Drug Combination Testing with in Vitro Clonal Cultures

1984 ◽  
pp. 224-231 ◽  
Author(s):  
M. S. Aapro
Keyword(s):  
Drug Combination ◽  
Clonal Cultures

scholarly journals SUSTAINED RELEASE TABLETS OF SORAFENIB-SILIBININ COMBINATIONS FOR THE TREATMENT OF HEPATOCELLULAR CARCINOMA

2018 ◽  
Vol 10 (5) ◽  
pp. 117
Author(s):  
Savita Mishra ◽  
Sandhya Hora ◽  
Vibha Shukla ◽  
Mukul Das ◽  
Harsha Kharkwal ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Drug Release ◽  
Sustained Release ◽  
Cell Line ◽  
Binding Affinity ◽  
Drug Combination ◽  
Docking Studies ◽  
Molecular Docking Studies ◽  
Weight Variation

Objective: The aim of this study was to develop polymer coated sustained release tablet using sorafenib and silibinin combination for the treatment of hepatocellular carcinoma.Methods: The qualitative analysis such as weight variation, friability, hardness, interaction studies, disintegration and in vitro release were performed to validate formulated tablets. We have maintained the acceptable official limits for weight variation, friability, hardness and disintegration time according to prescribed pharmacopoeial recommendation. In vitro drug release studies were performed using USP-II (paddle type) dissolution apparatus. The MTT assay was performed for assessment of Cell viability of drug combination for tablet formulation. Molecular docking studies have been performed to determine the combinatorial mode of action for the tablet formulation.Results: Friability and weight variation were less than 1% for each formulation, which were within range of prescribed pharmacopoeial recommendation. The hardness of 20 tablets showed 5-6.5Kg/cm2 for all formulations 5-6.5Kg/cm2. The optimized formulation resulted in 98% drug release after 28 h. The present study reports the synergistic effects of drug combination to inhibit cell growth in HepG2 cell line. Molecular docking studies showed that sorafenib has high binding affinity for B-Raf vascular endothelial growth factor receptor β and protein kinase B. Silibinin showed binding affinity with MAP kinase-11, protein phosphatase 2 A and tankyrase.Conclusion: The present study reports for the first time a novel formulation for sustained release and reduced toxicity of sorafenib with enhanced inhibitory effect of the drug combination on cancerous hepatic cell line as well collaborative mechanism of action for the formulation.

scholarly journals IN VITRO STUDY OF URSOLIC ACID COMBINATION FIRST-LINE ANTITUBERCULOSIS DRUGS AGAINST DRUG-SENSITIVE AND DRUG-RESISTANT STRAINS OF Mycobacterium tuberculosis

2017 ◽  
Vol 10 (4) ◽  
pp. 216 ◽  
Author(s):  
Dian Ayu Eka Pitaloka ◽  
Elin Yulinah Sukandar
Keyword(s):  
Ursolic Acid ◽  
Drug Combination ◽  
Resistant Strain ◽  
Inhibitory Concentration ◽  
In Vitro Study ◽  
Antimycobacterial Activity ◽  
Multidrug Resistant ◽  
Minimum Concentration ◽  
Different Strains

Objective: The resurgence of tuberculosis (TB) caused by Mycobacterium TB (MTB) is associated with the rapid spread of multidrug-resistant,therefore, the development of new antimycobacterial agents is necessary. The aim of this study was to evaluate the antimycobacterial activity ofursolic acid (UA) when it using alone and combination with TB drugs.Methods: MTB H37Rv strain, streptomycin-rifampicin resistant strain, and isoniazid-ethambutol resistant strain were evaluated by susceptibility testusing a serial number of UA (25-150 µg/mL). Minimum inhibitory concentration (MIC) was read as minimum concentration of drugs that completelyinhibit visible growth of organism. Activities of drug combination of UA with TB drug were determined in Lowenstein-Jensen media by calculatingthe fractional inhibitory concentration index.Results: The results showed that MIC of UA was 50 µg/mL against three different strains of MTB. The combination of UA and TB drugs displayedsynergistic interaction, and no antagonism result from the combination was observed for strains of MTB.Conclusion: These results indicate that UA may serve as a promising lead compound for future antimycobacterial drug development.Keywords: Ursolic acid, Tuberculosis, Drug combination, Susceptibility test

Evaluation of drug combination for glioblastoma based on an intestine–liver metabolic model on microchip

The Analyst ◽  
2017 ◽  
Vol 142 (19) ◽  
pp. 3629-3638 ◽  
Author(s):  
Mingsha Jie ◽  
Sifeng Mao ◽  
Hanyang Liu ◽  
Ziyi He ◽  
Hai-Fang Li ◽  
...  
Keyword(s):  
Drug Combination ◽  
Metabolic Model

Evaluation of drug combination and metabolism by constructing an in vitro intestine–liver–glioblastoma biomimetic model.

