Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Problem Formulation”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,531 records · Page 85Linked to original sources
PubMed2004

Pharmacogenetics: ethical problems and solutions.

Regulators, drug companies, academic scientists, bioethicists, clinicians and, increasingly, the general public are starting to realize that pharmacogenetics (PGx) will probably have a huge impact on the way in which we treat both common and rare diseases. But how much thought has gone into the ethical issues that the incorportation of phamacogenetic testing into drug discovery, prescription and use will entail? It seems that "quite a bit" is the answer, as the diverse viewpoints of representatives of all of these groups presented here illustrate. However, these views also highlight that now is the time to start formulating and implementing solutions to these potential problems.

Ethics, Medical↗
PubMed2002

Boundary layer variational principles: a case study.

Considering the model heat conduction problem in the setting of Grad's moment equations, we demonstrate a crossover in the structure of minima of the entropy production within the boundary layer. Based on this observation, we formulate and compare variation principles for solving the problem of boundary conditions in nonequilibrium thermodynamics.

Journal Article↗
PubMed2001

Phosphate supplementation for hypophosphataemia and parenteral nutrition.

Routine detection and treatment of acute hypophosphataemia is important in intensive care unit and many other hospitalized patients, but metabolic bone disease and hypophosphataemia are still experienced as a result of parenteral nutrition. A significantly common problem that faces the compounding pharmacist when formulating parenteral nutrition regimens is the difficulty associated with the successful avoidance of calcium phosphate precipitation. Although incorporation of the normal calcium and phosphate requirements into regimens for metabolically stable adults is usually achievable, it can prove impossible in paediatric and neonatal mixtures when using the standard inorganic sources that are currently licensed for use in the UK and USA. In other countries, where organic compounds are routinely available, this problem does not exist.

Bone Diseases↗
PubMed2002

A survey of essential national health research in nine developing countries.

A survey of Essential National Health Research (ENHR) was conducted between December 1997 and November 1998 in nine developing countries. A total of 27 respondents from seven South East Asian and two Caribbean countries completed questionnaires. Respondents included 14 men and 13 women with a median age of 48 years (range 25-69 years); 15 were researchers, seven were health providers, three policy makers and one a community representative (one no response). ENHR was formally adopted in five countries mainly through public policy statements. Seven countries had a mechanism in place for promotion of ENHR and national meetings were held in five countries in the year prior to the survey. A special activity was conducted in order to define health research priorities in eight countries and a list of these priorities was available in seven countries. The level of ENHR activity was ranked as low or moderate in most countries except India and Malaysia which were rated as moderate to high. Three countries reported that the process resulted in new or additional funds being made available for research, while India reported available funds being reallocated to meet the priorities defined. The respondents of six countries said that ENHR networking had led to tangible results, including improved collaboration among researchers and research institutions and the sharing of resources among different organizations (five countries). The ENHR process had resulted in research findings being used to formulate or change health policy in five countries. Most countries had not produced any new research protocols through the ENHR process. However, there were 250 new research protocols in India and 68 in Pakistan, of which 20 and between 25 and 35, respectively, were funded and 15 peer reviewed articles had been published from India. This survey does suggest that the ENHR process may be promoting health research on priority health problems and the use of results to formulate policy in selected countries. However, it is too early to assess the contribution of ENHR to health and development and a variety of different studies would be needed to conduct this assessment.

Developing Countries↗
PubMed1999

An investigation of the components of best nursing practice in the care of acutely ill hospitalized older patients with coincidental dementia: a multi-method design.

