BackgroundConventional ketamine hydrochloride solutions are acidic and hyperosmotic, limiting their tolerability for subcutaneous (SC) delivery. BB106 is a novel ketamine formulation using the multitude of sulfobutylether-beta-cyclodextrin (SBECD) anionic substitutions as ionic counterions to achieve a new ketamine-SBECD salt in solution at near-physiologic pH and isotonicity, thereby enabling SC administration. To support its development for pain and neuropsychiatric indications, we conducted nonclinical toxicology studies in rats and minipigs.MethodsA 2-week repeated-dose SC injection study in rats and a 4-week continuous SC infusion study in Göttingen minipigs were performed, each with a 2-week recovery phase. Assessments included clinical observations, body weights, food consumption, ophthalmology, electrocardiography, clinical pathology, toxicokinetics (TK), and histopathology.ResultsBB106 was well-tolerated in both species. No mortality or dose-limiting systemic toxicity occurred. Clinical signs were consistent with ketamine pharmacology (eg, transient ataxia) and resolved after dosing. Local site reactions were minimal, histologically mild, and reversible. No treatment-related lesions were observed in any of the systemic tissues examined (including liver, kidney, bladder, and brain). TK analyses confirmed consistent systemic exposure without accumulation. SBECD itself produced no adverse effects at the exposure levels tested.ConclusionRepeated SC bolus injections in rats and continuous SC infusion in minipigs demonstrated favorable local and systemic safety profiles for BB106. These findings support its feasibility as an alternative to intravenous ketamine for pain and psychiatric disorders. To our knowledge, this is the first toxicology report of SC administration of an SBECD salt formulation and the results support continued consideration as a potential medicine.

RC-0315 is a chemotherapy-exposed mesenchymal stem cell-derived secretome developed as a potential advanced therapy for idiopathic pulmonary fibrosis (IPF). A Good Laboratory Practice (GLP)-compliant repeated-dose toxicity study was conducted to evaluate the safety of RC-0315 following intratracheal (ITR) instillation in immunocompetent ICR and SCID mice. Animals received two cycles of three repeated ITR instillations of RC-0315 performed within a 7-day period and separated by a two-week interval. Mice were assigned to saline, vehicle, low-dose, or high-dose groups and were monitored for 3 days (main phase) or 13 weeks (recovery phase) post last administration. No test article-related mortality or toxic clinical signs were observed in either strain. Clinical pathology parameters, body weight, food consumption, and ophthalmologic findings remained within normal limits, with no dose-dependent alterations. Histopathological examination revealed no RC-0315-related adverse findings in the lungs or other organs, and no local toxicity was evident at the site of administration. These findings support the favorable safety profile of RC-0315 when administered via the clinically intended route.

BackgroundDutasteride, a potent 5 alpha-reductase inhibitor, has demonstrated efficacy in male pattern baldness (MPB) when administered orally, but concerns about systemic side effects limit its use. Topical formulations may offer a safer alternative. This Phase I trial evaluated the safety, local tolerability, usability, and exploratory efficacy of FOL100, a novel topical dutasteride lotion.MethodsIn this open-label, multicenter study, 79 men with mild-to-moderate MPB received FOL100 (n = 66) once daily for 24 weeks or oral finasteride (OF) 1 mg/day (n = 13). The trial was registered at ClinicalTrials.gov. Assessments included clinical safety, laboratory parameters, pharmacokinetics, hair counts via phototrichograms, hair morphology, and investigator and participant global improvement scales. Follow-up continued for 4 weeks post-treatment.ResultsIn the FOL100 group, treatment-related adverse events occurred in 10.6% of participants and were all mild and transient (mainly pruritus and erythema), with no treatment-related discontinuations. Serum dutasteride levels were undetectable in all FOL100-treated participants, and systemic dihydrotestosterone suppression was minimal and not statistically significant. Usability and tolerability ratings were consistently favorable, supporting good adherence potential. Exploratory efficacy analysis in the FOL100 group at Week 28 showed, using a bootstrap model, a significant increase in total hair count median from baseline (+11 hairs/cm2; -11.25, 27.50 Q1-Q3 range), along with improvements in follicular unit density. Global assessments by both investigators and subjects indicated stabilization or improvement in most participants. The small sample size in the OF arm precluded meaningful efficacy analysis.ConclusionsFOL100 demonstrated excellent safety, tolerability, and usability with promising signals of clinical benefit. These findings support further placebo-controlled studies to establish the therapeutic value of topical dutasteride in MPB. Trial Registration: identifier: NCT05611593ConclusionsFOL100 demonstrated excellent safety, tolerability, and usability with promising signals of clinical benefit. These findings support further placebo-controlled studies to establish the therapeutic value of topical dutasteride in MPB. Trial Registration: identifier: NCT05611593

