Anti-angiogenic and antioxidant effects of axitinib in human retinal endothelial cells: implications in diabetic retinopathy.

Diabetic retinopathy is a secondary microvascular complication of diabetes mellitus. This disease progresses from two stages, non-proliferative and proliferative diabetic retinopathy, the latter characterized by retinal abnormal angiogenesis. Pharmacological management of retinal angiogenesis employs expensive and invasive intravitreal injections of biologic drugs (anti-vascular endothelial growth factor agents). To search small molecules able to act as anti-angiogenic agents, we focused our study on axitinib, which is a tyrosine kinase inhibitor and represents the second line treatment for renal cell carcinoma. Axitinib is an inhibitor of vascular endothelial growth factor receptors, and among the others tyrosine kinase inhibitors (sunitinib and sorafenib) is the most selective towards vascular endothelial growth factor receptors 1 and 2. Besides the well-known anti-angiogenic and immune-modulatory functions, we hereby explored the polypharmacological profile of axitinib, through a bioinformatic/molecular modeling approach and in vitro models of diabetic retinopathy. We showed the anti-angiogenic activity of axitinib in two different in vitro models of diabetic retinopathy, by challenging retinal endothelial cells with high glucose concentration (fluctuating and non-fluctuating). We found that axitinib, along with inhibition of vascular endothelial growth factor receptors 1 (1.82 ± 0.10; 0.54 ± 0.13, phosphorylated protein levels in fluctuating high glucose vs . axitinib 1 µM, respectively) and vascular endothelial growth factor receptors 2 (2.38 ± 0.21; 0.98 ± 0.20, phosphorylated protein levels in fluctuating high glucose vs . axitinib 1 µM, respectively), was able to significantly reduce (p < 0.05) the expression of Nrf2 (1.43 ± 0.04; 0.85 ± 0.01, protein levels in fluctuating high glucose vs . axitinib 1 µM, respectively) in retinal endothelial cells exposed to high glucose, through predicted Keap1 interaction and activation of melanocortin receptor 1. Furthermore, axitinib treatment significantly (p < 0.05) decreased reactive oxygen species production (0.90 ± 0.10; 0.44 ± 0.06, fluorescence units in high glucose vs . axitinib 1 µM, respectively) and inhibited ERK pathway (1.64 ± 0.09; 0.73 ± 0.06, phosphorylated protein levels in fluctuating high glucose vs . axitinib 1 µM, respectively) in HRECs exposed to high glucose. The obtained results about the emerging polypharmacological profile support the hypothesis that axitinib could be a valid candidate to handle diabetic retinopathy, with ancillary mechanisms of action.

A deep eutectic-based, self-emulsifying subcutaneous depot system for apomorphine therapy in Parkinson's disease.

Apomorphine, a dopamine agonist, is a highly effective therapeutic to prevent intermittent off episodes in advanced Parkinson's disease. However, its short systemic half-life necessitates three injections per day. Such a frequent dosing regimen imposes a significant compliance challenge, especially given the nature of the disease. Here, we report a deep eutectic-based formulation that slows the release of apomorphine after subcutaneous injection and extends its pharmacokinetics to convert the current three-injections-a-day therapy into an every-other-day therapy. The formulation comprises a homogeneous mixture of a deep eutectic solvent choline-geranate, a cosolvent n-methyl-pyrrolidone, a stabilizer polyethylene glycol, and water, which spontaneously emulsifies into a microemulsion upon injection in the subcutaneous space, thereby entrapping apomorphine and significantly slowing its release. Ex vivo studies with gels and rat skin demonstrate this self-emulsification process as the mechanism of action for sustained release. In vivo pharmacokinetics studies in rats and pigs further confirmed the extended release and improvement over the clinical comparator Apokyn. In vivo pharmacokinetics, supported by a pharmacokinetic simulation, demonstrate that the deep eutectic formulation reported here allows the maintenance of the therapeutic drug concentration in plasma in humans with a dosing regimen of approximately three injections per week compared to the current clinical practice of three injections per day.

Minocycline Extended-Release Comparison with Doxycycline for the Treatment of Rosacea: A Randomized, Head-to-Head, Clinical Trial.

