Molecular modeling studies on structural requirement of diarylpropionitrile for selectivity to estrogen receptor subtypes

Molecular modeling techniques are widely used to discover drug candidates for selective disease. In the present study, ligand-based drug design techniques have been explored to find the structural requirement of diarylpropionitrile derivatives, a group of non-steroidal estrogen receptor (ER) modulators for selective binding to receptor subtypes. 2D/3D quantitative structure activity relationship (QSAR) and pharmacophore space modeling studies have been explored for this purpose. The classical QSAR models (R _α ² ?=?0.870, Q _α ² ?=?0.813, R _α-pred ² ?=?0.636; R _β ² ?=?0.853, Q _β ² ?=?0.745, R _β-pred ² ?=?0.565) show the importance of molecular refractivity, electronic contribution of atoms C₃, C₇, C₁₃ and C₁₄, and R₂ and R₄ substituents (Fig.?1) for specificity. The 3D QSAR, molecular fields (CoMFA, R _α ² ?=?0.999, Q _α ² ?=?0.679, R _α-pred ² ?=?0.678 and R _β ² ?=?0.999, Q _β ² ?=?0.611, R _β-pred ² ?=?0.691) and similarity (CoMSIA, R _α ² ?=?0.999, Q _α ² ?=?0.670, R _α-pred ² ?=?0.686 and R _β ² ?=?0.999, Q _β ² ?=?0.671, R _β-pred ² ?=?0.590) analyses show contour maps of steric, hydrophobic along with hydrogen bond (HB) donor and acceptor are important factors for binding affinity to both α- and β-subtypes. In addition, electronic contribution is crucial for α-subtype binding. Pharmacophore models derive the importance of HB acceptor and donor, aromatic ring, molecular steric, and hydrophobic interactions for selective binding to receptor subtypes. The derived models are correlated with structure-based molecular docking study, explaining the significant interactions between receptor and ligand for selective subtypes binding.

Mechanistic Modeling of Monocarboxylate Transporter-Mediated Toxicokinetic/Toxicodynamic Interactions Between γ-Hydroxybutyrate and l-Lactate

Overdose of γ-hydroxybutyrate (GHB) can result in severe respiratory depression. Monocarboxylate transporter (MCT) inhibitors, including l-lactate, increase GHB clearance and represent a potential treatment for GHB intoxication. GHB can also affect l-lactate clearance, and l-lactate has been reported to affect respiration. In this research, we characterize these toxicokinetic/toxicodynamic interactions between GHB and l-lactate using mechanistic modeling. Plasma, urine, and respiration data were taken from our previous study in which GHB and sodium l-lactate were administered alone and concomitantly in rats. A model incorporating active renal reabsorption for both agents fit GHB and l-lactate toxicokinetic data. The K_m for renal reabsorption of GHB (650 μg/mL) was close to its K_m for the proton-dependent MCT1 and that for l-lactate (13.5 μg/mL) close to its K_m for the sodium-dependent SMCT1. Inhibition of reabsorption by both agents was necessary to model concomitant drug administration. The metabolic K_m for l-lactate closely resembled that for MCT-mediated hepatic uptake in vitro, and GHB inhibited this process. l-lactate significantly inhibited respiration at a high dose, and an indirect response model was used to fit these data. GHB toxicodynamics was modeled as a direct effect delayed by nonlinear transport into the brain extracellular fluid, with a K_m value of 1,865 μg/mL for brain uptake which is similar to the in vitro K_m value determined in rat brain endothelial cells. This model was useful for characterizing multiple MCT-mediated interactions. Incorporation of many parameters that can be determined in vitro may allow for clinical translation of these interactions.     

