Autologous conditioned serum (Orthokine) injection for treatment of classical trigeminal neuralgia: results of a single-center case series.

BACKGROUND: Despite some advances, treatment of trigeminal neuralgia remains a significant challenge. This study determines the efficacy and safety of autologous conditioned serum (Orthokine) injection into the foramen oval to treat refractory trigeminal neuralgia. CASE PRESENTATION: This is a consecutive case series from the Pain and Palliative Care Department of Imam Reza University Hospital, Tabriz, Iran. Eleven Iranian patients, eligible according to the inclusion and exclusion criteria, aged 45.64 ±â€Š11.58 years (Four male and seven female, all Iranian) with established classical trigeminal neuralgia were injected with Orthokine (2 mL per injection) once a week for three consecutive weeks (total of four injections). Numeric rating scale scores for facial pain intensity and also carbamazepine daily dose were confirmed at pretreatment (T0) and at week 1 (T1), week 2 (T2), week 3 (T3), week 4 (T4), and month 2 (T5) posttreatment. Pain intensity was significantly reduced in the first 3 weeks of follow-up in comparison with baseline (T0 to T3) (8.18 ± 1.99 to 2.82 ± 2.13, p < 0.001), an effect that was retained at week 4 (T4) and month 2 (T5) follow-ups (2.82 ± 2.13 to 3.36 ± 2.69, p = 0.886). Carbamazepine consumption was significantly reduced in the first 3 weeks of follow-up in comparison with baseline (T0 to T3) (636.36 ± 307.48 to 200.00 ± 296.64, p = 0.003), an effect that was retained at week 4 and month 2 follow-ups (200.00 ± 296.64 to 200.00 ± 282.84, p = 0.802). There were no serious adverse events in participants. CONCLUSION: Orthokine injection led to consistent pain relief and reduced carbamazepine dosage in patients with trigeminal neuralgia, with acceptable safety.

Imino-2H-Chromene Based Derivatives as Potential Anti-Alzheimer's Agents: Design, Synthesis, Biological Evaluation and in Silico Study.

A new series of imino-2H-chromene derivatives were rationally designed and synthesized as novel multifunctional agents against Alzheimer's disease. A set of phenylimino-2H-chromenes as well as the newly synthesized iminochromene derivatives were evaluated as BACE1, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) inhibitors. The results indicated that among the iminochromene set, 10c bearing fluorobenzyl moiety was the most potent BACE1 inhibitor with an IC50 value 6.31 µM. In vitro anti-cholinergic activities demonstrated that compound 10a bearing benzyl pendant was the best inhibitor of AChE (% inhibition at 30 µM=24.4) and BuChE (IC50 =3.3 µM). Kinetic analysis of compound 10a against BuChE was also performed and showed a mixed-type inhibition pattern. The neuroprotective assessment revealed that compound 11b, a phenylimino-2H-chromene derivative with hydroxyethyl moiety, provided 32.3 % protection at 25 µM against Aß-induced PC12 neuronal cell damage. In addition, docking and simulation studies of the most potent compounds against BACE1 and BuChE confirmed the experimental results.

Dual potent c-Met and ALK inhibitors: from common feature pharmacophore modeling to structure based virtual screening.

Everyday plenty of people succumb to various forms of cancer across the world and it stands as one of the main reasons of death in our today's life. Receptor tyrosine kinases (RTKs) are a class of receptors involved in cancer progression. Since aberrant signaling has critical roles in cancer, both c-Met and ALK enzymes are regarded as attractive oncology targets for therapeutic objects. A number of potent dual inhibitors of c-Met and ALK are reported in literature that in the present work we based them to construct multiple common feature pharmacophore models and then applied them for ligand-based virtual screening. The score values of the models ranged from 22.489 to 28.169. The retrieved compounds from virtual screening were subjected to the docking study and the interaction pattern of common hits between two enzymes with high predicted affinity has been investigated. To this end, common hit compound ZINC000223394281 (z1) was directed to the molecular dynamics study and the results indicated that the hydrogen bond interaction between this compound and Asp1222 was mostly stable during the equilibrium time range. The life time of hydrogen bond made between the complex of ALK and Met1199 was also stable in 63%.

Cavity Preparation by Laser in Primary Teeth: Effect of 2 Levels of Energy Output on the Shear Bond Strength of Composite Restoration to Dentin.

