Lock and key colloids.

New functional materials can in principle be created using colloids that self-assemble into a desired structure by means of a programmable recognition and binding scheme. This idea has been explored by attaching 'programmed' DNA strands to nanometre- and micrometre- sized particles and then using DNA hybridization to direct the placement of the particles in the final assembly. Here we demonstrate an alternative recognition mechanism for directing the assembly of composite structures, based on particles with complementary shapes. Our system, which uses Fischer's lock-and-key principle, employs colloidal spheres as keys and monodisperse colloidal particles with a spherical cavity as locks that bind spontaneously and reversibly via the depletion interaction. The lock-and-key binding is specific because it is controlled by how closely the size of a spherical colloidal key particle matches the radius of the spherical cavity of the lock particle. The strength of the binding can be further tuned by adjusting the solution composition or temperature. The composite assemblies have the unique feature of having flexible bonds, allowing us to produce flexible dimeric, trimeric and tetrameric colloidal molecules as well as more complex colloidal polymers. We expect that this lock-and-key recognition mechanism will find wider use as a means of programming and directing colloidal self-assembly.

Chiral colloidal clusters.

Chirality is an important element of biology, chemistry and physics. Once symmetry is broken and a handedness is established, biochemical pathways are set. In DNA, the double helix arises from the existence of two competing length scales, one set by the distance between monomers in the sugar backbone, and the other set by the stacking of the base pairs. Here we use a colloidal system to explore a simple forcing route to chiral structures. To do so we have designed magnetic colloids that, depending on both their shape and induced magnetization, self-assemble with controlled helicity. We model the two length scales with asymmetric colloidal dumbbells linked by a magnetic belt at their waist. In the presence of a magnetic field the belts assemble into a chain and the steric constraints imposed by the asymmetric spheres force the chain to coil. We show that if the size ratio between the spheres is large enough, a single helicity is adopted, right or left. The realization of chiral colloidal clusters opens up a new link between colloidal science and chemistry. These colloidal clusters may also find use as mesopolymers, as optical and light-activated structures, and as models for enantiomeric separation.

Subdiffusion of a sticky particle on a surface.

Conventional diffusion (ΔR2(t))=2Dt gives way to subdiffusion (ΔR2(t))∼t(µ), 0<µ<1 when the waiting time distribution φ(τ) is nonintegrable. We have studied a model system, colloidal particles functionalized with DNA "sticky ends" diffusing on a complementary coated surface. We observe a crossover from subdiffusive to conventional behavior for (ΔR2(t)) and φ(τ) as temperature is increased near the particle-surface melting temperature consistent with a simple Gaussian distribution of sticky ends. Our results suggest that any system with randomness in its binding energy should exhibit subdiffusive behavior as it unbinds. This will strongly affect the kinetics of self-assembly.

Experimental measurement of the photonic properties of icosahedral quasicrystals.

Quasicrystalline structures may have optical bandgap properties-frequency ranges in which the propagation of light is forbidden-that make them well-suited to the scientific and technological applications for which photonic crystals are normally considered. Such quasicrystals can be constructed from two or more types of dielectric material arranged in a quasiperiodic pattern whose rotational symmetry is forbidden for periodic crystals (such as five-fold symmetry in the plane and icosahedral symmetry in three dimensions). Because quasicrystals have higher point group symmetry than ordinary crystals, their gap centre frequencies are closer and the gaps widths are more uniform-optimal conditions for forming a complete bandgap that is more closely spherically symmetric. Although previous studies have focused on one-dimensional and two-dimensional quasicrystals, where exact (one-dimensional) or approximate (two-dimensional) band structures can be calculated numerically, analogous calculations for the three-dimensional case are computationally challenging and have not yet been performed. Here we circumvent the computational problem by doing an experiment. Using stereolithography, we construct a photonic quasicrystal with centimetre-scale cells and perform microwave transmission measurements. We show that three-dimensional icosahedral quasicrystals exhibit sizeable stop gaps and, despite their quasiperiodicity, yield uncomplicated spectra that allow us to experimentally determine the faces of their effective Brillouin zones. Our studies confirm that they are excellent candidates for photonic bandgap materials.

Vicsek model by time-interlaced compression: A dynamical computable information density.

