PDE4 Inhibitors: Profiling Hits through the Multitude of Structural Classes

Cyclic nucleotide phosphodiesterases 4 (PDE4) are a family of enzymes which specifically promote the hydrolysis and degradation of cAMP. The inhibition of PDE4 enzymes has been widely investigated as a possible alternative strategy for the treatment of a variety of respiratory diseases, including chronic obstructive pulmonary disease and asthma, as well as psoriasis and other autoimmune disorders. In this context, the identification of new molecules as PDE4 inhibitors continues to be an active field of investigation within drug discovery. This review summarizes the medicinal chemistry journey in the design and development of effective PDE4 inhibitors, analyzed through chemical classes and taking into consideration structural aspects and binding properties, as well as inhibitory efficacy, PDE4 selectivity and the potential as therapeutic agents

Urinary excretion of herbicide co-formulants after oral exposure to roundup MON 52276 in rats

The toxicity of surfactants, which are an integral component of glyphosate-formulated products is an underexplored and highly debated subject. Since biomonitoring human exposure to glyphosate co-formulants is considered as a public health priority, we developed and validated a high-resolution mass spectrometry method to measure the urinary excretion of surfactants present in Roundup MON 52276, the European Union (EU) representative formulation of glyphosate-based herbicides. Quantification was performed measuring the 5 most abundant compounds in the mixture. We validated the method and showed that it is highly accurate, precise and reproducible with a limit of detection of 0.0004 μg/mL. We used this method to estimate the oral absorption of MON 52276 surfactants in Sprague-Dawley rats exposed to three concentrations of MON 52276 via drinking water for 90 days. MON 52276 surfactants were readily detected in urine of rats administered with this commercial Roundup formulation starting from a low concentration corresponding to the EU glyphosate acceptable daily intake. Our results provide a first step towards the implementation of surfactant co-formulant biomonitoring in human populations

Optimization, characterization and in vitro evaluation of curcumin microemulsions

Abstract The purpose of this study was to improve the solubility and the stability and oral uptake of curcumin by developing an o/w microemulsion, using food grade components. Three microemulsions were developed and characterized, stabilized by non ionic surfactants Cremophor EL, Tween 20, Tween 80 or Lecitin and containing a variety of oils, namely olive oil, wheat germ oil, vitamin E. Chemical and physical stabilities of three systems was also evaluated within two months. The oral absorption of curcumin from the best microemulsion was investigated in vitro using parallel artificial membrane permeability assay (PAMPA). The optimal formulation consisted of 3.3 g/100 g of vitamin E, 53.8 g/100 g of Tween 20, 6.6 g/100 g of ethanol and water (36.3 g/100 g), with a maximum solubility of curcumin up to 14.57 mg/ml and a percentage of permeation through the artificial membrane of about 70%

Evaluating thermogravimetric analysis for the measurement of drug loading in mesoporous silica nanoparticles (MSNs)

In this study, a thermogravimetric analysis (TGA) method for measuring the drug loading in mesoporous silica nanoparticles (MSNs) has been developed and evaluated in comparison with the drug loading quantification by high-performance liquid chromatography (HPLC). Indapamide was loaded into two different types of MSNs, namely Mobile Crystalline Material (MCM-41, pore size = 1.2 nm) and Santa Barbara Amorphous (SBA-15, pore size = 4.1 nm). Physical mixtures of the drug and silica gave a linear correlation between the observed and expected drug content for both TGA and HPLC, which were used for calibration purposes. The limit of detection (LOD) for the TGA method obtained from the physical mixture calibration curve was 0.77 % (w/w) and the r² value was 0.9936, whereas the HPLC had a LOD of 0.06 % (w/w) and an r² value of 0.9933. The sensitivity of the TGA method was well established using the drug loading studies, as it can detect the low loading of MCM-41 at 2.2 ± 0.21 % (w/w), compared to 5.1 ± 0.12 % (w/w) with the SBA-15. In all samples applied, the multiple comparison analysis showed an insignificant difference between the two methods (p > 0.05). The TGA data presented good evidence for using this technique as a sensitive, cost-effective, and low-variable quantitative analysis in the drug loading determination of the MSNs. TGA is not a selective method of quantification, but optimising the method using the pure and blank samples of MSNs and drug can significantly improve the sensitivity. This work provides a unique approach to apply TGA as a selective and more favourable method to characterise MSNs to do early formulation developments

The surfactant co-formulant POEA in the glyphosate-based herbicide RangerPro but not glyphosate alone causes necrosis in Caco-2 and HepG2 human cell lines and ER stress in the ToxTracker assay

The toxicity of co-formulants present in glyphosate-based herbicides (GBHs) has been widely discussed leading to the European Union banning the polyoxyethylene tallow amine (POEA). We identified the most commonly used POEA, known as POE-15 tallow amine (POE-15), in the widely used US GBH RangerPro. Cytotoxicity assays using human intestinal epithelial Caco-2 and hepatocyte HepG2 cell lines showed that RangerPro and POE-15 are far more cytotoxic than glyphosate alone. RangerPro and POE-15 but not glyphosate caused cell necrosis in both cell lines, and that glyphosate and RangerPro but not POE-15 caused oxidative stress in HepG2 cells. We further tested these pesticide ingredients in the ToxTracker assay, a system used to evaluate a compound's carcinogenic potential, to assess their capability for inducing DNA damage, oxidative stress and an unfolded protein response (endoplasmic reticulum, ER stress). RangerPro and POE-15 but not glyphosate gave rise to ER stress. We conclude that the toxicity resulting from RangerPro exposure is thus multifactorial involving ER stress caused by POE-15 along with oxidative stress caused by glyphosate. Our observations reinforce the need to test both co-formulants and active ingredients of commercial pesticides to inform the enactment of more appropriate regulation and thus better public and environmental protection