The Critical Role of Passive Permeability in Designing Successful Drugs

Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.     

Effect of treatment with 13-cis-retinoic acid and ara-C on the hematopoietic stem cells of patients with myelodysplastic syndromes

PURPOSE: To assess the "in vivo" effect of 13-cis-retinoic acid and low dose Ara-C in MDS as well as to establish "in vitro" advantage of retinoid dose-related growth pattern on bone marrow cultures as defined by culture timing and CFU-GM proliferative response. PATIENTS AND METHODS: We evaluated 28 patients diagnosed of MDS according to FAB classification, of whom 4 cases had RA, 8 cases SRA, 14 cases RAEB and 2 cases RAEB-T. Patients who had RA and SRA were treated with oral 13-cis-retinoic acid at doses of 20-40 mg daily for 4 months and those cases with RAEB and RAEB-T had subcutaneous Ara-C at doses of 3 mg/m2 twice a day for 21 days. The "in vivo" and "in vitro" effect of retinoic acid on the haemopoietic differentiation was evaluated by the growth CFU-GM in semisolid cell culture methods. RESULTS: Increasing in vitro concentrations of 13-cis retinoic acid did not enhance the growth of myelodysplastic progenitors. Nevertheless, our study did not find any beneficial therapeutic effect of retinoic compounds in MDS patients. In this study, low-dose Ara-C (3 mg/m2) showed similar effects when compared with higher doses reported by others. Furthermore, in terms of CFU-GM proliferation the concentration of colonies before and after treatment were fairly similar in all but two patients. CONCLUSIONS: The results drawn from our study demonstrated that there is no beneficial advantage of 13-cis-retinoic acid as a differentiation inducing agent on myelodysplastic patients. In contrast, lower doses of Ara-C showed similar effects on haemopoiesis of MDS patients than standard doses of 10-20 mg/m2 but with less side effects.     

Data structures for symbolic multi-valued model-checking

Multi-valued logics provide an interesting alternative to classical boolean logic for modeling and reasoning about systems. Such logics can be used for reasoning about partially-specified systems, effectively encode vacuity detection and query-checking problems, help in detecting inconsistencies, and many others.In our earlier work, we identified a useful family of multi-valued logics: those specified over finite distributive lattices where negation preserves involution, i.e., for every element a of the logic. Such structures are called quasi-boolean algebras, and model-checking over these not only extends the domain of applicability of automated reasoning to new problems, but can also speed up solutions to some classical verification problems.Symbolic model-checking over quasi-boolean algebras can be cast in terms of operations over multi-valued sets: sets whose membership functions are multi-valued. In this paper, we propose and empirically evaluate several choices for implementing multi-valued sets with decision diagrams. In particular, we describe two major approaches: (1) representing the multi-valued membership function canonically, using MDDs or ADDs; (2) representing multi-valued sets as a collection of classical sets, using a vector of either MBTDDs or BDDs. The naive implementation of (2) includes having a classical set for each value of the algebra. We exploit a result of lattice theory to reduce the number of such sets that need to be represented.The major contribution of this paper is the evaluation of the different implementations of multi-valued sets, done via a series of experiments and using several case studies.

Note: lack of influence of adherent Lactobacillus isolates on the attachment of Escherichia coli to the intestinal epithelial cells of chicken in vitro

Two Lactobacillus isolates, Lact. acidophilus I 26 and Lact. fermentum I 25, were selected, based on their poor aggregation with Escherichia coli and strong ability to adhere to ileal epithelial cells (IEC), to study in vitro interactions with E. coli O1:K1, O2:K1 and O78:K80 in an IEC radioactive-assay under the conditions of exclusion (lactobacilli and IEC, followed by the addition of E. coli), competition (lactobacilli, IEC and E. coli together) and displacement (E. coli and IEC, followed by the addition of lactobacilli). The results indicated that Lact. acidophilus I 26 and Lact. fermentum I 25 could not significantly reduce the attachment of E. coli O1:K1, O2:K1 and O78:K80 to IEC under the three conditions tested in vitro, except that the attachment of E. coli O1:K1 was slightly reduced by Lact. fermentum I 25 in the test for competition.     

Cytological studies on the developing vitreous as related to the hyaloid vessel system

The embryonic development of the cell population of the mammalian vitreous has been traced to two sources: the undifferentiated mesenchymal cells of the eye primordium and the primitive reticular cells of the bone marrow. Undifferentiated mesenchymal cells invade the future vitreous space in two ways: through the annular opening between the rim of the optic cup and the lens primordium, and through the open embryonic fissure. They differentiate into prevascular cells, hemangioblasts, and fibrocytes located in the area of the optic nerve head. From the very beginning of fetal development, another ameboid-type cell of mesenchymal origin makes its entrance into the vitreous through the hyaloid vessels; these monocyte-like cells differentiate into hyalocytes and populate a well-defined area of the cortical vitreous close to the retina and to the ora serrata. Gamma-irradiation (600 rads) of newly born rabbits and cats decreases the number of migrating amebocytes in their vitreous; 24 h later, however, they are replaced by monocytes from the hyaloid vessels.     

