Hormonal therapies for prostate cancer target the androgen receptor (AR) ligand-binding domain (LBD). Clinical development for inhibitors that bind to the N-terminal domain (NTD) of AR has yielded ralaniten and its analogues. Ralaniten acetate is well tolerated in patients at 3600 mgs/day. Clinical trials are ongoing with a second-generation analogue of ralaniten. Binding sites on different AR domains could result in differential effects on AR-regulated gene expression. Here, we provide the first comparison between AR-NTD inhibitors and AR-LBD inhibitors on androgen-regulated gene expression in prostate cancer cells using cDNA arrays, GSEA, and RT-PCR. LBD inhibitors and NTD inhibitors largely overlapped in the profile of androgen-induced genes that they each inhibited. However, androgen also represses gene expression by various mechanisms, many of which involve protein–protein interactions. De-repression of the transcriptome of androgen-repressed genes showed profound variance between these two classes of inhibitors. In addition, these studies revealed a unique and strong induction of expression of the metallothionein family of genes by ralaniten by a mechanism independent of AR and dependent on MTF1, thereby suggesting this may be an off-target. Due to the relatively high doses that may be encountered clinically with AR-NTD inhibitors, identification of off-targets may provide insight into potential adverse events, contraindications, or poor efficacy.

Topical antibiotics have long been used for the prevention and treatment of superficial skin and soft tissue infections; however, increasing evidence indicates that their clinical value is undermined by rising antimicrobial resistance, high rates of allergic sensitization, inadequate activity against biofilms, and a lack of wound-healing properties. Agents such as bacitracin, neomycin, polymyxin B, mupirocin, and fusidic acid act through narrow, target-specific mechanisms that facilitate resistance selection and provide limited benefit in chronic or polymicrobial wound environments. Contemporary antimicrobial stewardship frameworks therefore discourage routine use of topical antibiotics and increasingly favor non-antibiotic antiseptics with broad-spectrum activity and low resistance risk, including silver, iodine, polyhexamethylene biguanide, octenidine, and medical-grade honey. These modalities, however, primarily serve to reduce microbial burden and do not directly address the underlying biological impairments that prevent healing. Nitric oxide-releasing gels (NORGs) represent a novel class of topical antimicrobials that combine multi-target bactericidal activity with physiologic pro-healing effects. Nitric oxide exerts potent antimicrobial and antibiofilm effects via oxidative and nitrosative stress, disruption of metabolic pathways, inhibition of DNA replication, and interference with quorum sensing. Simultaneously, nitric oxide enhances angiogenesis, modulates inflammation, improves microvascular perfusion, and promotes fibroblast and keratinocyte function. Preclinical models and early-phase clinical studies demonstrate broad-spectrum efficacy—including activity against multidrug-resistant organisms—with favorable tolerability and minimal risk of resistance development. Although the current evidence base remains preliminary, NORGs offer a promising antimicrobial platform with the potential to reduce reliance on topical antibiotics while simultaneously addressing key barriers to wound healing. Larger randomized controlled trials, direct comparisons with established advanced dressings, and robust pharmacoeconomic evaluations are needed to define their optimal role within stewardship-aligned wound-care practice.

Onychomycosis is a therapeutically challenging fungal infection. Systemic antifungals are limited by adverse effects and drug interactions, while topical therapies may fail to achieve therapeutic nail bed concentrations. Nitric oxide (NO), a small, diffusible free radical with broad-spectrum antimicrobial activity, offers a novel approach to overcoming these barriers. We assessed the penetration and subsequent efficacy of a nitric oxide–releasing gel (NORG) in the treatment of onychomycosis. Ex vivo human nail models assessed NORG’s transungual penetration and antifungal activity via colorimetric, immunohistochemical, and microbiological assays. NORG eradicated Trichophyton mentagrophytes completely (0 CFU/g), outperforming terbinafine (3.58 ± 0.2 log₁₀ CFU/g). In an ex vivo infection model, NORG achieved fungal clearance within 14 days, continuing to Day 30 treatment end, with no regrowth during 21 days of incubation post-treatment. Clinical data from patients with onychomycosis who received topical NORG therapy show that NORG penetrated the nail plate and nail bed, as evidenced by s-nitrosothiol accumulation and progressive discoloration. The NORG formulation demonstrates in vitro efficacy; controlled trials are warranted to fully assess clinical efficacy and safety of this NORG formulation in humans, and establish optimal treatment protocols.

Introduction: Nitric oxide (NO)–based therapeutics represent a promising modality for overcoming the challenges of treating dermatophyte infections within keratinized tissues. Methods: This study evaluated the antifungal activity of a nitric oxide–releasing solution (NORS) against clinical isolates of Trichophyton mentagrophytes, Trichophyton tonsurans, and Epidermophyton floccosum, comparing MIC and MFC profiles to efinaconazole and assessing keratin associated inhibition relative to terbinafine. Results: NORS demonstrated potent fungicidal activity across all species, with MIC90 and MFC90 values consistently at 0.005 μg/mL. Unlike terbinafine, whose efficacy decreased significantly in keratin-rich environments, NORS retained antifungal activity in the presence of human nail keratin. Discussion: These results support further clinical evaluation of NO-based antifungals as potential treatments for onychomycosis and tinea pedis.

A commercially available nitric oxide (NO)-releasing solution (NORS) has demonstrated in vitro efficacy for dermatophytosis, but a NO-releasing gel (NORG) may be more suitable for patient self-application. We present a preliminary investigation of NORS for tinea pedis and an in vitro investigation of NORG for dermatophyte infection, to complement the existing published data and expand support for a possible role of NO formulations in superficial dermatophyte infection. In vitro usage of NORS and NORG is reviewed. The antifungal efficacy of NORG was assessed via time-kill assays, zone of inhibition tests with synthetic dermal membrane permeation, and scanning electron microscopy. A randomized, controlled pilot study of NORS for tinea pedis investigated the safety and efficacy of treatment over three consecutive days, with a day-31 follow-up. The NORG demonstrated rapid fungicidal activity against T. rubrum and T. mentagrophytes and effective dermal membrane penetration while retaining antifungal action. Significant morphological damage to fungal cells was noted, indicating possible fungicidal activity. The clinical NORS treatment reduced the clinical symptom severity score by 67% on average, with no significant safety findings. These findings, in addition to existing publications, support NO-releasing formulations as potential therapies that warrant further clinical investigation for superficial fungal infection.