Psoriasis is a systemic immune-mediated disease with ocular involvement. While biologic therapies reduce cardiovascular and musculoskeletal comorbidities, their impact on ocular health is not well characterised. We aimed to assess whether biologic therapy is associated with reduced ocular disease risk in psoriasis patients. We performed a large-scale, retrospective cohort study using the TriNetX Global Collaborative Network (>160 million patients worldwide). Adults with psoriasis initiating biologic therapy were compared with those receiving non-biologic systemic treatments. Cohorts were matched 1:1 by propensity scoring for demographic and clinical variables. Sixty-eight ocular outcomes were assessed over 6 to 120 months. Hazard ratios (HRs) were estimated using proportional hazards models. Among 30,911 biologic-treated and 35,832 non-biologic-treated patients with psoriasis, biologic therapy was consistently associated with reduced risk of ocular surface and corneal inflammation. The strongest associations were seen for dry eye disease (mean HR = 0.55, 95% confidence interval [CI; 0.42, 0.66], p = 0.0007), conjunctivitis (mean HR = 0.71, 95% CI [0.59, 0.86], p = 0.01), and keratitis (mean HR = 0.40, 95% CI [0.3, 0.56], p = 0.0007). These lower-risk associations were evident from 6 months and remained observable in the 10-year analysis window. No consistent reduction was observed for retinal or vitreous disease. Biologic therapy in psoriasis was associated with a lower risk of ocular surface disease. These observational findings may inform interdisciplinary management and consideration of ocular outcomes in treatment decisions.

Background/NeedUncontained power morcellation during laparoscopic gynecologic surgery risks intra-abdominal dissemination of benign or malignant tissue, a significant safety concern highlighted by FDA warnings. This has created a critical need for robust and reliable tissue containment systems that can be easily integrated into surgical workflows to mitigate this risk.Methodology and device descriptionThe LapBox Power Tissue Containment System is a single-use device featuring a dual-walled inflatable chamber designed to create a secure environment for morcellation. We conducted a Good Laboratory Practice (GLP)-compliant toxicology study in three female domestic pigs to assess its safety under simulated worst-case conditions. The device was inserted laparoscopically, and the internal dual-walled chamber of the device was inflated to a high pressure (∼160 mmHg) to simulate a localized worst-case compressive scenario, while the overall intra-abdominal insufflation was maintained at a standard 15 mmHg. Postoperative monitoring included clinical observation, bloodwork, and, at day 13, necropsy and histopathology.Preliminary ResultsAll procedures were completed without mortality, morbidity, or device-related complications. The LapBox maintained full structural integrity. Postoperative clinical, hematological, and biochemical parameters showed no adverse effects. Gross necropsy and detailed histopathology confirmed the absence of device-related ischemia, necrosis, thrombosis, or foreign-body reaction.Current statusThis preclinical study demonstrates that the LapBox Power system has an excellent safety profile and biocompatibility, even under extreme conditions. The device is ready for the next stage of evaluation. These findings support its translational potential and warrant further investigation in human clinical studies to confirm its safety and efficacy.

Background Occupational solar ultraviolet radiation (UVR) exposure is a major risk factor for keratinocyte carcinomas in outdoor workers. Individual causal attribution for medico-legal purposes requires partitioning risk contributions between occupational exposure and individual susceptibility factors—a question distinct from population-level burden estimation. This study is primarily a quantitative/methodological application of FAIR to occupational UV-related skin cancer. Methods This methodological framework study applies the FAIR approach (Filtering evidence, Association quantification, Individual partitioning, Reasoned interpretation) to occupational solar UVR and skin cancer. Meta-analyses (1995–2025) were reviewed and adjusted for phototype, sex, and immune status. Individual attribution was estimated using game-theory–based decomposition (Shapley values) and stochastic Monte Carlo simulation to propagate uncertainty. Preventive scenarios incorporated sector-specific compliance and long-term economic modeling. Results Mean occupational causal shares were 35% for squamous cell carcinoma (SCC), 25% for basal cell carcinoma (BCC), 10% for melanoma, and 50% for actinic keratosis. The probability of exceeding the 20% medico-legal attribution threshold reached 85% for SCC and 75% for BCC. Prevention reduced expected cases by 10-15% and healthcare costs by 8-12%. Conclusions The FAIR framework provides a transparent, reproducible approach for integrating epidemiological evidence with individual attribution. These quantitative thresholds support the clinical and medico-legal recognition of work-related skin cancers.