The main aim of this study was to examine, from the consumer's perspective, the components of best nursing practice in the care of acutely ill hospitalized elderly people who coincidentally suffered from dementia. Due to the complexity of the problem under investigation a triangulated design was formulated. This design comprised survey methodology, audit and critical incident technique. Data derived from each of these approaches were analysed first in isolation and subsequently combined at a conceptual level. The sample comprised 213 people aged 65 years and older, who were consecutive admissions from two acute medical and two acute care of elderly people wards. Sixty-six per cent of these individuals were found to suffer from cognitive impairment, 40% experiencing severe problems. The documentary survey revealed that patients with normal or severely abnormal cognitive functioning were more likely to have this noted than those with mild-moderate levels of impairment. No evidence of formal assessment was located and only 15% of these patients had items included in their nursing care plans associated with their chronic confusion. A sub-sample of 41 chronically confused people and their main hospital visitor were invited to participate in critical incident interviews. These conversations led to the identification of four major themes which reflected the most valued aspects of the nursing care which had been received or observed. The relationship between documentary care scores and the proportion of positive descriptions of care within each of the four themes was explored. The findings indicate that acute nursing care is deemed only to be at its best when it is delivered in tandem with dementia care. Discrete areas for practice development are identified and standards to guide nursing care are proposed. In addition to the practice development issues raised by the work, the methodological lessons further advance the practice of multi-method research.

Acute Disease↗
PubMed2006

Translation of an experimental oral vaccine formulation into a commercial product.

An effective experimental vaccine may fail to become a therapeutic reality for a number of scientific, regulatory or commercial reasons. In this review, we share some of our personal experiences as University-based researchers and provide an account of some of the problems that we have encountered during preliminary scale-up and assessment of an oral influenza vaccine formulation. Many of the problems we have faced have been non-scientific and related to identifying project-funding sources, finding suitable contract manufacturing companies that are GMP compliant, and protecting intellectual property generated from the scientific studies. The review is intended as a practical guide that will allow other researchers to adopt effective strategies to permit the translation of an effective experimental formulation to a viable commercial product.

Administration, Oral↗
PubMed2003

Paediatric medicines research in the UK: how to move forward?

There have been numerous studies to show that many of the medicines used in children are used off-label or are unlicensed for use in children. When children are prescribed unlicensed and off-label medications, some people may see them as unknowing participants in informal and uncontrolled experiments. However, the licensing status of a drug can be seen as a by-product of the real issues: the safety, efficacy and quality of these medicines in the current licensing system. It is important to conduct research in order to provide high quality data regarding safety and efficacy to support evidence-based paediatric prescribing. Clinical trials will always be an invaluable means of acquiring vital information about a drug; but when it comes to children, we may find that these trials are not always practical for technical, ethical and financial reasons; therefore, it is important to explore other methodologies in paediatric medicines research. Pharmacoepidemiological and prospective cohort studies could provide vital safety and efficacy data on paediatric medicines; however, resources need to be invested in the methodological research. Paediatric drug formulation research is under-resourced and under-valued, and, unfortunately, fatal and serious adverse reactions due to inappropriate formulations have been reported in many instances. Paediatric medication is a complex problem; we need to use all available tools for research on safety, efficacy and formulation. The reason for lack of progress in paediatric drug research is most likely due to lack of resources and research capacity. The industry and government should work together and invest more money in paediatric drug research. Finally, regulatory authorities, healthcare professionals and academics need to rethink the research strategy in order to provide better medicines for children.

Child↗
PubMed1995

Cyclosporin. A review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (Neoral).

