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PubMed2006

Impact of Drug Formulation on Abuse Liability, Safety and Regulatory Decisions. Proceedings and abstracts of a conference, Bethesda, Maryland, USA, April 2005.

In light of recent increased publicity concerning diversion and tampering with prescription medications, new formulations are being widely considered as a strategy to reduce risk. These approaches are occurring in a context where regulatory, law enforcement and research frameworks have not been fully developed to accommodate these new formulations. As a result, College on Problems of Drug Dependence sponsored the conference "Impact of Drug Formulation on Abuse Liability, Safety and Regulatory Decisions," held in North Bethesda, Maryland in April, 2005 with Edward Sellers and Charles R. Schuster serving as co-chairs. To accomplish the desired goals, papers on key topics were commissioned and these papers were presented at the conference along with submitted presentations from other invitees. This supplement to Drug and Alcohol Dependence contains the manuscripts arising from presentations at the meeting, a summary of recommendations, and abstracts of the other submitted papers. Our hope is that the proceedings of this meeting will contribute importantly to the consideration of the research, regulatory and public health issues raised by the development of new formulations designed to reduce the diversion and abuse of medications.

Chemistry, Pharmaceutical↗

PubMed2002

Microemulsion formulation for enhanced absorption of poorly soluble drugs. II. In vivo study.

Oral administration study of microemulsion formulations, which are known to improve the bioavailability of poorly soluble drugs, was performed using rats. Nitrendipine was used as a poorly soluble model drug, and its absorption was enhanced significantly by employing the microemulsion formulations compared to a suspension or an oil solution. The effect of the fed state on the oral absorption of nitrendipine became insignificant with the microemulsion formulations, although it affected the absorption from the suspension formulation significantly. The absorption behavior also varied with the type of surfactant. The absorption from Tween 80-based formulation was very rapid, while HCO-60-based formulation showed prolonged plasma concentration profile. However, the absorption from BL-9EX (polyoxyethylene alkyl ether)-based formulation was hardly observed. Damage to the gastrointestinal mucosa, which seems to be a serious problem of surfactant-based formulations, also differed with the type of surfactant employed. HCO-60 and Tween 80-based formulations were mild to the organs, while BL-9EX-based formulation caused serious damage. The behavior and absorption mechanism of the microemulsion formulations are discussed.

Administration, Oral↗

PubMed2002

Cortex segmentation: a fast variational geometric approach.

An automatic cortical gray matter segmentation from a three-dimensional (3-D) brain images [magnetic resonance (MR) or computed tomography] is a well known problem in medical image processing. In this paper, we first formulate it as a geometric variational problem for propagation of two coupled bounding surfaces. An efficient numerical scheme is then used to implement the geodesic active surface model. Experimental results of cortex segmentation on real 3-D MR data are provided.

Algorithms↗

PubMed1976

Entomopathogens: ecological manipulation of natural associations.

The control of insect pests with entomopathogens is unique, in that naturally occurring host-pathogen relations are manipulated to the benefit of man: protecting agricultural crops and forests or controlling insect vectors of disease. The isolation and identification of a virulent pathogen is the initial step in the development of a potential control agent. Production of the pathogen in adequate quantities must be possible either in vivo (insects) or in vitro (artificial medium). To insure usefulness, the pathogen must remain viable in the formulated form and after application in the field. Since inactivation rather than persistence is a problem, the pathogens must be formulated, protected, and applied to insure satisfactory pest control action. Studying the natural host--pathogen interactions will be necessary in order to manipulate the pathogen effectively, by introducing it at the most opportune time in the life cycle of the target pest. Generally, insect pathogens are more selective than conventional pesticides; this will limit their use and industrial development. Development, at least in part, by the public sector may be necessary and desirable. The most promising areas for the use of pathogens are in integrated pest management and in situations where pests have developed resistance to chemical control.

Animals↗

PubMed2000

Shade selection. Communicating with the laboratory technician.