Toxicologic pathologists play a crucial role in the evaluation of animal studies for drugs, environmental chemicals, medical devices, and other agents to determine their safety and potential toxic effects. A significant challenge in this domain is the differentiation between incidental or procedural changes and genuine treatment-related effects. Correct identification and interpretation of such findings are essential to ensure that safety assessments are accurate and reliable for subsequent approval for human use. This review presents several cases in which non-test item-related findings were encountered. By examining procedure-related findings and considering spontaneous background pathology, we underscore the need for meticulous pathological evaluation and proper contextual understanding to avoid misinterpretations that could lead to erroneous conclusions about a substance's safety profile. The insights shared in this review aim to enhance the proficiency of toxicologic pathologists in recognizing and managing various interpretative challenges, with the goal of ultimately improving the accuracy of toxicological assessments, thereby contributing to the safe development of new therapeutics and medical devices and sound characterization of potentially hazardous substances in our environment.

Background:Psoriatic alopecia is a distinct but underrecognized manifestation of psoriasis, leading to both non-scarring and scarring hair loss. While scalp involvement is common in psoriasis, the mechanisms underlying follicular damage and hair loss remain poorly understood. Diagnosis is challenging due to clinical and histopathological overlap with other alopecias, and treatment responses are often variable. Summary:This review examines the clinical presentation, pathogenesis, and management of psoriatic alopecia. The inflammatory process, primarily driven by the Th17/IL-23 axis, contributes to hair follicle disruption, sebaceous gland atrophy, and in severe cases, permanent alopecia. Trichoscopy and histopathology aid in diagnosis, but standardized criteria are lacking. Treatment strategies include topical corticosteroids, vitamin D analogs, and systemic biologics, but some patients remain refractory to conventional therapies. Paradoxical psoriatic alopecia induced by TNF inhibitors further complicates management, necessitating individualized treatment approaches. Key Messages:Psoriatic alopecia requires greater clinical recognition and research to improve diagnosis and treatment. A deeper understanding of its pathogenesis, particularly immune-mediated follicular damage, could lead to more effective therapies. Personalized treatment approaches, including novel biologics, hold promise for improving patient outcomes, but further studies are needed to optimize long-term management strategies.

OBJECTIVES:This exploratory study was aimed to evaluate the safety and preliminary efficacy of Epicare, a 1940 nm thulium-doped yttrium aluminum perovskite (Tm:YAP) laser, for fractional skin ablation in a swine model. The goal was to assess collagen remodeling and tissue responses across varied laser settings to optimize skin resurfacing applications. MATERIALS AND METHODS:Two female domestic swine were subjected to controlled fractional laser ablation using Epicare across 52 marked abdominal sites with varying energy settings. Macroscopic examinations of ablated sites were conducted immediately following ablation and at 1, 3, 7, 14, 22, and 29 days postablation. Histopathological evaluation was conducted immediately posttreatment, and at 1, 7, and 29 days postablation. Observed parameters included epidermal regeneration, dermal remodeling, inflammation, and collagen deposition. RESULTS:Macroscopic evaluations revealed a fractional, clear, and immediate impact of ablation, consisting primarily of erythema and edema, which resolved without complications by Day 14. Histopathological analysis indicated focal, cylinder-like structures associated with necrotic epidermis and dermis, which healed progressively (i.e. from day 1), transitioning to complete epidermal regeneration by Day 7 for most energy settings. By Day 29, advanced collagen deposition and no residual inflammation indicated effective dermal remodeling, consistent with rapid healing and minimal adverse reactions. CONCLUSIONS:Epicare demonstrated a favorable safety profile and effective tissue ablation. These findings support the laser's potential for dermatologic applications while emphasizing the need for further investigation to confirm its efficacy and optimal settings in human clinical trials.