Collective behavior, both in real biological systems and in theoretical models, often displays a rich combination of different kinds of order. A clear-cut and unique definition of "phase" based on the standard concept of the order parameter may therefore be complicated, and made even trickier by the lack of thermodynamic equilibrium. Compression-based entropies have been proved useful in recent years in describing the different phases of out-of-equilibrium systems. Here, we investigate the performance of a compression-based entropy, namely, the computable information density, within the Vicsek model of collective motion. Our measure is defined through a coarse graining of the particle positions, in which the key role of velocities in the model only enters indirectly through the velocity-density coupling. We discover that such entropy is a valid tool in distinguishing the various noise regimes, including the crossover between an aligned and misaligned phase of the velocities, despite the fact that velocities are not explicitly used. Furthermore, we unveil the role of the time coordinate, through an encoding recipe, where space and time localities are both preserved on the same ground, and find that it enhances the signal, which may be particularly significant when working with partial and/or corrupted data, as is often the case in real biological experiments.

Mechanisms of ordering in striped patterns.

We have studied the ordering dynamics of the striped patterns of a single layer of cylindrical block copolymer microdomains in a thin film. By tracking disclinations during annealing with time-lapse atomic force microscopy, we observe a dominant mechanism of disclination annihilation involving three or four disclinations (quadrupoles). Pairwise disclination annihilation events are suppressed as a result of the topological constraints in this system. The kinetic scaling laws with exponents observed here are consistent with topologically allowed annihilation events involving multiple disclinations. The results provide insight into two-dimensional pattern formation and may lead to the successful application of block copolymer lithography.

Diffusion through colloidal shells under stress.

The permeability of solids has long been associated with a diffusive process involving activated mechanism as originally envisioned by Eyring. Tensile stress can affect the activation energy but definitive experiments of the diffusion rate of species through a stressed solid are lacking. Here we use core-shell (liquid core-solid shell) colloidal particles that are sensitive to osmotic pressure to follow the permeation of encapsulated probes at various stresses. We unambiguously show that the tensile stress applied on colloidal shells linearly reduces the local energy barrier for diffusion.

A study of the pharmacokinetic interaction of istradefylline, a novel therapeutic for Parkinson's disease, and atorvastatin.

The effect of steady-state istradefylline, an agent for Parkinson's disease with P-glycoprotein and CYP3A inhibitory activity, on the pharmacokinetics of atorvastatin and its metabolites was evaluated in healthy volunteers. A single 40-mg dose of atorvastatin was administered to 20 subjects. After a 4-day washout, subjects received a single 40-mg atorvastatin dose following 40 mg istradefylline (n=16) or placebo (n=4) daily for 14 days. Plasma samples collected for 96 hours after atorvastatin administration, alone and in combination, were analyzed for atorvastatin, orthohydroxy atorvastatin, and parahydroxy atorvastatin. Istradefylline increased atorvastatin C(max) (53%), AUC(0-infinity) (54%), and t((1/2)) (27%); and increased AUC(0-infinity) for orthohydroxy atorvastatin (18%), but had no significant effect on its C(max) or t((1/2)); and had minimal effect on parahydroxy atorvastatin AUC(0-infinity). The lack of inhibition by istradefylline on metabolite systemic exposure, combined with increased atorvastatin systemic exposure, suggests a predominant P-glycoprotein inhibitory effect of istradefylline.

Nematic and almost-tetratic phases of colloidal rectangles.

Nonspherical colloids can exhibit liquid-crystalline phases with different degrees of broken orientational and translational symmetry. Here we investigate hard rectangles consisting of photolithographically prepared disks standing on edge. We observe a conventional Kosterlitz-Thouless transition from isotropic to nematic with almost smectic behavior at high density. But just on the isotropic side of the isotropic to nematic transition we observe an unusual regime where short-range tetratic correlations dominate over nematic correlations. This occurs due to the proliferation of Ising-like pi/2 grain boundaries that disrupt nematic order, but preserve tetratic correlations, at lengths shorter than the spacing between free disclinations.

Clinical trial simulation of docetaxel in patients with cancer as a tool for dosage optimization.