Improved superaugmented eccentric connectivity indices

Topochemical versions of all the four superaugmented eccentric connectivity indices (denoted by: ^SAc ξ₄ ^c, ^SAc ξ₅ ^c, ^SAc ξ ₆ ^c , and ^SAc ξ ₇ ^c ) were utilized for the development of models for prediction of hiCE and hCE1 inhibitory activities. The values of these topochemical indices were computed for each of the 65 analogs constituting the data set using an in-house computer program. Resulting data was analyzed and suitable models were developed after identification of the active ranges by maximization of moving average with regard to active derivatives. Subsequently, two biological activities were assigned to each analog using proposed models, which were then compared with the reported hiCE and hCE1 inhibitory activities. Statistical significance of topological indices/models was investigated through sensitivity, specificity, and Matthews correlation coefficient (MCC). The overall accuracy of prediction varied from a minimum of 81% for a model based upon ^SAc ξ ₄ ^c to a maximum of 92% in case of a model based upon ^SAc ξ ₅ ^c with regard to hiCE inhibitory activity and from a minimum of 85% for a model based upon ^SAc ξ ₄ ^c to a maximum of 94% in case of a model based upon ^SAc ξ ₇ ^c with regard to hCE1 inhibitory activity. An excellent relationship between new generation superaugmented eccentric connectivity topochemical indices ( ^SAc ξ ₄ ^c , ^SAc ξ ₅ ^c , ^SAc ξ ₆ ^c , and ^SAc ξ ₇ ^c ) and hiCE and hCE1 inhibitory activities can be attributed to the sensitivity of the proposed topological indices toward nature, number, and relative position of heteroatom. High predictability amalgamated with high potency of the active ranges offer proposed models a vast potential for providing lead structures for development of potent and selective hiCE and hCE1 inhibitors.     

Relationship between plasma or serum drug concentration and amount of drug in the body at steady state upon multiple dosing

The average amount of drug in the body at steady state ( \(\bar X\) )upon repetitive dosing in a two-compartment open system is related to the average steady-state plasma level ( \(\bar C\) )by the apparent volume of distribution at steady state V_ss rather than by V_β,the apparent volume of distribution at pseudodistribution equilibrium, despite the fact that \(\bar C\) is directly proportional to 1/V_β.Multiplication of \(\bar C\) by \(\ddot V_\beta \) results in an overestimate of \(\bar X\) the magnitude of which depends on the distribution and elimination parameters of the drug. The significance and utility of the volume parameters, V_β and V_ss,employed in multicompartment systems are considered.     

Application of in vitro-in vivo extrapolation (IVIVE) and physiologically based pharmacokinetic (PBPK) modelling to investigate the impact of the CYP2C8 polymorphism on rosiglitazone exposure

Purpose

To predict the impact of the CYP2C8*3 genotype on rosiglitazone exposure in the absence and presence of trimethoprim.

Methods

Prior in vitro and in vivo information for rosiglitazone and trimethoprim were collated from the literature. Specifically, data on the frequency of the different allelic forms of CYP2C8 and their metabolic activity for rosiglitazone were incorporated into a physiologically-based pharmacokinetic (PBPK) model within the Simcyp Simulator (V11.1) to predict differences in the relative exposure of rosiglitazone according to CYP2C8*3 genotype in a virtual population.

Results

Following multiple doses of 8 mg rosiglitazone, the predicted mean AUC_(0–24) was 37 % lower in CYP2C8*3 homozygotes compared with wildtype homozygotes (p?< ?0.001), which was consistent with the 36 % lower value observed in vivo (p?< ?0.001) Kirchheiner et al. (Clin Pharmacol Ther 80:657–667, 2006). Predicted median AUC ratios of rosiglitazone in the presence and absence of trimethoprim ranged from 1.35 to 1.66 for ten virtual trials of subjects with the CYP2C8*1/*1 genotype, which included the observed value of 1.42. In subjects with the CYP2C8*1/*3 genotype, the predicted AUC ratios for all trials were higher than the observed value of 1.18 Kirchheiner et al. (Clin Pharmacol Ther 80:657–667, 2006).

Conclusions

Investigating the drug interactions in individuals with rare allelic forms of drug metabolising enzymes is fraught with many practical problems. Current study demonstrates the utility of prior in vitro metabolism data from such allelic forms to predict the relative exposure of a drug as a function of genotype. However, in vitro inhibition data obtained in one allelic variant (e.g. CYP2C8*1) may not be adequate to predict the in vivo interactions in another allele (e.g. CYP2C8*3), since the inhibitory characteristics of perpetrator might be different in each allelic variant in the same way as that of metabolism of the victim drug by such variants of the enzyme.     

