The numerous stray cats and dogs worldwide pose a huge burden on local governments, keeping residents safe and healthy, and maintaining clean cities with good traffic situations. To effectively control the populations of these stray animals, while considering animal welfare, researchers have suggested the use of levonorgestrel (LNG) as a contraceptive method. However, the potential side effects of LNG on these animals need to be evaluated before widespread application. Since dogs and cats play important roles in the transmission of Toxoplasma gondii as intermediate and definitive hosts, respectively, it is critical to assess the safety of LNG from the perspective of its effect on Toxoplasma susceptibility. In this study, the susceptibility of mice to T. gondii infection was investigated in vivo and in vitro with the presence of LNG. As a result, LNG increased the risk of infection, which was probably associated with the downregulation of IFN-γ levels, but not with the alteration of host sex hormone levels. Concurrently, the presence of LNG enhanced the expression of its ligand, the progesterone receptor (PGR), on the host cells. The promotional effect of LNG on T. gondii infection was attenuated when the PGR gene was knocked down. This investigation represents the inaugural study of LNG's side effects on T. gondii infection in mice, underscoring the significance of choosing or developing suitable contraceptive drugs for stray animals.

01 Dec 2024·Journal of Controlled Release

Next-generation 3D printed multipurpose prevention intravaginal ring for prevention of HIV, HSV-2, and unintended pregnancy

Article

Author: Little, Dawn ; Cottrell, Mackenzie L ; Kelley, Kristen ; Dahl, Denali K ; Kashuba, Angela D M ; Srinivasan, Priya ; Janusziewicz, Rima ; Smith, James ; Benhabbour, S Rahima ; King, Jasmine L ; Bachman, Shanon ; Zhang, Jining ; Shrivastava, Roopali ; Sykes, Craig ; Schauer, Amanda P

Globally, nearly half of all pregnancies are unintended, ∼1.3 million new human immunodeficiency virus (HIV) infections are reported every year, and more than 500 million people are estimated to have a genital herpes simplex virus (HSV-2) infection. Here we report the first 3D printed multipurpose prevention technology (MPT) intravaginal ring (IVR) for prevention of HIV, HSV-2, and unintended pregnancy. The IVRs were fabricated using state-of-the-art Continuous Liquid Interface Production (CLIP™) 3D printing technology using a biocompatible silicone-urethane based resin. Anti-HIV drug (Dapivirine, DPV), anti-herpes drug (Pritelivir, PTV) and a contraceptive drug (Levonorgestrel, LNG) were loaded in a macaque size IVR (25 mm outer diameter, OD; 6.0 mm cross-section, CS) allometrically scaled from the human size (54 mm OD; 7.6 mm CS) IVR analogue. All three active pharmaceutical ingredients (APIs) were loaded in the IVR using a single-step drug loading process driven by absorption. DPV, PTV, and LNG elicited zero-order release kinetics in vitro in simulated vaginal fluid (SVF) at pH 4 and pH 8 relevant to human and macaque vaginal pH respectively. CLIP 3D printed MPT IVRs remained stable after 6 months of storage at 4 °C with no change in physical, dimensional, or mechanical properties and no change in drug concentration and absence of drug degradation byproducts. The MPT IVRs elicited sustained release of all three APIs in macaques for 28 days with median plasma concentrations of 138 pg/mL (DPV), 18,700 pg/mL (PTV), and 335 pg/mL (LNG). Safety studies demonstrated that the MPT IVRs were safe and well tolerated in the macaques with no observed change or abnormalities in vaginal pH and no significant changes in any of the 22 mucosal cytokines and chemokines tested including pro-inflammatory (IL-1β, IL-6, IL-8, IFN-γ, TNF-α, IL-17, IL-18) and anti-inflammatory (IL-10, IL-12) cytokines while the MPT IVR was in place or after its removal. Additionally, MPT IVRs elicited no observed alterations in systemic CD4+ and CD8+ T cells during the entire study. Collectively, the proposed MPT IVR has potential to expand preventative choices for young women and girls against unintended pregnancy and two highly prevalent sexually transmitted infections (STIs).

01 Dec 2024·Current Drug Delivery

Transdermal Drug Delivery System of Linagliptin Sustained-release Microparticle Gels: In vitro Characterization and In vivo Evaluation

Article

Author: Guo, Song ; Liu, Jiayan ; Hong, Shuai ; Piao, Jingshu ; Piao, Mingguan

Background:Linagliptin (LNG) exhibits poor bioavailability and numerous side effects, significantly limiting its use. Transdermal drug delivery systems (TDDS) offer a potential solution to overcome the first-pass effect and gastrointestinal reactions associated with oral formulations.Objective:The aim of this study was to develop LNG microparticle gels to enhance drug bioavailability and mitigate side effects.Methods:Linagliptin hyaluronic acid (LNG-HA) microparticles were prepared by spray drying method and their formulation was optimized via a one-factor method. The solubility and release were investigated using the slurry method. LNG-HA microparticle gels were prepared and optimised using in vitro transdermal permeation assay. The hypoglycaemic effect of the LNG-HA microparticle gel was examined on diabetic mice.Results:The results indicated that the LNG-HA microparticle encapsulation rate was 84.46%. Carbomer was selected as the gel matrix for the microparticle gels. Compared to the oral API, the microparticle gel formulation demonstrated a distinct biphasic release pattern. In the first 30 minutes, only 43.56% of the drug was released, followed by a gradual release. This indicates that the formulation achieved a slow-release effect from a dual reservoir system. Furthermore, pharmacodynamic studies revealed a sustained hypoglycemic effect lasting for 48 hours with the LNG microparticle gel formulation.Conclusion:These findings signify that the LNG microparticle gel holds significant clinical value for providing sustained release and justifies its practical application.

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Indication	Highest Phase	Country/Location	Organization	Date
Contraception	Phase 1	-	Contraception Research and Development	-

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