Additional file 2: of Prediction of HIV-1 protease cleavage site using a combination of sequence, structural, and physicochemical features

The 1625 dataset. (PDF 599 kb

Additional file 5: of Prediction of HIV-1 protease cleavage site using a combination of sequence, structural, and physicochemical features

The ROC plots for the four benchmark datasets. (PDF 675 kb

Aggregation and Morphological Aptitude of Drug-Based Ionic Liquids in Aqueous Solution

Here, we present how replacing the usual inorganic counter ion with a pharmaceutically active aromatic one can greatly affect the interfacial as well as bulk properties of ionic liquids (ILs). We have synthesized a series of novel drug-based ILs, namely, 1-alkyl-3-methylimidazolium diclofenate ([C<i>_n</i>mim]­[DF]; <i>n</i> = 6, 8, 10, 12, and 14) abbreviated as DF-ILs, wherein DF^– is a well-recognized analgesic and nonsteroidal anti-inflammatory drug. We show strong synergistic interactions between C<i>_n</i>mim⁺ and aromatic DF^– attributed to reduced electrostatic repulsions and increased hydrophobicity from their incorporation, reflecting a 300-fold smaller critical aggregation concentration than that of their Cl^– analogue [C<i>_n</i>mim]­[Cl]. Interfacial properties for such strongly associating systems are discussed and clearly established to have remarkably improved properties than those of their Cl^– analogues. The decreasing polarity of the cybotactic region of pyrene with increase in the chain length “<i>n</i>” indicates an increased extent of packing of cationic head groups in the Stern layer. DF^– ion seems to play a vital role in the formation of the resulting aggregates, as probed by small angle neutron scattering and transmission electron microscopy. The thermodynamical insights of the aggregation process have been studied using isothermal titration calorimetry and temperature-dependent conductivity experiments. Unilamellar vesicles are formed at extremely low concentration, and also it is the first report that puts into picture the formation of vesicles for [C₆mim]­[DF] with such a short chain

Composition and Concentration Gradient Induced Structural Transition from Micelles to Vesicles in the Mixed System of Ionic Liquid–Diclofenac Sodium

Catanionic surfactant–hydrotrope mixtures have proven to be a striking alternative to tune microstructures over a wide range of compositions and also to minimize precipitation that is normally observed in catanionic mixtures at an equimolar ratio. These mixtures are supposed to be of great relevance in biological systems when a hydrotrope is a “drug”. Keeping this in view, here we report composition- and dilution-induced structural changes in a catanionic mixture comprising ionic liquids (ILs), such as 1-dodecyl-3-methylimidazolium bromide (C₁₂mimBr)/1-tetradecyl-3-methylimidazolium bromide (C₁₄mimBr), and a drug, diclofenac sodium (DFNa), in aqueous solution. The structural changes are probed by small-angle neutron scattering (SANS), dynamic light scattering (DLS), and zeta-potential measurements. SANS data and size distribution curves clearly depict the formation of low curvature structures on going from the cation-rich to anion-rich composition up to a 0.7 mole fraction of DFNa (<i>X</i>_DFNa). The amphiphilic nature of DFNa is supposed to alter the surface charge density, which is provoked by its incorporation into resulting aggregates, as confirmed by modified zeta-potential values. The modification of the average packing parameter resulting from the IL and DFNa complexation equilibrium seems to play a vital role in bringing out structural transitions of mixed aggregates. We also focused our attention to study the effect of dilution in concentrations ranging from 100 to 25 mM. At <i>X</i>_DFNa = 0.0 and 0.1, the size of prolate ellipsoids decreases on dilution, mimicking classic behavior, but an opposite trend is observed at other <i>X</i>_DFNa values. Dilution-induced transformation to larger aggregates is thought to be driven by the release of DFNa molecules from the mixed micelles on account of the critical micelle concentration (cmc) (solubility) mismatch between the two components. The role of other interactions such as cation−π and π–π in stabilizing the mixed aggregates in addition to hydrophobic interactions is probed by ¹H NMR

<i>SLC22A1</i> and <i>ABCB1</i> haplotypes association with imatinib pharmacokinetics in Asian patients with CML (n = 38).