In situ relationships between spatial–temporal variations in potential ecological risk indexes for metals and the short-term effects on periphyton in a macrophyte-dominated lake: a comparison of structural and functional metrics

Heavy metals may adversely affect the structure and function of the periphyton community in lake ecosystems. We carried out samplings of three habitats at eight sites located in the Lake Baiyangdian that is strongly influenced by wastewater discharge (Sites 1 and 2), aquaculture and densely populated villages (Sites 3, 6, and 8), and the least disturbed (Sites 4, 5, and 7). Cu, Ni, Pb, Zn, Hg, Cd, and Cr were determined in these samples, and the periphyton community was simultaneously studied. The contamination factor (C _f ⁱ ) was estimated for every metal as the ratio between pre-industrial records from sediments (C _n ⁱ ) and present concentration values (C ⁱ ), and the individual potential risk (E _r ⁱ ) was calculated by multiply the toxic response factor (Tr ⁱ ) and C _f ⁱ for a given substance were based on Hakanson’s methodology. The RI was obtained for each sampling site by summing the values of E _r ⁱ first and the average was calculated across the sampling sites. The results showed that the RI for all three habitats was lower than 94, and they are in decreasing order: wastewater discharge, aquaculture and densely populated villages, and the least anthropogenic impacted. When the three sampling seasons were compared, August appeared to show the highest risk, followed by April and November. The RI values showed negative correlations (r = ?0.444 to ?0.851, p < 0.05) with the structural and functional metrics. The best correlation was detected between chlorophyll c/chlorophyll a (Chl c/a) ratio and E _r ⁱ Hg (r = ?0.851, p < 0.01). Our results suggest the periphyton community can be used in bio-monitoring.     

Bayesian Approach to Estimate AUC,Partition Coefficient and Drug Targeting Index for Studies with Serial Sacrifice Design

Purpose

The current study presents a Bayesian approach to non-compartmental analysis (NCA), which provides the accurate and precise estimate of AUC ₀ ^∞ and any AUC ₀ ^∞ -based NCA parameter or derivation.

Methods

In order to assess the performance of the proposed method, 1,000 simulated datasets were generated in different scenarios. A Bayesian method was used to estimate the tissue and plasma AUC ₀ ^∞ s and the tissue-to-plasma AUC ₀ ^∞ ratio. The posterior medians and the coverage of 95% credible intervals for the true parameter values were examined. The method was applied to laboratory data from a mice brain distribution study with serial sacrifice design for illustration.

Results

Bayesian NCA approach is accurate and precise in point estimation of the AUC ₀ ^∞ and the partition coefficient under a serial sacrifice design. It also provides a consistently good variance estimate, even considering the variability of the data and the physiological structure of the pharmacokinetic model. The application in the case study obtained a physiologically reasonable posterior distribution of AUC, with a posterior median close to the value estimated by classic Bailer-type methods.

Conclusions

This Bayesian NCA approach for sparse data analysis provides statistical inference on the variability of AUC ₀ ^∞ -based parameters such as partition coefficient and drug targeting index, so that the comparison of these parameters following destructive sampling becomes statistically feasible.     

The Bateman function revisited: A critical reevaluation of the quantitative expressions to characterize concentrations in the one compartment body model as a function of time with first-order invasion and first-order elimination

