Machine learning model for anti-cancer drug combinations: Analysis, prediction, and validation.

Drug combination therapy is a highly effective approach for enhancing the therapeutic efficacy of anti-cancer drugs and overcoming drug resistance. However, the innumerable possible drug combinations make it impractical to screen all synergistic drug pairs. Moreover, biological insights into synergistic drug pairs are still lacking. To address this challenge, we systematically analyzed drug combination datasets curated from multiple databases to identify drug pairs more likely to show synergy. We classified drug pairs based on their MoA and discovered that 110 MoA pairs were significantly enriched in synergy in at least one type of cancer. To improve the accuracy of predicting synergistic effects of drug pairs, we developed a suite of machine learning models that achieve better predictive performance. Unlike most previous methods that were rarely validated by wet-lab experiments, our models were validated using two-dimensional cell lines and three-dimensional tumor slice culture (3D-TSC) models, implying their practical utility. Our prediction and validation results indicated that the combination of the RTK inhibitors Lapatinib and Pazopanib exhibited a strong therapeutic effect in breast cancer by blocking the downstream PI3K/AKT/mTOR signaling pathway. Furthermore, we incorporated molecular features to identify potential biomarkers for synergistic drug pairs, and almost all potential biomarkers found connections between drug targets and corresponding molecular features using protein-protein interaction network. Overall, this study provides valuable insights to complement and guide rational efforts to develop drug combination treatments.

Effects of Red and Infrared Laser Therapy in Patients with Tinnitus: A Double-Blind, Clinical, Randomized Controlled Study Combining Light with Ultrasound, Drugs and Vacuum Therapy.

BACKGROUND: tinnitus is a symptom with no specific cause known to date, and there are no associated pharmacogenomics of hearing disorders and no FDA-approved drugs for tinnitus treatment. The effectiveness of drug treatments is not reproducible on idiopathic patients and inexistent in refractory patients. Personalized treatments for these patients are a great clinical need. Our study investigated the outcome of potential alternative and complementary treatment modalities for idiopathic and refractory tinnitus patients. METHODS: we were the first to evaluate the tinnitus handicap inventory (THI) score changes over the course of treatment up to 15 days after complete cessation of treatment for novel transmeatal low-level laser therapy (LLLT) modalities using light alone, as well as LLLT combined with vacuum therapy (VT), ultrasound (US), Ginkgo biloba (GB) and flunarizine dihydrochloride (FD), while also comparing all treatment outcomes with laser puncture (LP), FD alone and GB alone. RESULTS: a positive treatment outcome (superior to a placebo effect) was achieved by using either LP or transmeatal LLLT, whereas short-term antagonistic effects of VT, US, GB and FD when combined with LLLT. For transmeatal LLLT, an improvement in the treatment outcome was observed by increasing the irradiation time from 6 min to 15 min (with 100-mW of applied laser power at 660 nm). Finally, a lasting therapeutic effect higher than the placebo was observed at 15 days after treatment upon combining LLLT with VT, GB or by using FD alone, by using the transmeatal LLLT alone or by using LP. CONCLUSIONS: LP and Transmeatal LLLT can be promising alternative treatments for idiopathic and refractory tinnitus patients. Future studies should investigate the long-term effects of LLLT in tinnitus patients, as well as the dosimetry and wavelength of transmeatal LLLT.

Molecular recognition of flunarizine dihydrochloride and ß-cyclodextrin inclusion complex by NMR and computational approaches.

BACKGROUND: Flunarizine dihydrochloride (FLN) is used in the prophylactic treatment of migraine, vertigo, occlusive peripheral vascular disease and epilepsy. Cyclodextrins (CDs) are chiral, truncated cone shaped macrocycles known for their inner hydrophobic and outer hydrophilic site. They form complexes with hydrophobic drug molecules and enhance the solubility and bioavailability of such compounds by enhancing drug permeability through mucosal tissues. NMR spectroscopy and computational docking have been recognized as an important tool for the interaction study of CDs-drug inclusion complexes in solution state. RESULTS: The structural assignments of FLN and ß-CD protons were determined by 1H NMR and 2D 1H-1H COSY NMR spectroscopy. 1H NMR spectroscopic studies of FLN, ß-CD and their mixtures confirmed the formation of ß-CD-FLN inclusion complex in solution. 1H NMR titration data for ß-CD-FLN inclusion complex showed 1:1 stoichiometry, an association constant of K a  = 157 M-1 and change in Gibbs free energy of ∆G = - 12.65 kJ mol-1. The binding constant of the ß-CD inclusion complex with two nearly similar structures, FLN and cetirizine dihydrochloride, were compared. Two-dimensional 1H-1H ROESY spectral data and molecular docking studies showed the modes of penetration of the aromatic rings from the wider rim side into the ß-CD cavity. The possible geometrical structures of the ß-CD-FLN inclusion complex have been proposed in which aromatic rings protrude close to the narrower rim of the ß-CD truncated cone. CONCLUSION: NMR spectroscopic studies of FLN, ß-CD and FLN:ß-CD mixtures confirmed the formation of 1:1 inclusion complex in solution at room temperature. Two-dimensional 1H-1H ROESY together with molecular docking study confirmed that the F-substituted aromatic ring of FLN penetrates into ß-CD truncated cone and the tail of aromatic rings were proximal to narrower rim of ß-CD. The splitting of aromatic signals of FLN in the presence of ß-CD suggests chiral differentiation of the guest FLN by ß-CD.

