New Compounds Discovery and Development in Medicine — Advances in Research on Potential Therapeutic Agents and Drug Candidates, 2nd Edition

Background: A series of 3,5-benzylidene-4-piperidones, 1a–n, were prepared to evaluate the hypothesis that the placement of different groups in the ortho-location of the aryl rings led to compounds with greater cytotoxic potencies than structural analogs. Methods: The bioevaluation of 1a–n was undertaken using human Molt/4C8 and CEM cells as well as murine L1210 cells. Correlations were sought between the interplanar angles θ_A and θ_B and the cytotoxic potencies. A QSAR analysis was also undertaken. In order to evaluate whether these compounds demonstrated greater toxicity to neoplasms than non-malignant cells, 1a–n were evaluated against HSC-2, HSC-3, HSC-4 and HL60 neoplasms as well as non-malignant HGF, HPC and HPLF cells. Results: A positive correlation was noted between the interplanar angle θ_A of one of the aryl rings and the adjacent olefinic linkage with IC₅₀ values in the Molt4/C8 screens. The QSAR analysis revealed a positive correlation between the Hansch pi (π) value of the aryl substituents and the IC₅₀ values of the compounds towards the Molt4/C8 and CEM cells. The dienones in series 1 demonstrated higher tumor-selective toxicity towards HSC-2, HSC-3, HSC-4 and HL-60 neoplasms than HGF, HPC and HPLF cells. Conclusions: The bioevaluations revealed some support for greater cytotoxic potencies to be displayed by compounds having ortho-substituents. Full article

Background: The activation of the growth hormone receptor (GHR) is a major determinant of body growth. Defective GHR signaling, as seen in human Laron dwarfism, resulted in low plasma IGF-1 concentrations and limited growth, but also marked absence in the development of breast cancer and type 2 diabetes. In vitro, we identified a small molecule (C#1) that inhibits the translation of GHR mRNA to receptor protein. Methods: Before its application in humans as a potential anticancer drug, C#1 was tested in animals to evaluate whether it could be administered to achieve a plasma concentration in vivo that inhibits cell proliferation in vitro without causing unwanted toxicity. To evaluate the efficacy and toxicity of C#1, a group of six intact female Beagle dogs was treated daily each morning for 90 days with an oral solution of C#1 in Soiae oleum emulgatum at a dose of 0.1 mg/kg body weight. During treatment, dogs were closely monitored clinically, and blood samples were taken to measure plasma C#1 concentrations, complete blood counts (CBC), clinical chemistry, and endocrinology. At the end of the treatment, dogs were euthanized for gross and histopathological analysis. An additional group of six female Beagle dogs was included for statistical reasons and only evaluated for efficacy during treatment for 30 days. Results: Daily administration of C#1 resulted in a constant mean plasma concentration of approximately 50 nmol/L. In both groups, two out of six dogs developed decreased appetite and food refusal after 4–5 weeks, and occasionally diarrhea. No significant effects in CBC or routine clinical chemistry were seen. Plasma IGF-1 concentrations, used as biomarkers for defective GHR signaling, significantly decreased by 31% over time. As plasma growth hormone (GH) concentrations decreased by 51% as well, no proof of GHR dysfunction could be established. The measured 43% decrease in plasma acylated/non-acylated ghrelin ratios will also lower plasma GH concentrations by reducing activation of the GH secretagogue receptor (GHSR). C#1 did not directly inhibit the GHSR in vivo, as shown in vitro. There were no significant effects on glucose, lipid, or folate/homocysteine metabolism. Conclusions: It is concluded that with daily dosing of 0.1 mg C#1/kg body weight, the induction of toxic effects prevented further increases in dosage. Due to the concomitant decrease in both IGF-1 and GH, in vivo inhibition of GHR could not be confirmed. Since the concept of specific inhibition of GHR synthesis by small molecules remains a promising strategy, searching for compounds similar to C#1 with lower toxicity should be worthwhile. Full article