<p><i>SLC22A1 and ABCB1</i> haplotypes were stratified according to specific combination haplotype profiles and associations were checked with imatinib (A) clearance, CL and (B) trough concentration, C_0h. A trend towards low clearance and high C_0h was observed from S_low-A_low, S_low-A_high, S_high-A_low to S_high-A_high. The simultaneous possession of S_low with A_low was associated with a 73.2% higher clearance and 41.2% lower trough concentration than patients carrying other haplotype combinations.</p

<i>SLC22A1</i> haplotypes association with imatinib pharmacokinetics in Asian patients with CML (n = 38).

<p>The patients were divided in two groups according to copy numbers of <i>SLC22A1</i> haplotypes AGT and CGC, S_low (0 or 1 copy) and S_high (2 copies). <i>SLC22A1</i> haplotypes were significantly associated with imatinib (A) clearance, CL and (B) trough concentration, C_0h. Patients harboring S_high haplotypes had 33.4% lower clearance and 50% higher trough concentration than patients with S_low haplotypes_.</p

Linkage disequilibrium plots of <i>SLC22A1</i> polymorphisms in healthy Asians.

<p>Pairwise LD matrices represent moderate to strong linkage between <i>SLC22A1</i> polymorphisms among (A) Chinese, (B) Malay and (C) Indian ethnic groups.</p

<em>SLC22A1-ABCB1</em> Haplotype Profiles Predict Imatinib Pharmacokinetics in Asian Patients with Chronic Myeloid Leukemia

<div><h3>Objective</h3><p>This study aimed to explore the influence of <em>SLC22A1, PXR, ABCG2, ABCB1 and CYP3A5*3</em> genetic polymorphisms on imatinib mesylate (IM) pharmacokinetics in Asian patients with chronic myeloid leukemia (CML).</p> <h3>Patients and Methods</h3><p>Healthy subjects belonging to three Asian populations (Chinese, Malay, Indian; n = 70 each) and CML patients (n = 38) were enrolled in a prospective pharmacogenetics study. Imatinib trough (C_0h) and clearance (CL) were determined in the patients at steady state. Haplowalk method was applied to infer the haplotypes and generalized linear model (GLM) to estimate haplotypic effects on IM pharmacokinetics. Association of haplotype copy numbers with IM pharmacokinetics was defined by Mann-Whitney U test.</p> <h3>Results</h3><p>Global haplotype score statistics revealed a <em>SLC22A1</em> sub-haplotypic region encompassing three polymorphisms (rs3798168, rs628031 and IVS7+850C>T), to be significantly associated with IM clearance (<em>p</em> = 0.013). Haplotype-specific GLM estimated that the haplotypes AGT and CGC were both associated with 22% decrease in clearance compared to CAC [CL (*10⁻² L/hr/mg): CAC vs AGT: 4.03 vs 3.16, <em>p</em> = 0.017; CAC vs CGC: 4.03 vs 3.15, <em>p</em> = 0.017]. Patients harboring 2 copies of AGT or CGC haplotypes had 33.4% lower clearance and 50% higher C_0h than patients carrying 0 or 1 copy [CL (*10⁻² L/hr/mg): 2.19 vs 3.29, <em>p</em> = 0.026; C_0h (*10⁻⁶ 1/ml): 4.76 vs 3.17, <em>p</em> = 0.013, respectively]. Further subgroup analysis revealed <em>SLC22A1</em> and <em>ABCB1</em> haplotypic combinations to be significantly associated with clearance and C_0h (<em>p</em> = 0.002 and 0.009, respectively).</p> <h3>Conclusion</h3><p>This exploratory study suggests that <em>SLC22A1-ABCB1</em> haplotypes may influence IM pharmacokinetics in Asian CML patients.</p> </div

Influence of <i>SLC22A1</i> haplotypes on imatinib clearance, CL and trough concentration, C_0h using haplotype specific generalized linear model.

a<p>Reference: Imatinib pharmacokinetics parameters values corresponding to haplotype CAC were used as reference to compare with other three haplotypes.</p

Clinical correlates with imatinib trough in patients on 400 mg standard dose.

<p>Associations of clinico-demographic characteristics and response parameters with imatinib trough and <i>SLC22A1</i> haplotypes were evaluated statistically. Abbreviations: CCyR, complete cytogenetic response; MMR, major molecular response; BMI, body mass index; BSA, body surface area.</p>a, b, c<p><i>p</i>-values were calculated using ^aMann-Whitney, ^bFisher exact and ^cKendall Tau correlation tests, respectively.</p