The Bateman function, $A''(e^{ - k_e t} - e^{ - k_a t} )$ , quantifies the time course of a first-order invasion (rate constant k_a) to, and a first-order elimination (rate constant k_e) from, a one-compartment body model where A″=(γDose)k_a/(k _a?k _e) V. The rate constants (whenk _a>3k _e) are frequently determined mined by the “method of residuals” or “feathering”. The rate constantk _a is actually the sum of rate constants for the removal of drug from the invading compartment. “Flip-flop”, the interchange of the values of the evaluated rate constants, occurs whenk _e>3k _a. Whether ?k _a or ?k _e is estimable from the terminal lnC-t slope can be determined from which apparent volume of distribution,V, derived from the Baterman function is the most reasonable. The Bateman function and “feathering” fail when the rate constants are equal. The time course is then expressed byC=γDtk e ^?kt . The determination of such equalk values can be obtained by the nonlinear fitting of suchC-t data with random error to the Bateman function. Also, rate constant equality can be concluded when 1/t _max and the k _min (value ofk _e at the minimum value of $e^{ - k_e t_{max} } /k_e$ plotted against variablek _e values) are synonymous or whenk _min t _max approximates unity. Simpler methods exist to evaluateC-t data. When a drug has 100% bioavailability, regression ofDose/V/C onAUC/C in the nonabsorption phase givesk _e no matter what is the ratio ofm=k _a /k _e . Sincek _e t _max=lnm/(m?1),m can be determined from the given table relatingm andk _e t _max. When γ is unknown,k _e can be estimated from the abscissas of intersections of plots of $C_{max} e^{k_e t_{max} }$ andk _e AUC, both plotted vs. arbitrary values ofk _e, and γD/V values are estimable from the ordinate of the intersection. Also, when γ is unknown,k _e can be estimated from the abscissas of intersections (or of closest approaches) of $e^{k_e t_{max} } /k_e$ andAUC/C _max, both plotted vs. arbitrary values ofk _e. TheC-t plot of the Modified Bateman function, $C = Be^{ - \lambda _2 t} - Ae^{ - \lambda _1 t}$ , does not commence at the origin (i.e., whent _c=0=0 and when a lag time does not exist). However,T _C=0 = ln(A/B/(λ₁-λ₂ whenA>B. AUC ^A″ without time lag is the same asAUC ^A≠B and $A'' = Be^{ - \lambda _2 t} = Ae^{ - \lambda _1 t}$ . Thet _max of theC-t plot of the latter ist _c=0 later than thet _max of theC-t plot of the former which commences att=0. However, (AUMC _uncorr ^A≠B )_∞ =B/λ ₂ ² -A/λ ₁ ² differs fromAUMC _corr ^A≠B ) =A″t _C=0 (1/λ₂-1/λ₁ +A″(1/λ ₂ ² -1/λ ₁ ² ). (AUMC _corr ^A″ ) =A″(1/λ ₂ ² -1/λ ₁ ² ) whenC-t plots start att=0.AUMC _uncorr ^{A ≠ B} is not valid. The (MRT _uncorr ^{A ≠ B} )_∞ is also an invalidMRT estimate, $(B/\lambda _2^2 - A/\lambda _1^2 )/e^{t_{c = 0} } (B/\lambda _2 - A/\lambda _1 )$ , but whenA>B, C-t curves which start at the origin,C _t=0 , haveMRT values displaced byMRT _corr ^{A ≠ B} =MRT ^{[A′ or A' = A = B]} ; +t _C=0 . Thet _max of the Bateman function is also displaced byt _C=0 when theA exceeds theB of its modified form. Dose-dependent pharmacokinetics can be concluded fromC-t data generated by various firstorder invading nonintravenous doses if drug absorption is 100%. Thek _e values can be determined if the apparent volume of distribution of the one-compartment body model is known. Plots ofm/AUC _t ^p vs. timet have a slope of — CL_ME, (the negative of the clearance of the metabolite) and an intercept of the clearance of the precursor, CL_PM, provided that all of the precursor had been absorbed. Similar studies could determine the appararent volume of distribution of the metabolite and the clearance (and thus the rate constant,k _PM=CL_PM/V _P) of the precursor to the metabolite.     

Surface characterization of 2-hydroxypyrimidine sulphate by inverse gas chromatography

The net retention volumes, V _N , of n-alkanes and polar probes on 2-hydroxypyrimidine sulphate (2-HPS) drug surface are determined at 323.15, 328.15 and 333.15 K using inverse gas chromatography. The dispersive surface free energy, $ \gamma_{S}^{d} $ of 2-HPS are evaluated by applying Schultz method as well as Dorris–Gray method and found that $ \gamma_{S}^{d} $ values are higher by 8 per cent in the latter method. The $ \gamma_{S}^{d} $ values are decreasing in both the methods with increase of temperature. The specific component of the free energy of adsorption, $ \Updelta G_{a}^{S} $ , for polar probes are obtained by three methods proposed by Schultz et al., Saint Flour–Papirer and Sawyer–Brookman. The Lewis acid–base parameters, K _a and K _b , are calculated using $ \Updelta G_{a}^{S} $ values. The surface character value, S = (K _b /K _a ) according to the Schultz et al., is found to be 3.9 whereas the S value in the other two methods are found to be 6.2 and 5.6. The results demonstrate that the 2-HPS powder surface contain relatively more basic sites and can interact strongly in the acidic media.     