Shade selection for anterior crowns has always set up a communications problem between the dentist and laboratory technician. Over the years, many different techniques have been formulated to help overcome the problem. These techniques include picture taking, drawing diagrams and using multiple porcelain shade guides. However, they have not completely erased the difficulty of communicating the choice of the proper shade of an anterior crown. This was especially true in the 1990's when all-ceramic crowns were introduced. Popular techniques dentists use for communicating shade selections will be reviewed, along with guidelines for making the proper selection. Many dentists are familiar only with the techniques they were taught in dental school and/or residency program and are unaware of the superior methods that can be used. This type of review can be extremely helpful to restorative dentists.

Ceramics↗

PubMed1995

Analysis of cancer rates using excess risk age-period-cohort models.

BACKGROUND: Recently the age-period-cohort (APC) model has become a popular epidemiological tool. However, it is well known that the model suffers from the identifiability problem. The simple multiplicative formulation of the model in terms of the age, period, and cohort variables without resorting to the underlying biology also casts doubt on the interpretability of the model parameters. METHODS: Excess risk APC models for cancers are developed based on carcinogenesis processes in human populations. These models have the beneficial feature of biological plausibility and do not suffer from the identifiability problem. Apart from the age, period, and cohort effects, a new kind of effect, the impact effect, is also introduced into the models. A computer program has been developed to fit the models which contain non-linear as well as restricted parameters. RESULTS: Two published mortality datasets are used to demonstrate the methodology. The proposed models fit better than the conventional APC model in both examples. CONCLUSIONS: Despite all the merits of the proposed models, several statistical issues should be investigated further before accepting this methodology as a general data-analytical tool.

Adult↗

PubMed1977

[Difficulties of a clinician in planning psychopharmacological trials (author's transl)].

From the clinical examinators point of view, we present a few problems in planning psychopharmacological trials. Our main topic is not answering the questions but formulating them in a more precise manner. The following problems are discussed: formulation of hypotheses, choice of experimental designs (open, double-blind, placebo-controlled), effects of placebo, choice of reference substances, duration of trials, pharmacopsychiatric acute trials, frequence and interval of assessments, size and kind of patient sample, fixed or flexible dosage schedule, pretreatment, wash-out, additional medication, choice of the assessement instrument and double assessment of the initial values.

Clinical Trials as Topic↗

PubMed2006

A shape-from-shading method of polyhedral objects using prior information.

We propose a new method for recovering the 3D shape of a polyhedral object from its single 2D image using the shading information contained in the image and the prior information on the object. In a strict sense, we cannot recover the shape of a polyhedron from an incorrect line drawing, even if it is practically almost correct. In order to overcome this problem, we propose a flexible face positioning method that can permit inconsistencies in the recovered shape that arise from vertex-position errors contained in incorrect line drawings. Also, we propose to use prior information about the horizontality and verticality of special faces and the convex and concave properties of the edges in order to attain good solutions and present a method of formulating such prior information as physical constraints. The shape-from-shading method is formulated as a minimization problem of a nonlinear cost function with the nonlinear constraints and its solution is searched by a global optimization algorithm. In the experiments with a synthetic image and three kinds of real images, shapes that are similar to those of the actual objects were recovered in all cases. As a result, the proposed method has proven to be effective in the shape recovery of simple-shape polyhedral objects.

Algorithms↗

PubMed2006

Psychogenic disorders: a pragmatic approach for formulation and treatment.

Four perspectives can provide a comprehensive yet flexible approach to the evaluation of a patient in distress with a psychogenic disorder. Each individual patient will have a different combination of the four perspectives that formulate the patient's problems. The perspectives identify the patient with a psychogenic disorder as a patient who is a composite of personal vulnerabilities and strengths but afflicted with diseases, struggling through life events, and motivated to behave for various reasons. Each individual perspective has its own logical process for evaluation and subsequently directed treatment. Although the perspectives are complementary, they each remain distinct and essential to the formulation of a patient's disability. This comprehensive and integrated formulation of a patient supports an approach to complex psychogenic cases that defy a simple list of diagnoses and nonspecific treatments. The patient does not have to fit into one theoretical approach to receive an available treatment. The treatments prescribed are now designed from the individual formulation and relevant perspectives.

