte cultures, did not elicit a positive response in a rat bone marrow micronucleus test for clastogencity/aneugenicity, and did not give a positive response in the rat liver comet assay for DNA damage. Collectively, the weight of evidence from these studies, combined with a large margin of safety and efficient detoxification through Phase II conjugation supports the interpretation that molindone hydrochloride does not pose a genotoxic risk to humans at the anticipated clinical dose levels.

Reversibility of dopamine receptor antagonist-induced hyperprolactinemia and associated histological changes in Tg RasH2 wild-type mice.

The purpose of this study was to better understand the biological effects of increased prolactin levels induced in mice by dopamine D2 receptor antagonist molindone treatment. Toxicokinetics, prolactin levels, and reproductive tissue histology were evaluated in Tg rasH2 wild-type mice treated orally with molindone at 0, 5, 15, and 50mg/kg/day for 6 months, followed by a 2-month posttreatment recovery period. A greater than dose-proportional increase in molindone exposure ([AUC]0‒24) was observed on Day 180 for both sexes. Statistically significant (P<0.01) increases in prolactin levels were observed in most treatment groups compared with controls at 0.5h postdose on Days 1 and 180. Prolactin levels returned to baseline levels during the recovery period. Microscopic changes attributable to hyperprolactinemia, including corpora lutea enlargement and interstitial cell atrophy in the ovaries, and atrophy of the uterus and vagina were observed on Day 180. These changes were reversed during the recovery period in the 5- and 15-mg/kg/day treatment groups. Mice receiving molindone at 50mg/kg/day also showed signs of reversal on histologic examination.

SAR genotoxicity and tumorigenicity predictions for 2-MI and 4-MI using multiple SAR software.

CONTEXT: Caramel coloring chemicals, 2-methylimidazole (2-MI) and 4-methylimidazole (4-MI) have been used extensively in coloring soft drinks. The health effects of these chemicals have been concerned in the recent years. OBJECTIVE: In the present investigation, 2- and 4-MI were subjected to three commonly used structure-activity relationship (SAR) software to understand the utility of such software as a method of alternatives to animal testing in predicting potential genotoxicity and tumorigenicity. MATERIALS AND METHODS: Three SAR software: Osiris, ToxTree and DEREK, were used. Published procedures and/or manuals of respective software were utilized to generate data outputs and the data were evaluated in comparison with available toxicological data on 2- and 4-MI. RESULTS: The results show that these software predicted genotoxic activity in comparison with published genotoxicity for 2- and 4-MI. However, only one of three software used (Osiris) predicted imidazole ring in 4-MI to be tumorigenic; other software predicted them to be negative. DISCUSSION: Based on the weight of evidence of SAR results observed in this study and the genotoxicity and tumorigenicity reported using actual in vitro and in vivo animal testing in literature, it was concluded that the models used are useful for routine screening of chemicals; however, for better prediction, additional models may be employed. Software's ability to predict health effects depends on the type of structural alerts used as knowledgebase in developing such software. CONCLUSION: Three computational software used in this study predicted genotoxic activity of 2- and 4-MI, but did not predict tumorigenicity conclusively when compared to literature reported animal data. Additional mechanistic non-clinical studies may be conducted to better understand reported tumorigenicity.

In vitro skin penetration of dazmegrel delivered with a bioelastic matrix.

The penetration of dazmegrel, a selective thromboxane synthetase inhibitor, through excised human and greyhound skin was measured. A bioelastic matrix was used for topical delivery. Results demonstrated that dazmegrel readily penetrated the skin. Penetration through greyhound skin was significantly greater than penetration through human skin. Penetration through greyhound skin was not significantly different between 4, 24, and 48 h of exposure for the low and intermediate doses studied.