scholarly journals Clonal Heterogeneity in the Neuronal and Glial Differentiation of Dental Pulp Stem/Progenitor Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Fraser I. Young ◽  
Vsevolod Telezhkin ◽  
Sarah J. Youde ◽  
Martin S. Langley ◽  
Maria Stack ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Dental Pulp ◽  
Experimental Models ◽  
Cellular Heterogeneity ◽  
Striatal Neurons ◽  
Cord Injury ◽  
Clonal Cultures ◽  
Important Challenge ◽  
A Cell

Cellular heterogeneity presents an important challenge to the development of cell-based therapies where there is a fundamental requirement for predictable and reproducible outcomes. Transplanted Dental Pulp Stem/Progenitor Cells (DPSCs) have demonstrated early promise in experimental models of spinal cord injury and stroke, despite limited evidence of neuronal and glial-like differentiation after transplantation. Here, we report, for the first time, on the ability of single cell-derived clonal cultures of murine DPSCs to differentiatein vitrointo immature neuronal-like and oligodendrocyte-like cells. Importantly, only DPSC clones with high nestin mRNA expression levels were found to successfully differentiate into Map2 and NF-positive neuronal-like cells. Neuronally differentiated DPSCs possessed a membrane capacitance comparable with primary cultured striatal neurons and small inward voltage-activated K+but not outward Na+currents were recorded suggesting a functionally immature phenotype. Similarly, only high nestin-expressing clones demonstrated the ability to adopt Olig1, Olig2, and MBP-positive immature oligodendrocyte-like phenotype. Together, these results demonstrate that appropriate markers may be used to provide an early indication of the suitability of a cell population for purposes where differentiation into a specific lineage may be beneficial and highlight that further understanding of heterogeneity within mixed cellular populations is required.

Nimbolide from Azadirachta indica and its derivatives plus first-generation cephalosporin antibiotics: a novel drug combination for wound-infecting pathogens

RSC Advances ◽  
2015 ◽  
Vol 5 (109) ◽  
pp. 89503-89514 ◽  
Author(s):  
S. R. Dhanya ◽  
S. Nishanth Kumar ◽  
Vandana Sankar ◽  
K. G. Raghu ◽  
B. S. Dileep Kumar ◽  
...  
Keyword(s):  
Azadirachta Indica ◽  
Drug Combination ◽  
First Generation ◽  
Bacterial Pathogens ◽  
Generation Cephalosporin ◽  
Amide Derivatives ◽  
Cephalosporin Antibiotics ◽  
Novel Drug ◽  
Derivatives Of

We evaluate the in vitro efficacy of nimbolide, desacetylnimbin, and the amide derivatives of nimbolide in combination with first-generation cephalosporin antibiotics against major wound-associated bacterial pathogens.

scholarly journals Activities of the human immunodeficiency virus type 1 (HIV-1) protease inhibitor nelfinavir mesylate in combination with reverse transcriptase and protease inhibitors against acute HIV-1 infection in vitro.

1997 ◽  
Vol 41 (10) ◽  
pp. 2159-2164 ◽  
Author(s):  
A K Patick ◽  
T J Boritzki ◽  
L A Bloom
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitors ◽  
Drug Combination ◽  
Cellular Cytotoxicity ◽  
Immunodeficiency Virus ◽  
Nelfinavir Mesylate ◽  
Acute Hiv ◽  
Hiv 1

Nelfinavir mesylate (formerly AG1343) is a potent and selective, nonpeptidic inhibitor of human immunodeficiency virus type 1 (HIV-1) protease that was discovered by protein structure-based design methodologies. We evaluated the antiviral and cytotoxic effects of two-drug combinations of nelfinavir with the clinically approved antiretroviral therapeutics zidovudine (ZDV), lamivudine (3TC), dideoxycytidine (ddC; zalcitabine), stavudine (d4T), didanosine (ddI), indinavir, saquinavir, and ritonavir and a three-drug combination of nelfinavir with ZDV and 3TC against an acute HIV-1 strain RF infection of CEM-SS cells in vitro. Quantitative assessment of drug interaction was evaluated by a universal response surface approach (W. R. Greco, G. Bravo, and J. C. Parsons, Pharm. Rev. 47:331-385, 1995) and by the method of M. N. Prichard and C. Shipman (Antiviral Res. 14:181-206, 1990). Both analytical methods yielded similar results and showed that the two-drug combinations of nelfinavir with the reverse transcriptase inhibitors ZDV, 3TC, ddI, d4T, and ddC and the three-drug combination with ZDV and 3TC resulted in additive to statistically significant synergistic interactions. In a similar manner, the combination of nelfinavir with the three protease inhibitors resulted in additive (ritonavir and saquinavir) to slightly antagonistic (indinavir) interactions. In all combinations, minimal cellular cytotoxicity was observed with any drug alone and in combination. These results suggest that administration of combinations of the appropriate doses of nelfinavir with other currently approved antiretroviral therapeutic agents in vivo may result in enhanced antiviral activity with no associated increase in cellular cytotoxicity.

