Co-Delivery of Aceclofenac and Methotrexate Nanoparticles Presents an Effective Treatment for Rheumatoid Arthritis.

Background: Rheumatoid arthritis (RA) is a common acute inflammatory autoimmune connective tissue arthropathy. The genetic studies, tissue analyses, experimental animal models, and clinical investigations have confirmed that stromal tissue damage and pathology driven by RA mounts the chronic inflammation and dysregulated immune events. Methods: We developed methotrexate (MTX)-loaded lipid-polymer hybrid nanoparticles (MTX-LPHNPs) and aceclofenac (ACE)-loaded nanostructured lipid carriers (ACE-NLCs) for the efficient co-delivery of MTX and ACE via intravenous and transdermal routes, respectively. Bio-assays were performed using ex-vivo skin permeation and transport, macrophage model of inflammation (MMI) (LPS-stimulated THP-1 macrophages), Wistar rats with experimental RA (induction of arthritis with Complete Freund's adjuvant; CFA and BCG), and programmed death of RA affected cells. In addition, gene transcription profiling and serum estimation of inflammatory, signaling, and cell death markers were performed on the blood samples collected from patients with RA. Results: Higher permeation of ACE-NLCs/CE across skin layers confirming the greater "therapeutic index" of ACE. The systemic delivery of MTX-loaded LPHNPs via the parenteral (intravenous) route is shown to modulate the RA-induced inflammation and other immune events. The regulated immunological and signaling pathway(s) influence the immunological axis to program the death of inflamed cells in the MMI and the animals with the experimental RA. Our data suggested the CD40-mediated and Akt1 controlled cell death along with the inhibited autophagy in vitro. Moreover, the ex vivo gene transcription profiling in drug-treated PBMCs and serum analysis of immune/signalling markers confirmed the therapeutic role co-delivery of drug nanoparticles to treat RA. The animals with experimental RA receiving drug treatment were shown to regain the structure of paw bones and joints similar to the control and were comparable with the market formulations. Conclusion: Our findings confirmed the use of co-delivery of drug nanoformulations as the "combination drug regimen" to treat RA.

Comparison of two doses of leucovorin in severe low-dose methotrexate toxicity - a randomized controlled trial.

BACKGROUND: Leucovorin (folinic acid) is a commonly used antidote for severe toxicity with low-dose methotrexate, but its optimum dose is unclear, varying from 15 to 25 mg every 6-h. METHODS: Open-label RCT included patients with severe low-dose (≤ 50 mg/week) methotrexate toxicity defined as WBC ≤ 2 × 10^9/L or platelet ≤ 50 × 10^9/L and randomized them to receive either usual (15 mg) or high-dose (25 mg) intravenous leucovorin given every 6-h. Primary outcome was mortality at 30-days and secondary outcomes were hematological recovery and mucositis recovery. TRIAL REGISTRATION NUMBER: CTRI/2019/09/021152. RESULTS: Thirty-eight patients were included, most with underlying RA who had inadvertently overdosed MTX (taken daily instead of weekly). At randomization, the median white blood and platelet count were 0.8 × 10^9/L and 23.5 × 10^9/L. 19 patients each were randomized to receive either usual or high-dose leucovorin. Number (%) of deaths over 30-days was 8 (42) and 9 (47) in usual and high-dose leucovorin groups (Odds ratio 1.2, 95% CI 0.3 to 4.5, p = 0.74). On Kaplan-Meier, there was no significant difference in survival between the groups (hazard ratio 1.1, 95% CI 0.4 to 2.9, p = 0.84). On multivariable cox-regression, serum albumin was the only predictor of survival (hazard ratio 0.3, 95% CI 0.1 to 0.9, p = 0.02). There was no significant difference in hematological or mucositis recovery between the two groups. CONCLUSION: There was no significant difference in survival or time-to hematological recovery between the two doses of leucovorin. Severe low-dose methotrexate toxicity carried a significant mortality.

Diagnostic dilemma-dengue or Japanese encephalitis?

Dengue and Japanese encephalitis (JE) are arboviral diseases that are common in the tropical countries. JE virus is a classical neurotropic virus. The dengue virus, however, is usually not considered to be neurotropic, even though in recent years, reports of direct central nervous system involvement in dengue has been described. Here, we report a case wherein the patient had magnetic resonance imaging evidence of bilateral thalamic and brainstem involvement with positive serologies for both dengue and JE. We also discuss the diagnostic challenge in these cases.