Compounds from plant extracts make dermatocosmetic products more effective as they avoid the adaptation and resistance of the organism and achieve a synergistic effect of the molecular properties of interest. Acmella oleracea extract is considered to have great potential in preventing oxidative damage and improving the appearance of the skin. The purpose of this article is to support the product formulated by preliminary studies of two types of O/W emulsions with 3% and 5% concentrations of Acmella oleracea extract. Physico-chemical methods were performed to evaluate the stability, microbiological control, rheological behavior and diffusion through the membrane. Good homogeneity, structural strength and flexibility, adequate skin diffusion, and high physico-chemical and microbiological stability were confirmed. The conclusions lead to the idea that these results require further in vivo studies as well as studies of toxicity and cytotoxicity to obtain the necessary data to place this product on the market. Full article

To evaluate the efficacy of human placenta hydrolysate (HPH) in a mice model of CFA-induced inflammatory pain. TNF-α, IL-1β, and IL-6 are key pro-inflammatory cytokine factors for relieving inflammatory pain. Therefore, this study investigates whether HPH suppresses CFA-induced pain and attenuates the inflammatory process by regulating cytokines. In addition, the relationship between neuropathic pain and HPH was established by staining GFAP and Iba-1 in mice spinal cord tissues. This study was conducted for a total of day 28, and inflammatory pain was induced in mice by injecting CFA into the right paw at day 0 and day 14, respectively. 100 μL of 20% glucose and polydeoxyribonucleotide (PDRN) and 100, 200, and 300 μL of HPH were administered intraperitoneally twice a week. In the CFA-induced group, cold and mechanical allodynia and pro-inflammatory cytokine factors in the spinal cord and plantar tissue were significantly increased. The five groups of drugs evenly reduced pain and gene expression of inflammatory factors, and particularly excellent effects were confirmed in the HPH 200 and 300 groups. Meanwhile, the expression of GFAP and Iba-1 in the spinal cord was increased by CFA administration but decreased by HPH administration, which was confirmed to suppress damage to peripheral ganglia. The present study suggests that HPH attenuates CFA-induced inflammatory pain through inhibition of pro-inflammatory cytokine factors and protection of peripheral nerves. Full article

Glaucoma is the second leading cause of blindness worldwide and is, in most cases, a consequence of elevated intraocular pressure (IOP), ultimately resulting in the death of retinal ganglion cells (RGCs). Current treatments are mostly focused on normalizing IOP, but we propose the additional use of neuroprotective agents, including methylene blue (MB), to block the loss of RGCs. Wistar rats were subjected to episcleral vein cauterization (EVC) in the left eye while the right eye was sham-operated. One week later, they were divided into two groups, which were injected with either 2.0 mg/kg MB or phosphate-buffered saline (PBS), twice a day, for 7 days. Fifteen days after surgery, rats were tested with scotopic electroretinography (ERG) or pattern electroretinography (PERG). After sacrifice, the number of RGCs and the thickness of the inner retina (IR) were evaluated both in the peripheral and central areas of the retina. Scotopic ERG showed a marked reduction (p < 0.0001) on the a- and b-wave amplitude and oscillatory potential (OP) complexity of the eyes subjected to EVC. These parameters were significantly (p < 0.01) restored by the application of MB. PERG indicated that EVC was responsible for a very significant decrease in N2 amplitude (p < 0.0001) and prolongation of N2 implicit time (p < 0.0001). Treatment with MB significantly restored N2 amplitude (p < 0.0001). In parallel with the ERG results, morphological analysis showed a significant loss of RGCs (p < 0.0001) and IR thickness (p < 0.0001) in both the peripheral and central retinas subjected to EVC, which was significantly prevented (p < 0.0001) by MB treatment. We have shown that MB treatment can be effective in preventing physiological and morphological hallmarks of optic neuropathy in a model of ocular hypertension, which faithfully recapitulates human open-angle glaucoma. Due to its high safety profile, this drug could therefore represent a new pharmacologic strategy to prevent vision loss in glaucoma patients. Full article