Synergistic effect of 1-butyl-2,3-dimethylimidazolium bis (trifluoromethanesulfonyl) imide and titanium oxide on the redox behaviour of flunarizine in solubilized media.

Titanium oxide nanoparticles and 1-butyl-2,3-dimethylimidazolium bis (trifluoromethanesulfonyl) imide modified glassy carbon electrode (TiO2/IL/GCE) has been fabricated for electrochemical sensing of flunarizine (FRH). The electrochemical properties and morphology of the prepared nanocomposite were studied by electrochemical impedance spectroscopy (EIS) and transmission electron microscopy (TEM). The response of the electrochemical sensor was found to be proportional to the concentrations of FRH in the range from 0.5 µgmL-1 to 16 µgmL-1. The detection limit obtained was 0.03 µgmL-1. The proposed method was also applied to the determination of FRH in pharmaceutical formulation and human serum with good recoveries.

Nanoemulsion for Migraine Prophylaxis Nasal Drug Delivery: Preparation, Characterization and in vitro Evaluation.

BACKGROUND: Flunarizine dihydrochloride is used as a prophylaxis to migraine. Flunarizine dihydrochloride nanoemulsion was fabricated in this research work. Since, it is a low soluble high permeable drug, work was designed to enhance the solubility and the same can be administered as nasal drug delivery for faster onset of action and therapeutic effect. OBJECTIVE: To fabricate a nanoemulsion of flunarizine dihydrochloride by using surfactant and co-surfactants. METHODS: The experimental work involved compatibility studies by using FTIR, crystallinity study by XRD. The prepared nanoemulsion was studied by photon correlation spectroscopy by master sizer 2000 for the particle size analysis and characterized for D10, D50 and D90 MPS, span and uniformity. Further studies were conducted by Laser light scattering technique by delsa nano common and TEM. RESULTS: The study demonstrated that the formulations (FNE 1 -FNE 5) demonstrated the MPS of 14, 22.7, 326.7, 14.3 and 40.73 respectively. The formulae FNE1 and FNE5 demonstrated the MPS of 214.6±179.9 and 2118.6 ±1503.6 with the diameter of 127.8 and 1307, respectively. The zeta potential of FNE1 was -3.84 mV and other parameters such as TEM and drug release studies were also reported. CONCLUSION: The nanoemulsion of Flunarizine dihydrochloride was prepared successfully by using cremophor and labrafil which was better than the existed formula prepared by tween 80. The optimised formula demonstrated lower droplet size, satisfactory zeta potential, and high drug loading reproducible drug release profile.

Development and Validation of a HPTLC Method for Simultaneous Quantitation of Flunarizine Dihydrochloride and Propranolol Hydrochloride in Capsule Dosage Form.

A simple, precise, accurate, and rapid high-performance thin layer chromatographic method has been developed and validated for the simultaneous quantitation of flunarizine dihydrochloride and propranolol hydrochloride in a combined capsule dosage form. The method was carried out on precoated silica gel 60 F254 TLC aluminum plate, (20×10 cm(2)). The solvent system was ethyl acetate:methanol:glacial acetic acid in the proportion of 8:1:1, (v/v/v). R f value for flunarizine dihydrochloride and propranolol hydrochloride was found to be 0.62±0.02 and 0.18±0.02, respectively. The linearity regression analysis for calibration showed 0.999 and 0.999 for flunarizine dihydrochloride and propranolol hydrochloride with respect to peak area and height in the concentration range of 50-350 ng/spot and 500-3500 ng/spot, respectively. Accuracy of recovery studies was found to be 98-100.28 and 99.11-99.45% for flunarizine dihydrochloride and propranolol hydrochloride, respectively. The amounts of drug in marketed formulation were 100.5 and 101.25% of flunarizine dihydrochloride and propranolol hydrochloride, respectively. The method developed can be used for routine analysis in bulk drug and capsule dosage form.