Optical second harmonic generation in CsLiB6O10 nanocrystallites incorporated to the olygoether photopolymer matrices induced by acustical field

Optical second harmonic generation in CsLiB₆O₁₀ (CLBO) large-sized nanocrystallites (15–40 nm) incorporated into the olygoether photopolymer matrices has been found at liquid helium temperature (LHeT). The second harmonic generation (SHG) has been measured for the source wavelength of the YAG : Nd laser ( = 1.06 m). Increasing acoustical power (up to 18.1 W/cm²) and acoustical frequencies at 14 kHz give maximal values of the output SHG. The measured SHG ₂₂₂ tensor component was comparable with the one for the traditional nonlinear optical crystals such as KH₂PO₄, KTiOPO₄, LiNbO₃. With decreasing temperature below 28 K the acoustically induced SHG signal strongly increases. A correlation between the acoustically induced SHG and low-frequency Raman modes has been found. The maximal acoustically induced SHG has been observed for the nanocrystallite concentration about 3.1% (in weighting units) and the crystallite sizes lying within the 35–40 nm. The SHG tensor coefficients were higher than for the proper CLBO crystals at least on the 13%. Advantageous and drawbacks of the presented model are discussed. The theory of the observed phenomena is explained on the ground of ab initio band energy calculations with taking into account of anharmonic electron-phonon interactions.     

A simple breathing circuit minimizing changes in alveolar ventilation during hyperpnoea

Many clinical and research situations require maintenance of isocapnia, which occurs when alveolar ventilation (V'A) is matched to CO2 production. A simple, passive circuit that minimizes changes in V'A during hyperpnoea was devised. It is comprised of a manifold, with two gas inlets, attached to the intake port of a nonrebreathing circuit or ventilator. The first inlet receives a flow of fresh gas (CO2=0%) equal to the subject's minute ventilation (V'E). During hyperpnoea, the balance of V'E is drawn (inlet 2) from a reservoir containing gas, the carbon dioxide tension (PCO2) approximates that of mixed venous blood and therefore contributes minimally to V'A. Nine normal subjects breathed through the circuit for 4 min at 15-31 times resting levels. End-tidal PCO2 (Pet,CO2) at rest, 0, 1.5 and 3.0 min were (mean+/-SE) 5.1+/-0.1 kPa (38.1+/-1.1 mmHg), 4.9+/-0.1 kPa (36.4+/-1.1 mmHg), 5.0+/-0.2 kPa (37.8+/-1.6 mmHg) and 5.0+/-0.2 kPa (37.6+/-1.4 mmHg) (p=0.53, analysis of variance (ANOVA)), respectively; without the circuit, Pet,CO2 would be expected to have decreased by at least 2.7 kPa (20 mmHg). Six anaesthetized, intubated dogs were first ventilated at control levels and then hyperventilated by stepwise increases in either respiratory frequency (fR) from 10 to 24 min(-1) or tidal volume (VT) from 400 to 1,200 mL. Increases in fR did not significantly affect arterial CO2 tension (Pa,CO2) (p=0.28, ANOVA). Only the highest VT decreased Pa,CO2 from control (-0.5 +/- 0.3 kPa (-3.4 +/- 2.3 mmHg), p<0.05). In conclusion, this circuit effectively minimizes changes in alveolar ventilation and therefore arterial carbon dioxide tension during hyperpnoea.     

Interaction of rabbit C-reactive protein with phospholipid monolayers studied by microfluorescence film balance with an externally applied electric field

C-reactive protein (CRP) is one of the most characteristic acute-phase proteins in humans and many other animals. It binds to phosphorylcholine in a calcium-dependent manner. In addition, CRP activates the complement systems via the classical pathway. The interaction between rabbit CRP (rCRP) and model biological membrane is studied using dimyristoylphosphatidylethanolamine and dipalmitoylphosphatidylcholine monolayers. Observations with fluorescence microscopy indicate that rCRP is more likely to be incorporated in the liquid phase of monolayers. Such incorporation does not depend on the presence of calcium and is not inhibited by phosphocholine. The area occupied by the protein when incorporated into the monolayer was estimated. The dipole moment density of the protein crossing the air/water interface was measured by applying an external electric field. Our results indicate that calcium binding leads to a conformational change in CPR, which might modify the orientation of CRP in the monolayer. In addition, a negative charge or negative difference in dipole moment density facilitates the incorporation of CPR into the monolayer.