Synthesis and cytotoxic evaluation of novel 2,3-di-O-alkyl derivatives of l-ascorbic acid

A new series of 2,3-di-O-alkyl derivatives of 5,6-O-isopropylidene-l-ascorbic acid were synthesized using phase transfer catalysis in aqueous media. These derivatives were screened for their superoxide radical scavenging activity and anticancer activity against human breast cancer cell line (MCF-7), leukemic cell line (HL-60), and cervical cell line (HeLa). All these derivatives exhibited enhanced scavenging effect than l-ascorbic acid except for the 4-fluorobenzyl or 2/4-chlorobenzyl alkyl group either at 3-O and/or 2-O position displayed pro-oxidant activity. These pro-oxidant derivatives (2c–e, m) exhibited potent anticancer activities against all the cell lines (IC₅₀ = 25.79–57.21 μM). However, these compounds were also cytotoxic to human normal leukemic macrophages THP-1. On the other hand, antioxidant derivatives displayed albeit slight (2k, IC₅₀ = 57.96–63.45 μM), but selective inhibitory effect toward all tumor cell lines. Thus, pro-oxidant and antioxidant properties can be used to predict the cytotoxic selectivity of drug against normal and cancer cells.     

A novel saponin from Manilkara hexandra seeds and anti-inflammatory activity

Chromatographic separation of acetone precipitate of the seeds of Manilkara hexandra has resulted in a novel saponin, 3-O-(β-d-apiofuranosyl-(1 → 3)-β-d-glucopyranosyl)-28-O-(α-l-rhamnopyranosyl(1 → 3)-β-d-xylopyranosyl(1 → 4)-α-l-rhamnopyranosyl(1 → 2)-α-l-arabinopyranosyl)-16-α-hydroxyprotobassic acid (Saponin 3), together with two known saponins isolated for the first time from the family Sapotaceae, viz, 3-O-β-d-glucopyranosyl(1 → 6)[(β-d-apiofuranosyl-(1 → 3)]-β-d-glucopyranosyl)-28-O-(α-l-rhamnopyranosyl(1 → 3)-β-d-xylopyranosyl(1 → 4)-α-l-rhamnopyranosyl(1 → 2)-α-l-arabinopyranosyl)-16α-hydroxyprotobassic acid (Saponin 1), 3-O-(β-d-glucopyranosyl)-28-O-(α-l-rhamnopyranosyl(1 → 3)-β-d-xylopyranosyl(1 → 4)-α-l-rhamnopyranosyl(1 → 2)-α-l-arabinopyranosyl)-protobassic acid, and 3-O-(β-d-glucopyranosyl)-28-O-(α-l-rhamnopyranosyl(1 → 3)-β-d-xylopyranosyl(1 → 4)-α-l-rhamnopyranosyl(1 → 2)-α-l-arabinopyranosyl)-protobassic acid (Saponin 2). Also, three known phenolic compounds were isolated for the first time from the species hexandra, viz, gallic acid, myrecetin, and quercetin. The chemical structures of the isolated saponin compounds were established by spectral techniques (UV, ¹H, ¹³C NMR, and MS). The acetone fraction containing the crude saponin mixture possessed a significant inhibitory effect on LPS-induced nitric oxide to the extent of 60 % compared to the LPS-stimulated cells and to the extent of 20 % compared to the control level showing significant anti-inflammatory activity. Acetone and MeOH seed extracts as well as the crude saponin fraction of M. hexandra showed no antioxidant activity as measured by DPPH assay (SC₅₀ = 217.65, 496.68, and 562.38 μg/ml, respectively) compared to that of ascorbic acid (SC₅₀ = 12.9). The MeOH seed extract showed no cytotoxic activity against three different human cancer cell lines, viz, colon carcinoma (HCT-116), hepatocellular carcinoma (Hep-G2), and breast adenocarcinoma (MCF-7), estimated by MTT assay (IC₅₀ = 95.20, 73.39, and 79.15 μg/ml, respectively).     