Adult↗

PubMed1993

APLOGEN: an object-oriented genetic algorithm performing Monte Carlo optimization.

Problem-solving and modelling within a biological context often need a level of descriptive accuracy that is unlikely to be capable of analytical treatment, especially if the mathematical background of the biologist is poor. Furthermore solver-model maintenance is often difficult without the availability of trained specialists. Better prospects are found in the genetic algorithm field. Genetic algorithms are a set of procedures formulated to solve complex problems without specifying rules for intermediate steps. This approach becomes feasible performing a Monte Carlo simulation of the natural evolution process, in which population improvement (search for solutions) in a considered environment (the specific problem domain) is achieved by following the genetic paradigm. Starting with a randomly constituted sample of individuals, drawn from the population of admissible values and expressed as binary strings, random mating brings about individuals of the next generation. Parents are chosen with a greater probability as the number of constraints violated by each individual becomes smaller. During the constitution of each generation the presence of some genetic operators causes the improvement of population diversity and its maintenance. Genetic operators are simple string transformation rules, generally independent of a specific context. We have developed the constant core of a minimal genetic algorithm, from which can be derived genetic problem-solvers in specific domains. An applicative example--a constrained matrix equation on signed integers--is also realized to show graphically the algorithm dynamics.

Algorithms↗

PubMed2005

Linear theory for control of nonlinear stochastic systems.

We address the role of noise and the issue of efficient computation in stochastic optimal control problems. We consider a class of nonlinear control problems that can be formulated as a path integral and where the noise plays the role of temperature. The path integral displays symmetry breaking and there exists a critical noise value that separates regimes where optimal control yields qualitatively different solutions. The path integral can be computed efficiently by Monte Carlo integration or by a Laplace approximation, and can therefore be used to solve high dimensional stochastic control problems.

Journal Article↗

PubMed2000

Active constrained truncated Newton method for simple-bound optical tomography

In the past, nonlinear unconstrained optimization of the optical imaging problem has focused on Newton-Raphson techniques. Besides requiring expensive computation of the Jacobian, the unconstrained minimization with Tikhonov regularization can pose significant storage problems for large-scale reconstructions, involving a large number of unknowns necessary for realization of optical imaging. We formulate the inverse optical imaging problem as both simple-bound constrained and unconstrained minimization problems in order to illustrate the reduction in computational time and storage associated with constrained image reconstructions. The forward simulator of excitation and generated fluorescence, consisting of the Galerkin finite-element formulation, is used in an inverse algorithm to find the spatial distribution of absorption and lifetime that minimizes the difference between predicted and synthetic frequency-domain measurements. The inverse approach employs the truncated Newton method with trust region and a modification of automatic reverse differentiation to speed the computation of the optimization problem. The reconstruction results confirm that the physically based, constrained minimization with efficient optimization schemes may offer a more logical approach to the large-scale optical imaging problem than unconstrained minimization with regularization.

Journal Article↗

PubMed1975

Alcoholism as a mental health problem of Native Americans. A review of the literature.

Alcoholism among North American Indians and Eskimos is generally considered a major public health and community mental health problem, and increasingly so. All too often alcoholism and alcoholic (and the simple avoidance of these terms) are used indiscriminantly, obscuring important avenues for serious consideration. A major consideration is the extent to which the heavy drinking so common among indian men corresponds to "alcoholism" in the dominant culture. Considerations of culture stress (deculturative and acculturative) and cultural intoxication-permitting factors are essential in any dynamic formulation of Native Americans' problem drinking. A crucial individual motive is that drunkenness can provide short-cut gratification by providing fantasy solutions to culture-bound problems.

Alcoholism↗

PubMed1995

Role of computational chemistry in support of hazard identification (ID): mechanism-based SARs.

A mechanism-based structure-activity relationship (SAR) study examines the structural basis for a chemical/biological activity by targeting a single or a few stages in a postulated mechanism of action. Computational chemistry approaches provide a valuable complement to experiment for probing such associations, but require a highly focused viewpoint that neglects much of the full biological and chemical interaction problem. Research questions are formulated in terms of fundamental structure and reactivity properties and are designed to test key assumptions of a postulated mechanism of activity. The results of such studies can aid in the generation of new hypotheses, suggest new experiments, and provide scientific rationale for extrapolation in hazard identification (ID). Toxicologists and computational chemists bring very different, yet complementary viewpoints, approaches, and expertise to bear on the hazard ID problem. However, improved communication and interaction between these two groups is needed to most productively address hazard ID issues.