Introduction: One of the main applications of laser in dentistry is the removal of dental caries and preparation of restorative cavities. The morphology and wettability of laser prepared surfaces are different from that of those prepared with conventional method which may affect the quality of the adhesive potential of bonding agents in these surfaces. This study aimed to assess the shear bond strength of a total-etch and self-etch adhesive system to primary tooth dentin prepared by two different energy densities of Er:YAG laser in comparison with surfaces prepared by bur. Methods: A total of 60 human primary second molars extracted for orthodontic purposes were selected and randomly divided into 3 main groups of equal (n=20). Group A: Preparation of dentin surface by bur; group B: Preparation of dentin surface by laser with 300 mJ energy level; group C: Preparation of dentin surface by laser with 400 mJ energy level. In each of the main groups, the teeth were randomly assigned to 2 subgroups. Composite resin material was bonded with the total-etch adhesive system in subgroups A1, B1, and C1 and with the self-etch adhesive system in subgroups A2, B2, and C2. The samples were thermo-cycled, and composite restorations shear bond strength was measured in MPa. Data were analyzed using two-way analysis of variance (ANOVA), and P values less than 0.05 were considered statistically significant. Results: The highest and the lowest shear bond strength values were observed in group A2 (Preparation by bur- Composite resin material bonded by Clearfil SE Bond) and group C2 (Preparation by laser with 400 mJ energy level - Composite resin material bonded by Clearfil SE Bond), respectively. The results showed no statistically significant differences between the study subgroups (P > 0.05). Conclusion: It is concluded that in terms of shear bond strength to dentin, Single Bond and Clearfil SE Bond adhesive agents adequately perform in primary tooth dentin prepared by Er: YAG laser with energy levels of 300 and 400 mJ and frequency of 10 Hz.

Clustering and Sampling of the c-Met Conformational Space: A Computational Drug Discovery Study.

BACKGROUND: c-Met kinase plays a critical role in a myriad of human cancers, and a massive scientific work was devoted to design more potent inhibitors. OBJECTIVE: In this study, 16 molecular dynamics simulations of different complexes of potent c-Met inhibitors with U-shaped binding mode were carried out regarding the dynamic ensembles to design novel potent inhibitors. METHODS: A cluster analysis was performed, and the most representative frame of each complex was subjected to the structure-based pharmacophore screening. The GOLD docking program investigated the interaction energy and pattern of output hits from the virtual screening. The most promising hits with the highest scoring values that showed critical interactions with c-Met were presented for ADME/Tox analysis. RESULTS: The screening yielded 45,324 hits that all of them were subjected to the docking studies and 10 of them with the highest-scoring values having diverse structures were presented for ADME/Tox analyses. CONCLUSION: The results indicated that all the hits shared critical Pi-Pi stacked and hydrogen bond interactions with Tyr1230 and Met1160 respectively.

Prediction of cytotoxic activity of a series of 1H-pyrrolo[2,3-b]pyridine derivatives as possible inhibitors of c-Met using molecular fingerprints.

Cancer is a leading cause of death all over the world. HGF/MET signaling pathway is involved in many cancers and its inhibition has great potential as an effective therapeutic intervention. A series of 1H-pyrrolo [2,3-b]pyridine derivatives has recently been identified with cytotoxic activity, and most of them exhibited considerable potencies with IC50 values under 10 µM. The present study was carried out with the specific aim to shed light upon the quantitative structure activity relationship (QSAR) to design and predict the activity of new potent inhibitors using molecular fingerprints and some 2D and 3D descriptors. The built model was statistically significant in terms of R2 = 0.90 and R2pred = 0.91 values. Fingerprint PubchemFP759 (1-chloro-2-methylbenzene) was the most effective fragment in the biological activity and just appeared in the most active compound 7j with a pIC50 value of 8.0. A similarity search study was applied based on compounds 7c and 17e, with reported inhibitory activity against c-Met kinase, which showed that also other compounds could possess similar effects against c-Met enzyme. The most promising compound 7g-cl was subjected to docking and molecular dynamics simulation. Two hydrogen bonds between Lys1110, Met1160, and 7g-cl were stable during the equilibrium time range. The suggested modifications might be considered in future studies to design more efficient anticancer agents.