BACKGROUND: Pharmacokinetic and pharmacodynamic analyses conducted during the development of docetaxel showed that patients with non-small-cell lung cancer with high baseline alpha1-acid glycoprotein levels had shorter time to progression and time to death. To assess whether such patients might benefit from dose intensification, we initiated a series of clinical trial simulations. METHODS: Pharmacokinetic and pharmacodynamic models for time to progression, death, and drop-out were developed and validated with the use of phase II data from 151 patients with non-small-cell lung cancer. The simulation process, in which these models were combined with a previously reported model for safety, was evaluated by comparison of the original phase II data with the predicted results. Simulations were undertaken for the evaluation of whether a trial (phase III) of 125 mg/m2 of docetaxel versus 100 mg/m2 of docetaxel in patients with high alpha1-acid glycoprotein levels would show improved survival. RESULTS: The hazard models showed that lower alpha1-acid glycoprotein levels, fewer number of organs involved, and higher docetaxel cumulative area under plasma concentration-time curve were significantly associated with enhanced time to progression and time to death. The simulation process produced data patterns similar to actual patterns. In the simulated phase III trial, although median survival was slightly longer in the 125 mg/m2 docetaxel group than in the 100 mg/m2 group (5.49 months versus 5.31 months, respectively), the difference was significant in only 6 of 100 trials. CONCLUSIONS: The low power to detect a difference due to dose intensification was the basis for the decision not to perform such a trial. The simulation exercise yielded valuable insight into how pharmacokinetic- and pharmacodynamic-based simulation of clinical trials may have an impact on decision making in drug development.

Unusual absorption profile of phenytoin in a massive overdose case.

The pharmacokinetics of phenytoin was evaluated in a nonepileptic adult man after the ingestion of an undetermined amount of the drug following an apparent suicide attempt. A serum phenytoin concentration of 45 micrograms/mL was observed on admission 12 hours after ingestion. Phenytoin concentrations steadily increased, reached a maximum of 114 micrograms/mL four days later, then fluctuated at about 100 micrograms/mL for a week, and slowly declined to undetectable levels within the following week. At 96.5 micrograms/mL, the unbound serum concentration was 2.5 times that observed in therapeutic drug concentrations. Computer fitting of the data indicated that the Michaelis-Menten constants, apparent volume of distribution, and renal clearance of phenytoin were consistent with those parameters reported after therapeutic doses. However, phenytoin absorption was best described by parallel first- and zero-order rate processes, with the latter proceeding for as long as two weeks following drug ingestion. This protracted absorption appears to be a result of the presence of a large concretion of phenytoin in the gastrointestinal tract, having a slow disintegration and dissolution attributable to the limited solubility of the drug in the gastrointestinal tract and to the patient's diminished intestinal motility.

Absolute oral versus inhaled bioavailability: significance for inhaled drugs with special reference to inhaled glucocorticoids.

Orally inhaled drugs provide great benefit in the treatment of asthma as they are delivered directly to the site of action, i.e. the lung. The absolute oral inhaled bioavailability of a glucocorticoid results from the combination of the bioavailability of the dose delivered to the lung and the bioavailability of the dose delivered into the gastrointestinal (GI) tract. The majority of the dose delivered to the lung is absorbed and available systemically. For the portion of the glucocorticoid dose delivered orally, bioavailability depends upon absorption from the GI tract and the extent of first pass/pre-systemic metabolism in the GI tissue and liver. Since this oral component of the delivered dose does not provide any beneficial therapeutic effect but can contribute to the systemic side effects, it is desirable for the absolute oral bioavailability of inhaled glucocorticoids to be relatively low (which is the case with most of the glucocorticoids, < 25%). Another approach to limiting systemic exposure from inhaled delivery is to improve the effectiveness of the oral inhaled formulation and delivery device, by increasing the fraction of the total inhaled dose which reaches the lung. Since current inhalation technology can provide respirable fractions in the range of 30-50%, what is the significance of the oral component of systemic exposure in relation to the overall systemic exposure following the oral inhalation administration of glucocorticoids? Below a certain point (approximately 25%), lower oral bioavailability of inhaled drugs may not be clinically important with respect to systemic exposure if the lung targeting is good (30%).

Pharmacokinetics/pharmacodynamics in drug development: an industrial perspective.