Algorithms↗

PubMed1992

A fluid-structure interaction problem in biomechanics: prestressed vibrations of the eye by the finite element method.

The object of this work has been to develop a mechanical and numerical model of the eye submitted to vibrations, and in particular, to calculate the influence of intraocular pressure (IOP) on the eye resonance frequencies. Our mechanical model of the eye relies upon the theory of the mechanics of continuous media. The numerical model results from a model analysis of the vibrations of the eye using a finite element method (FEM) for discretization. The eye can be schematically represented as a prestressed shell, filled by an inviscid barotropic compressible fluid, which leads us to formulate and solve a problem of vibrations of a coupled fluid-structure system. The corneoscleral shell has been modeled as a thin and thick shell, taking into account material nonlinearities in the thick case. Numerical results obtained for the attached eye demonstrate a fair sensitivity of the resonance frequencies to the variations of the IOP; thus, founding the interest of the surveillance of the resonance frequency of the eye.

Humans↗

PubMed1992

Oral contraceptives and cycle control: a critical review of the literature.

Control of spotting and breakthrough bleeding and absence of withdrawal bleeding, collectively termed cycle control, is the single most important determinant of whether a new user of oral contraceptives (OCs) will continue this method. However, information about different OC preparations and how they affect such problems, including the effects of progestogen and estrogen phasing and the components of these hormones, is scant and confusing. Studies cited in this report reveal highly variable rates of bleeding problems in women taking OCs: after 6 months of OC use, the prevalence of spotting varied between 0% and 8.5%; of breakthrough bleeding, 0% and 12.2%; and of amenorrhea, 0% and 5.8%. At least some of this variation is attributable to differing study populations and cultures, study designs, and the manner in which data were collected and reported. However, methodologic weaknesses were common, often involving lack of randomization and blinding, and attrition rates were high. Despite these limitations, it is clear that the frequency of bleeding problems decreases with continuing use of OCs, emphasizing the need for patient reassurance about the transient nature of these problems. In addition, gestodene-containing preparations appear to offer better cycle control than do desogestrel-containing preparations and levonorgestrel-containing preparations better control than norethindrone-containing preparations. However, the strongest lesson to emerge is the need for more rigorous studies to adequately address questions of comparative bleeding problems, particularly with newer triphasic formulations. These conclusions underscore the importance of counseling new OC users about the possibility of bleeding problems, reassuring them that most such problems are temporary, and, that if compliance is maintained, these will not impair contraceptive efficacy.

Contraceptives, Oral, Combined↗

PubMed2006

Efficient schemes for robust IMRT treatment planning.

We use robust optimization techniques to formulate an IMRT treatment planning problem in which the dose matrices are uncertain, due to both dose calculation errors and interfraction positional uncertainty of tumour and organs. When the uncertainty is taken into account, the original linear programming formulation becomes a second-order cone program. We describe a novel and efficient approach for solving this problem, and present results to compare the performance of our scheme with more conventional formulations that assume perfect knowledge of the dose matrix.

Algorithms↗

PubMed1990

Theoretical studies of protein conformation by means of energy computations.

In this review we describe fundamental concepts and applications of conformational energy computations, with emphasis on some recent advances and problems being investigated. The formulation of potential energy functions is described, including the nature of the intramolecular force field, the representation of interactions with the solvent, and considerations of entropy contributions. Approaches to the search for the optimal potential energy are summarized. Examples cited among applications of conformational energy computations include refinement of X-ray crystallographic structures, the use of computations in conjunction with NMR data, prediction of the structures of proteins based on either homology or on other procedures that surmount the multiple-minima problem, the analysis of hierarchical levels of structure and assembly, and interactions in enzyme-substrate complexes.

Algorithms↗