OBJECTIVE: Minocycline efficacy for the treatment of papulopustular rosacea (PPR) has not been evaluated in clinical trials at levels demonstrated to stay below the antimicrobial threshold. We assessed the efficacy, safety, and dose response of DFD-29, a minocycline extended-release oral capsule. Two studies are reported (NCT03340961). METHODS: A single-center open-label, three-arm, Phase I pharmacokinetic study randomized 24 healthy subjects aged 18 to 45 years to receive 21 days of once-daily dosing with DFD-29 40 or 20mg, or doxycycline 40mg. Blood samples were collected over 24 hours on Days 1 and 21 to plot mean plasma concentration levels. A multicenter Phase II clinical trial randomized 205 subjects with mild-to-severe PPR 1:1:1:1 to receive once-daily DFD-29 40 or 20mg, doxycycline 40mg, or placebo for 16 weeks. Co-primary endpoints were the proportion of subjects achieving treatment success (IGA grade 0 or 1 and ≥2-grade improvement) at Week 16, and a reduction in total inflammatory lesion count at Week 16. RESULTS: Pharmacokinetic analysis demonstrated that minocycline plasma levels of DFD-29 40mg were approximately half those of doxycycline 40mg after 21 days, with DFD-29 20mg even lower, demonstrating a dose response. In the Phase II trial, DFD-29 40mg met both co-primary endpoints, achieving IGA treatment success in 66.0 percent subjects versus 11.5 percent placebo (p<0.0001), 31.9 percent DFD-29 20mg (p=0.007), and 33.3 percent doxycycline 40mg (p<0.0010), and a mean reduction in lesion counts of -19.2 versus -7.3 placebo (p<0.0001), -12.6 DFD-29 20mg (p=0.0070), and -10.5 doxycycline 40mg (p=0.0004). LIMITATIONS: MIC values and plasma concentrations shown for antibacterial threshold data are mean values; fast absorbers/slow metabolizers could exceed the threshold, causing resistance selection pressure. CONCLUSION: DFD-29 40mg demonstrated significantly greater efficacy than placebo, DFD-29 20mg, and doxycycline 40mg at plasma concentrations predicted to be below the antimicrobial threshold for the treatment of PPR.

The effect of food and formulation on the population pharmacokinetics of cholesteryl ester transferase protein inhibitor DRL-17822 in healthy male volunteers.

We aimed to characterise the population pharmacokinetics of cholesteryl ester transferase protein inhibitor DRL-17822 in healthy males and explore the effect of food and formulation on the oral absorption of DRL-17822 in 4 phase I studies. DRL-17822 was dosed orally (2-1000 mg) in 2 different drug formulations (nanocrystal formulation and amorphous solid dispersion formulation) after either an overnight fast, or a low-fat, continental or high-fat breakfast. A 2-compartment model with 6 transit absorption compartments best characterised the data. Additionally, a strong interaction of food and formulation on bioavailability was observed and parsimoniously characterised in the model by binning combinations of food state and formulation with similar bio-availabilities. The final model adequately characterised the pharmacokinetic data of DRL-17822 in healthy males including the complex interaction of food and drug formulation. The amorphous solid dispersion formulation has a lower food effect on bioavailability compared with the nanocrystal formulation.

Effect of Food on the Pharmacokinetics of 2 Formulations of DRL-17822, a Novel Selective Cholesteryl Ester Transfer Protein (CETP) Inhibitor, in Healthy Males.

DRL-17822 is a novel selective cholesteryl ester transfer protein inhibitor that showed an increased exposure, including an increase of >20-fold of maximum concentration and area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration, following a high-fat breakfast using a nanocrystal formulation. To reduce this effect of food, we generated an amorphous solid dispersion formulation. In this study, we compared the food effect of both formulations of DRL-17822 in a 2-part randomized, open-label, 4-way crossover study involving healthy adult males 18-45 years of age. In both parts of the study, 12 subjects received both formulations of DRL-17822 in both the fasted and fed states; a low-fat breakfast was provided in the first part and a high-fat breakfast in the second part. Compared to the nanocrystal formulation, the amorphous solid dispersion formulation substantially increased DRL-17822 exposure in the fasted state, including increased maximum concentration, area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration, and area under plasma concentration-time curve from time zero to infinity. Following a high-fat breakfast, DRL-17822 exposure was increased to a lesser extent in the amorphous solid dispersion formulation compared to the nanocrystal formulation (P < .001). Moreover, compared to the nanocrystal formulation the amorphous solid dispersion formulation caused a more pronounced increase in high-density lipoprotein in the fasted state. Consuming breakfast increased the effect of DRL-17822 on high-density lipoprotein. Taken together, our results indicate that by improving its formulation, DRL-17822 has a favorable exposure profile and therefore a more predictable food effect profile.

Selected players in the inflammation cascade and drugs that target these inflammation genes against metastasis.

Despite many recent advances the prognosis of cancer patients with metastasis still remains poor. In metastatic invasion, tumor cells interact with endothelial cells through several distinct adhesion molecules. Adherent tumor cells extravasate into tissues by degrading basement membranes with matrix degrading enzymes such as heparanases and matrix metalloproteinases. Endothelial expression of matrix degrading enzymes and adhesion molecules are under the control of inflammatory cytokines. These inflammatory proteins and the signaling pathways involved in the expression of these genes are under intense investigation as therapeutic targets to prevent tumor growth and metastasis. The current review focuses on selected players of the inflammation cascade and drugs that target these inflammatory genes.