Numerical validation and properties of a rapid binding approximation of a target-mediated drug disposition pharmacokinetic model

Target mediated drug disposition (TMDD) describes the phenomenon where high affinity binding of a drug to its pharmacological target (enzymes or receptors) significantly alters the pharmacokinetic profile of the drug. A rapid binding model replaces the often inestimable binding micro-constants (k _on and k _off) of TMDD models with the equilibrium dissociation constant (K _D) by assuming rapid binding of the drug to its target. The purpose of this study is to examine the validity of the rapid binding assumption and the pharmacokinetic properties of this model. Temporal profiles of free drug in plasma and a non-specific distribution site, free receptor, and the pharmacodynamically relevant, drug–receptor complex obtained from the rapid binding model compared favorably with the full TMDD model for small values of the parameter ɛ, which represents the ratio of the time required for drug–receptor binding relative to the time required for drug to be cleared from the system. The effect of escalating drug doses on the temporal characteristics and the comparison between the two models has been numerically investigated. A closer match between the full and rapid binding models is observed for high doses. Analysis for very large doses (Dose/V _c) relative to endogenous steady-state receptor concentration (R _ss), reveals that the rapid binding model reduces to a standard two compartmental model with a plasma compartment with linear drug elimination and a peripheral compartment. Decreasing clearance with increasing dose and decreasing R _ss indicates that for drugs exhibiting TMDD, the relative ratio of R _ss and dose is an important determinant of the pharmacokinetic properties rather than the individual parameters alone. An analytical solution derived for clearance shows that the primary elements of the apparent clearance of the drug are the linear clearance given by k _el V _c, the non-linear clearance due to drug–receptor complex internalization (k _int), and the ratio of AUC values of the receptor complex to that of free drug. Overall, simulations and analytical techniques applied here provide a better understanding of the validity of the rapid binding model and provide guidelines for its application. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Identification of the L-menthol binding site in guinea-pig lung membranes

1. L-Menthol inhibits both neurokinin A and capsaicin-induced bronchoconstriction in the guinea-pig and relaxes pre-constricted guinea-pig isolated bronchi. Structure-activity relationships have been defined for the action of (−)-menthol and related compounds on cold receptors, suggesting an action of L-menthol at a pharmacological receptor. We have performed radioligand binding studies to characterize the binding sites for [³H]-L-menthol in whole cell membranes prepared from guinea-pig lung tissue.
2. In kinetic studies, [³H]-L-menthol was found to bind rapidly and reversibly. Binding of [³H]-L-menthol to lung membranes was found to be time-dependant becoming fully associated to its site within 40 min, and half-maximum association occurred within 8 min (t_1/2=8 min). [³H]-L-menthol was fully dissociated from its binding site within 8 min, (t_1/2=2 min).
3. Inhibition studies presented a pharmacological profile of the ‘L-menthol site''. Capsaicin, capsazepine, D-menthol, eugenol, {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390 and camphor were all found to displace [³H]-L-menthol binding. In contrast WS3, noradrenaline, 5-hydroxytryptamine, spiperone, flunarazine, bepridil and nicardipine were without effect.
4. We have identified a L-menthol binding site in the guinea-pig, which may represent a site common to a variety of compounds.

     

Exploring structural requirement and binding interactions of β-amyloid cleavage enzyme inhibitors using molecular modeling techniques