In a health care environment dominated by the growth of managed care organizations, generic competition, therapeutic substitution and drug utilization review, drug development is an extremely risky proposition. Consequently, it is imperative to incorporate a mechanistic approach to drug development that combines a thorough understanding of a drug at the molecular/cellular level with a rigorous preclinical, and clinical pharmacology program. This should enable the sponsor to evaluate multiple hypotheses during the early "learning" phases of clinical development (Phases I and IIA) and to eliminate nonpromising candidates early on while drug development costs are low. Clinical research done properly in the early stages of drug development will also set the stage for designing and conducting optimal "confirming" registrational Phase IIB/III studies for promising drug candidates. Pharmacokinetics (PK) and pharmacodynamics (PD) modeling and simulation are crucial components of a mechanistic approach to optimal drug development and their application has significant impact in both early and late development efforts. This communication describes several applications of pharmacokinetics and pharmacodynamics modeling and simulation that were important in guiding, optimizing and ensuring the success of development efforts for drug candidates in the therapeutic areas of cardiology and oncology. These examples are used to illustrate and discuss the use of the current state-of-the-art in pharmacokinetics and pharmacodynamics modeling and simulation at numerous stages in the development cycle and to postulate on future directions in this area.

Pharmacokinetics of tinidazole in male and female subjects.

Tinidazole is a potent nitroimidazole compound active against, and used to treat, Trichomonas vaginalis infections in males and females. Speculation exists in the literature that observed differences in tinidazole plasma concentrations between males and females may be due to sex-mediated pharmacokinetic differences. To investigate this phenomenon, a study was designed to determine the pharmacokinetics of tinidazole in male and female subjects. Six male and six female volunteers were each administered a single 2-Gm oral dose of tinidazole. Plasma and urine samples, collected over a 72-hour period, were assayed by a sensitive and specific HPLC assay. Results demonstrate a significant correlation between tinidazole oral plasma clearance and body weight and apparent volume of distribution of tinidazole and body weight for male and female subjects, respectively. There were no apparent sex-mediated differences in weight-normalized pharmacokinetic parameters as documented by statistically equivalent mean oral plasma clearances (36.1 and 35.4 ml/kg/hour), apparent volumes of distribution (0.65 and 0.63 liter/kg), and elimination half-lives (12.3 and 12.3 hours, males and females, respectively). Mean area under the tinidazole plasma concentration-versus-time curve and mean peak plasma concentration of tinidazole were 1.3 times greater for females than for males, apparently due to the smaller mean body weight of females and consequently a 1.3 times greater administered dose to the females on a weight basis.

Suprofen concentrations in human breast milk.

Six healthy females who had been nursing their infants for 6 to 11 months received a single, 200-mg oral dose of suprofen, an analgesic which has been evaluated clinically. Blood and milk samples were collected at discrete times over an 8-hour period and suprofen concentrations in milk and plasma were determined by HPLC. The binding of suprofen to milk and plasma proteins was determined by equilibrium dialysis. The maximum concentrations of suprofen in the milk ranged from 0.118 to 0.232 microgram/ml and occurred from 1 to 2 hours after dose administration. The maximum plasma suprofen concentrations ranged from 13.8 to 28.3 micrograms/ml and occurred from 0.5 to 2 hours after dosing. Within any subject, the peak suprofen concentration in milk was 0.5 to 0.9 per cent of the peak concentration in plasma. Suprofen was extensively bound to plasma proteins (99.4 per cent) and minimally bound to milk proteins (10 per cent). The average milk/plasma ratio based on area-under-the-curve measurements was approximately 0.014, or 1.4 per cent. This ratio agrees well with an estimated value of 1.2 per cent for the pH-dependent, passive diffusion of suprofen from plasma into milk. From these data, it appears that there would be minimal suprofen exposure to a nursing infant after administration of recommended doses to the nursing mother.

Comparative bioavailability of suprofen after coadministration with food or milk.

Suprofen is a nonsteroidal analgesic with demonstrated efficacy in the treatment of mild to moderate pain associated with a variety of clinical conditions. Because nonsteroidal analgesic agents may cause gastrointestinal side effects, they are frequently prescribed with food or milk. The purpose of this study was to evaluate the effects of a standard meal and milk alone on the rate and extent of absorption of suprofen. In a randomized three-way cross-over study, 24 healthy volunteers each received a single 200-mg oral dose of suprofen in the fasted state half an hour after a standard meal or half an hour after an 8-ounce glass of milk. The influence of food and milk was greater on the rate than on the extent of absorption of suprofen as illustrated by a more pronounced effect on Cmax than on AUC. In addition, food had a greater influence on the bioavailability of suprofen than milk. Food decreased the mean Cmax to 44% and the mean AUC to 81% relative to the fasted state, whereas milk decreased the mean Cmax to 74% and the mean AUC to only 87% of the respective parameters in the fasted state. Symmetrical confidence intervals demonstrated that the mean AUCmilk was within only 19% and the mean AUCfood was within only 25% of the mean AUC in the fasted state, with 95% confidence.

