Halogenation of drugs is commonly used to enhance membrane binding and permeation. We quantify the effect of replacing a hydrogen residue by a chlorine or a trifluoromethyl residue in position C-2 of promazine, perazine, and perphenazine analogues. Moreover, we investigate the influence of the position (C-6 and C-7) of residue CF(3) in benzopyranols. The twelve drugs are characterized by surface activity measurements, which yield the cross-sectional area, the air-water partition coefficient, and the critical micelle concentration. By using the first two parameters (A(D) and K(aw)) and the appropriate membrane packing density, the lipid-water partition coefficients, are calculated in excellent agreement with the lipid-water partition coefficients measured by means of isothermal titration calorimetry for small unilamellar vesicles of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine. Replacement of a hydrogen residue by a chlorine and a trifluoromethyl residue enhances the free energy of partitioning into the lipid membrane, on average by deltaG(lw) approximately -1.3 or -4.5 kJ mol(-1), respectively, and the permeability coefficient by a factor of approximately 2 or approximately 9, respectively. Despite exhibiting practically identical hydrophobicities, the two benzopyranol analogues differ in their permeability coefficients by almost an order of magnitude; this is due to their different cross-sectional areas at the air-water and lipid-water interfaces.

Talin, an actin-binding protein, is assumed to anchor at the membrane via an intrinsic amino acid sequence. Three N-terminal talin fragments, 21-39 (S19), 287-304 (H18), and 385-406 (H17) have been proposed as potential membrane anchors. The interaction of the corresponding synthetic peptides with lipid model systems was investigated with CD spectroscopy, isothermal titration calorimetry, and monolayer expansion measurements. The membrane model systems were neutral or negatively charged small unilamellar vesicles or monolayers with a lateral packing density of bilayers (32 mN/ m). S19 partitions into charged monolayers/bilayers with a penetration area A p ‫؍‬ 140 ؎ 30 Å 2 and a free energy of binding of ⌬G 0 ‫؍‬ ؊5.7 kcal/mol, thereby forming a partially ␣-helical structure. H18 does not interact with lipid monolayers or bilayers. H17 penetrates into neutral and charged monolayers/bilayers with A p ‫؍‬ 148 ؎ 23 Å 2 and A p ‫؍‬ 160 ؎ 15 Å 2 , respectively, forming an ␣-helix in the membrane-bound state. Membrane partitioning is mainly entropy-driven. Under physiological conditions the free energy of binding to negatively charged membranes is ⌬G 0 ‫؍‬ ؊9.4 kcal/mol with a hydrophobic contribution of ⌬G h ‫؍‬ ؊7.8 kcal/mol, comparable to that of post-translationally attached membrane anchors, and an electrostatic contribution of ⌬G h ‫؍‬ ؊1.6 kcal/mol. The latter becomes more negative with decreasing pH. We show that H17 provides the binding energy required for a membrane anchor.Talin is a widespread actin-binding protein present in focal cell adhesions and ruffling membranes of moving cells (1, 2). In fibroblasts, talin binding to lipid membranes is associated with the establishment of a signaling cascade, mediated either by integrins (3, 4) leading to the formation of focal adhesions or, alternatively, by layilin (5) leading to a nucleation of actin assembly in membrane ruffles. In platelets, talin redistributes from the cytoplasm to the membrane during activation (6) where it colocalizes with the GPIIb/IIIa complex (7). Talin analogues have been identified in lower organisms like Dictyostelium (8) and Caenorhabditis elegans (9), the N termini and C termini being most preserved.Reasons to assume that talin is involved in a polarized assembly of the actin cytoskeleton by nucleating actin filament growth at lipid interfaces (10, 11) were provided from the finding that Dictyostelium mutants, which lack the entire protein, are massively impaired in adhesion and motility (12), and HeLa cells, when down-regulated in talin expression by antisense RNA, exhibit a reduced rate in cell spreading (13). Antibodies directed against talin, when microinjected were shown to inhibit fibroblast migration (14).Some of talin's functions have been attributed to specific protein domains. Calpain or thrombin cleavage in vitro yields two parts with 190 and 47 kDa, respectively. The C-terminal 190-kDa portion was shown to carry the actin binding sites (15) in form of a conserved sequence, the (I/L)WEQ module (16), and to be responsible f...

Despite the limitations of an uncontrolled, open-label study, the results from this study indicate that lactoferrin in mild to moderate acne vulgaris is well tolerated and may lead to an overall improvement in acne lesion counts in the majority of affected adolescents and young adults when administered as a dietary supplement on a twice daily regimen. Further randomized, placebo-controlled trials of longer duration appear warranted.

A fixed-dose pediatric formulation of artesunate and mefloquine (Artequin Pediatric) has been developed. In this open, non-comparative study in Cameroonian children with uncomplicated falciparum malaria, the safety and efficacy of this formulation was tested, with a particular emphasis on the risk of neuropsychiatric adverse events (AEs). In total, 220 subjects, weighing between 10 and 20 kg, were enrolled; 213 qualified for analysis. Artesunate-mefloquine was given once daily for 3 days. Overall, 13.1% of patients reported mild to moderate neuropsychiatric AEs (elicited through a structured questionnaire or reported spontaneously) out of which 3.8% (mainly insomnia) were considered drug-related. Other drug-related AEs were infrequent (< 3%). Polymerase chain reaction-corrected cure rate (adequate clinical and parasitological response) determined by survival analysis at 28 and 63 days was 96.6%. New infections were observed in 11.2% of evaluable patients at 63 days. The new formulation was well tolerated and efficacious in the population investigated.

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