Vitiligo, a chronic autoimmune skin depigmentation disease with an unpredictable course, has been associated with several comorbid autoimmune and psychological conditions. Our current understanding of vitiligo burden and management in the real world is limited. This real-world analysis presents data on vitiligo epidemiology, comorbidities, and treatment of patients in Israel. This retrospective study analyzed data from the Maccabi Health Services database. Prevalent patients with vitiligo in 2021 were matched to patients in the general population on the basis of age group, gender, and socioeconomic status. Patient demographics, vitiligo incidence and prevalence, comorbidities, and treatment patterns are reported. Data are presented as percentages, mean, median, P values, and standard mean differences (SMD). In this analysis, 11,412 patients with vitiligo were matched to patients from the general population. Incidence and prevalence rates increased over time from 2005 to 2021. Compared to the general population, patients with vitiligo were more likely to have an immune-mediated comorbidity (29.7

Knee osteoarthritis (OA) poses a significant health care burden globally, necessitating innovative therapeutic approaches. CCoat, a novel poly(2-[methacryloyloxy]ethyl phosphorylcholine) (pMPC)ylated liposome device, protects the cartilage surface of the joint from mechanical wear through an entropy-favored process. Two preclinical studies were performed to explore the safety of CCoat following repeated intra-articular (IA) injections into the knee joint (i.e., femorotibial joint) in Sprague-Dawley rats. The studies involved 2 or 3 IA injections, at an interval of 2 or 3 weeks, and an observation period of 1 or 13 weeks after the last injection. Assessments included clinical, histopathological, and immunofluorescent evaluations. In study 1, no mortality or abnormal clinical signs occurred. At 1 week post last injection, histopathology revealed minimal vacuolated macrophages beneath the synovial membrane, predominantly M2-like, indicating a nonadverse response. Immunofluorescent staining supported M2-like macrophage predominance. Study 2 confirmed these findings with no systemic effects over 13 weeks. Statistical analyses indicated no significant differences in body weight, clinical pathology, or organ weights compared with controls. Results affirming the safety of pMPCylated liposomes following repeated IA injections in rat. This novel lubricant coating approach shows promise in OA therapy, with this safety assessment supporting its potential clinical application.

In neurosurgical interventions, effective closure of the dura mater is essential to prevent cerebrospinal fluid leakage and minimize post-operative complications. Biodegradable synthetic materials have the potential to be used as dura mater grafts owing to their regenerative properties and low immunogenicity. This study evaluated the safety of ArtiFascia, a synthetic dura mater graft composed of poly(l-lactic-co-caprolactone acid) and poly(d-lactic-co-caprolactone acid), in a rabbit durotomy model. Previously, ArtiFascia demonstrated positive local tolerance and biodegradability in a 12-month preclinical trial. Here, specialized stains were used to evaluate potential brain damage associated with ArtiFascia use. Histochemical and immunohistochemical assessments included Luxol Fast Blue, cresyl Violet, Masson's Trichrome, neuronal nuclei,, Glial Fibrillary Acidic Protein, and ionized calcium-binding adaptor molecule 1 stains. The stained slides were graded based on the brain-specific reactions. The results showed no damage to the underlying brain tissue for either the ArtiFascia or control implants. Neither inflammation nor neuronal loss was evident, corroborating the safety of the ArtiFascia. This approach, combined with previous histopathological analyses, strengthens the safety profile of ArtiFascia and sets a benchmark for biodegradable material assessment in dura graft applications. This study aligns with the Food and Drug Administration guidelines and offers a comprehensive evaluation of the potential neural tissue effects of synthetic dura mater grafts.

D-PLEX100 (D-PLEX) is a novel product candidate made of a polymer-lipid-based matrix (PLEX platform) which contains doxycycline that is being released at a constant rate for 30 days. D-PLEX was developed to prevent surgical site infections, which are a major global health challenge. Previous studies have shown its safety in adult humans, adult swine, and adult rabbits. The aim of this study was to assess the toxicity and safety of D-PLEX also in juvenile animals to support future clinical trials in pediatric patients. Yucatan miniature swine were selected as a model, primarily due to their relatively larger mass. D-PLEX or placebo (formulation without doxycycline) was administered locally to abdominal incisions, and the animal's safety parameters were followed for 9 months and compared to sham-control swine. There was no evidence of any systemic safety concern or local toxicity at the incision site in D-PLEX-treated animals. D-PLEX was detected after 1 month and was fully resorbed at the 3-month time point. The surgical incision sites were fully healed at the 6-month time point in all D-PLEX-treated animals. Toxicokinetic (TK) assessments revealed that doxycycline exhibited low Cmax and therefore minimal systemic exposure following a single dose of local administration. This study provides evidence for the safety of D-PLEX and PLEX-based formulation in juvenile miniature swine and supports its further testing in clinical pediatric population. In addition, it can be used as a reference for future preclinical studies aiming to evaluate the safety of other PLEX-based product candidates for the pediatric population.