β-Amyloid precursor protein cleavage enzyme (BACE) has been shown to be an attractive therapeutic target to control Alzheimer’s disease (AD). Inhibition of β-secretase enzyme can prevent the deposition of Aβ (β-amyloid) peptides, which is thought to be the major cause of AD. The present study has been considered to explore 3D-QSAR, HQSAR, and pharmacophore mapping studies of BACE inhibitors. Contour maps of 3D-QSAR studies (CoMFA: R ² = 0.998, se = 0.067, Q ² = 0.765, R _pred ²  = 0.772, r _m ²  = 0.739; CoMSIA: R ² = 0.992, se = 0.125, Q ² = 0.730, R _pred ²  = 0.713, r _m ²  = 0.687) explain the importance of steric and electrostatic, along with hydrogen-bond (HB) acceptor and donor for binding affinity to BACE. HQSAR study (R ² = 0.941, se = 0.326, Q ² = 0.792, R _pred ²  = 0.713, r _m ²  = 0.709) indicates the important fragments of the molecular fingerprints that might be crucial for binding affinity. Pharmacophore space modeling (R ² = 0.937, rmsd = 0.937, Q ² = 0.935, R _pred ²  = 0.709, r _m ²  = 0.837) describes that HB acceptor, donor, hydrophobic, and steric are the important features for interaction with receptor cavity. Finally, the models are adjudged through the docking study elucidating the interactions between the receptor and the ligand, indicating the structural requirements of potent BACE inhibitors.     

Adult age and ex vivo protein binding of lorazepam, oxazepam and temazepam in healthy subjects

AIM

To see if adult age correlates with ex vivo protein binding of lorazepam, oxazepam and temazepam in healthy subjects.

METHODS

Sixty healthy drug free subjects were recruited in the age groups 18–39, 40–64 and ≥65 years. Plasma albumin concentrations were determined. Ex vivo unbound fractions (f_u) were assessed by spiking samples and measuring the free and total concentrations.

RESULTS

No correlation of age with f_u was seen. The study was powered to demonstrate a change in f_u of ≥7–10%. A decline in plasma albumin concentration of ∼0.03 g l⁻¹ year⁻¹ was seen with increasing age (P = 0.032) and was associated with increased f_u of lorazepam (P = 0.009) and oxazepam (P = 0.014).

CONCLUSIONS

There was no association of adult age with ex vivo f_u of lorazepam, oxazepam or temazepam in healthy subjects.     

Ionically Fixed Polymeric Nanoparticles as a Novel Drug Carrier

Purpose

In this study, we have prepared a novel polymeric drug delivery system comprised of ionically fixed polymeric nanoparticles (IFPN) and investigated their potential as a drug carrier for the passive targeting of water-insoluble anticancer drugs.

Materials and Methods

For this purpose, the physicochemical characteristics of the IFPN were investigated by comparing them with conventional polymeric micelles. IFPN containing paclitaxel were prepared and evaluated for in vitro stability and in vivo pharmacokinetics.

Results

The IFPN were successfully fabricated using a monomethoxypolyethylene glycol-polylactide (mPEG-PLA) diblock copolymer and a sodium salt of d,l-poly(lactic acid) (d,l-PLACOONa) upon the addition of CaCl₂. The transmittance of the IFPN solution was much lower than that of a polymeric micelle solution at the same polymer concentration implicating an increase in the number of appreciable particles. The particle size of the IFPN was approximately 20～30 nm which is in the range of particle sizes that facilitate sterile filtration using a membrane filter. The IFPN also have a regular spherical shape with a narrow size distribution. The zeta potential of the IFPN was almost neutral, similar to that of the polymeric micelles. In contrast, mixed micelles with a combination of mPEG-PLA and d,l-PLACOONa prior to the addition of Ca²⁺ showed a negative charge (?17 mV), possibly due to the carboxyl anion of polylactic acid exposed on the surface of the micelles. The IFPN formulation was highly kinetically stable in aqueous medium compared to the polymeric micelle formulation. The molecular weight of d,l-PLACOONa in the IFPN and the mPEG-PLA/d,l-PLACOONa molar ratio had a great influence upon the kinetic stability of the IFPN. Pharmacokinetic studies showed that the area under the concentration vs time curve (AUC) of IFPN in blood was statistically higher (about two times) when compared with that of Cremophor EL-based formulation (Taxol^® equivalent) or polymeric micelle formulation.

Conclusions

The results suggests that the IFPN were retained in the circulation long enough to play a significant role as a drug carrier in the bloodstream, possibly resulting in improved therapeutic efficiency. Therefore, the IFPN are expected to be a promising novel polymeric nanoparticulate system for passive tumor targeting of water-insoluble anticancer drugs including paclitaxel.