Soluble Interleukin-6 (IL-6) Receptor With IL-6 Stimulates Megakaryopoiesis From Human CD34+ Cells Through Glycoprotein (gp)130 Signaling

Blood ◽  
1999 ◽  
Vol 93 (8) ◽  
pp. 2525-2532 ◽  
Author(s):  
Xingwei Sui ◽  
Kohichiro Tsuji ◽  
Yasuhiro Ebihara ◽  
Ryuhei Tanaka ◽  
Kenji Muraoka ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Ex Vivo ◽  
Serum Free ◽  
Human Cd34 ◽  
Receptor Component ◽  
Cd34 Cells ◽  
Interleukin 6 Receptor ◽  
Clonal Cultures

Abstract We have recently shown that stimulation of glycoprotein (gp) 130, the membrane-anchored signal transducing receptor component of IL-6, by a complex of human soluble interleukin-6 receptor (sIL-6R) and IL-6 (sIL-6R/IL-6), potently stimulates the ex vivo expansion as well as erythropoiesis of human stem/progenitor cells in the presence of stem cell factor (SCF). Here we show that sIL-6R dose-dependently enhanced the generation of megakaryocytes (Mks) (IIbIIIa-positive cells) from human CD34+ cells in serum-free suspension culture supplemented with IL-6 and SCF. The sIL-6R/IL-6 complex also synergistically acted with IL-3 and thrombopoietin (TPO) on the generation of Mks from CD34+ cells, whereas the synergy of IL-6 alone with TPO was barely detectable. Accordingly, the addition of sIL-6R to the combination of SCF + IL-6 also supported a substantial number of Mk colonies from CD34+ cells in serum-free methylcellulose culture, whereas SCF + IL-6 in the absence of sIL-6R rarely induced Mk colonies. The addition of monoclonal antibodies against gp130 to the suspension and clonal cultures completely abrogated the megakaryopoiesis induced by sIL-6R/IL-6 in the presence of SCF, whereas an anti-TPO antibody did not, indicating that the observed megakaryopoiesis by sIL-6R/IL-6 is a response to gp130 signaling and independent of TPO. Furthermore, human CD34+ cells were subfractionated into two populations of IL-6R–negative (CD34+ IL-6R−) and IL-6R–positive (CD34+ IL-6R+) cells by fluorescence-activated cell sorting. The CD34+IL-6R− cells produced a number of Mks as well as Mk colonies in cultures supplemented with sIL-6R/IL-6 or TPO in the presence of SCF. In contrast, CD34+ IL-6R+cells generated much less Mks and lacked Mk colony forming activity under the same conditions. Collectively, the present results indicate that most of the human Mk progenitors do not express IL-6R, and that sIL-6R confers the responsiveness of human Mk progenitors to IL-6. Together with the presence of functional sIL-6R in human serum and relative unresponsiveness of human Mk progenitors to IL-6 in vitro, current results suggest that the role of IL-6 may be mainly mediated by sIL-6R, and that the gp130 signaling initiated by the sIL-6R/ IL-6 complex is involved in human megakaryopoiesis in vivo.

scholarly journals Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozole

2018 ◽  
Vol 10 ◽  
pp. 175883591878685 ◽  
Author(s):  
Hiroshi Umehara ◽  
Yoshimi Maekawa ◽  
Fumito Koizumi ◽  
Makiko Shimizu ◽  
Toshio Ota ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Drug Combination ◽  
Phase I Trial ◽  
Kinase Inhibitor ◽  
Her2 Positive ◽  
Grade 3 ◽  
Mcf 7

Background: KW-2450 is an oral dual insulin-like growth factor-1 receptor/insulin receptor tyrosine kinase inhibitor. We investigated the in vitro and in vivo preclinical activity of KW-2450 plus lapatinib and letrozole and conducted a phase I trial of the triple-drug combination in one male and 10 postmenopausal female patients with advanced/metastatic hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Methods: A series of in vitro and in vivo animal studies was undertaken of KW-2450 in combination with lapatinib and hormonal agents. The phase I trial was conducted to establish the safety, tolerability, and recommended phase II dose (RP2D) of KW-2450 administered in combination with lapatinib and letrozole. Results: Preclinical studies showed KW-2450 and lapatinib act synergistically to induce in vitro apoptosis and inhibit growth of HER2-positive MDA-MB-361 and BT-474 breast cancer cell lines. This combined effect was confirmed in vivo using the MDA-MB-361 xenograft model. KW-2450 showed synergistic in vitro growth inhibition with letrozole and 4-hydroxytamoxifen in ER-positive MCF-7 breast cancer cells and MCF-7-Ac1 aromatase-transfected MCF-7 cells. In the phase I study, dose-limiting toxicity (DLT; grade 3 rash and grade 3 hyperglycemia, respectively) occurred in two of three patients at the dose of KW-2450 25 mg/day plus lapatinib 1500 mg/day and letrozole 2.5 mg/day. The RP2D of the triple-drug combination was established as KW-2450 25 mg/day, lapatinib 1250 mg/day, and letrozole 2.5 mg/day with no DLT at this dose level. Conclusions: The proposed phase II study of the RP2D for the triple-drug combination did not progress because of anticipated difficulty in patient enrollment and further clinical development of KW-2450 was terminated.

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