In vitro and in vivo techniques used in drug development for evaluation of dose delivery of inhaled corticosteroids.

Oral inhaled corticosteroids are important in the treatment of asthma since their delivery is targeted directly to the lung, which is the site of action. Triamcinolone acetonide (TAA) is an effective and safe corticosteroid that is marketed as a metered-dose inhaler (MDI) with an integrated spacer (Azmacort) for the treatment of asthma. Due to the phasing out of chlorofluorocarbon (CFC) propellants, Azmacort has been reformulated with a non-CFC propellant. Due to the complexities of oral inhaled formulations and the topical nature of drug delivery to the lung for efficacy, the reformulation of oral inhaled MDIs requires careful consideration and support throughout their development, using a combination of in vitro and in vivo studies to ensure clinical comparability for both efficacy and safety. This paper describes a chronological series of studies designed to support the reformulation of Azmacort. These included in vitro studies to estimate respirable fraction, in vivo pulmonary deposition studies, in vivo pharmacokinetic-pharmacodynamic studies to estimate the systemic effects of each formulation, and final clinical studies in adult and pediatric patients to confirm the clinical comparability of the new formulation of Azmacort. The results of these studies, performed at various stages during the development of new formulations, were critical in guiding the reformulation efforts for Azmacort.

Pharmacokinetic and pharmacodynamic evaluation of warfarin and nefazodone coadministration in healthy subjects.

Nefazodone, an antidepressant with serotonin and norepinephrine receptor modulating activity, is highly protein bound and eliminated by oxidative metabolism. This study evaluated the potential for clinically significant drug interactions with warfarin and nefazodone coadministration. Eighteen subjects received warfarin daily for 14 days, achieving steady-state warfarin concentrations and a stable prothrombin ratio. Nefazodone 200 mg every 12 hours (n = 12) or placebo every 12 hours (n = 6) was then added to the daily warfarin dose for the next 7 days in a double-blind, randomized design. No serious or unexpected adverse events or events suggestive of abnormal bleeding occurred during coadministration. The addition of nefazodone had no effect on the unbound fraction of total warfarin in plasma or on the steady-state pharmacokinetics of R-warfarin based on within-subject or comparison to placebo-treated subjects. The steady-state AUCTAU over the dosing interval and Cmax of S-warfarin decreased by 12%; however, this change is clinically insignificant because the prothrombin ratio and bleeding time remained unchanged. The steady-state minimum concentrations for nefazodone and metabolites, achieved on coadministration day 3, were typical of healthy men treated with this nefazodone dosage. In conclusion, warfarin and nefazodone coadministration was safe and well-tolerated with no clinically significant interactions.

Pharmacokinetic/pharmacodynamic modeling in drug research and development.

The two domains in clinical pharmacology dealing with optimizing dosing recommendations are pharmacokinetics and pharmacodynamics. However, the usefulness of these disciplines is limited if viewed in isolation. Pharmacokinetic/pharmacodynamic (PK/PD) relationships and modeling builds the bridge between these two classical disciplines of clinical pharmacology. It links the concentration-time profile as assessed by pharmacokinetics to the intensity of observed response as quantified by pharmacodynamics. Thus, the resulting so-called integrated PK/PD-models allow the description of the complete time course of the desired and/or undesired effects in response to a drug therapy. PK/PD-modeling can elucidate the causative relationship between drug exposure and response and provide a better understanding of the sequence of events that result in the observed drug effect. This information can then be used to streamline the drug development process and dose optimization. This consensus paper presents an update on the current state of PK/PD-modeling from an academic, industrial and regulatory perspective.

Periodic oscillation of a colloidal disk near a wall in an optical trap.

Colloidal disks can be stably trapped using optical tweezers. However, when the tweezers press the disk against an opposing wall, we observe an instability leading to periodic motion which we model using coupled nonlinear equations. The resulting "switchback" oscillation involves combined orientational and translational motion of the disk. This observation reveals a new degree of freedom in colloidal architectures, that is, the ability to drive translational motion from a static light field energy source.