The microemulsion-based formulation of cyclosporin (Neoral; referred to as the microemulsion formulation in this review) is a microemulsion preconcentrate which has been developed to overcome problems associated with the poor and unpredictable absorption of the standard oral formulation of this drug. These include marked intra- and interpatient variability in the extent of absorption, a poor correlation between trough blood concentrations of cyclosporin and total systemic exposure, and the need for regular monitoring of blood cyclosporin concentrations. In healthy volunteers and renal or liver transplant recipients, administration of the microemulsion formulation resulted in cyclosporin absorption which was significantly faster, more extensive and more predictable than that seen with the standard oral formulation. Furthermore, measurement of whole-blood trough cyclosporin concentrations provided a better estimate of systemic drug exposure in renal transplant recipients who received the microemulsion formulation than in those who received the standard formulation. Systemic exposure of cyclosporin delivered by the new formulation appears to be relatively unaffected by food intake. Initial data suggest that drug absorption from the microemulsion formulation is enhanced in comparison with that achieved from the standard formulation in liver transplant recipients undergoing biliary diversion or with cholestasis, although absorption from the new formulation does not appear to be completely independent of bile. Preliminary results from other groups that experience cyclosporin malabsorption from the standard formulation (patients with cystic fibrosis or diabetes, and children) are also encouraging. Clinical trials specifically designed to investigate the relative immunosuppressive efficacy of the microemulsion formulation have not been reported; further data are required to fully establish the relationship between the more rapid and extensive absorption of cyclosporin from the microemulsion formulation and the probability of graft rejection or adverse events (including nephrotoxicity and hypertension). However, no statistically significant differences have been noted between the 2 formulations in the incidence of these events in studies to date. The incidence of rejection in new renal or liver transplant recipients treated for a minimum of 3 months was approximately 31 to 50% in those receiving the microemulsion formulation and approximately 24 to 56% in those receiving the standard formulation. Thus, although confirmation of existing efficacy and tolerability data is required, the characteristic pharmacokinetic properties of the microemulsion formulation make it an attractive option for the oral delivery of cyclosporin in transplant recipients, offering more predictable and more extensive drug absorption than the standard formulation. The microemulsion formulation may be of particular benefit in patients who show poor absorption of cyclosporin from the standard oral formulation, such as liver transplant recipients with biliary diversion or cholestasis.

Animals↗
PubMed2006

The IMRT information process-mastering the degrees of freedom in external beam therapy.

The techniques and procedures for intensity-modulated radiation therapy (IMRT) are reviewed in the context of the information process central to treatment planning and delivery of IMRT. A presentation is given of the evolution of the information based radiotherapy workflow and dose delivery techniques, as well as the volume and planning concepts for relating the dose information to image based patient representations. The formulation of the dose shaping process as an optimization problem is described. The different steps in the calculation flow for determination of machine parameters for dose delivery are described starting from the formulation of optimization objectives over dose calculation to optimization procedures. Finally, the main elements of the quality assurance procedure necessary for implementing IMRT clinically are reviewed.

Animals↗
PubMed1994

Representations of metabolic knowledge: pathways.

The automatic generation of drawings of metabolic pathways is a challenging problem that depends intimately on exactly what information has been recorded for each pathway, and on how that information is encoded. The chief contributions of the paper are a minimized representation for biochemical pathways called the predecessor list, and inference procedures for converting the predecessor list into a pathway-graph representation that can serve as input to a pathway-drawing algorithm. The predecessor list has several advantages over the pathway graph, including its compactness and its lack of redundancy. The conversion between the two representations can be formulated as both a constraint-satisfaction problem and a logical inference problem, whose goal is to assign directions to reactions, and to determine which are the main chemical compounds in the reaction. We describe a set of production rules that solves this inference problem. We also present heuristics for inferring whether the exterior compounds that are substrates of reactions at the periphery of a pathway are side or main compounds. These techniques were evaluated on 18 metabolic pathways from the EcoCyc knowledge base.

Animals↗
PubMed2000

Rhabdomyolysis and acute renal failure resulting from alcohol and drug abuse.

Rhabdomyolysis is a common cause of acute renal failure (ARF) associated with drug misuse. Abuse of the gel formulation of temazepam has been a particular problem in the West of Scotland. We performed a retrospective review of dialysis-dependent ARF from rhabdomyolysis and drug misuse in the West of Scotland, 1986-1997. We identified 76 patients, of whom 87% were male. Seventeen cases occurred in the first 6 years, compared with 59 in the subsequent 6 years. Median age was 32. Thirty cases followed intravenous drug misuse, 46 followed oral drug misuse. The substances most frequently misused were alcohol (54%), heroin (24%) and parenteral temazepam (17%). The temazepam cases all followed the introduction of the gel formulation. Three out of 4 patients requiring limb amputation had injected temazepam. Of intravenous drug misusers tested, 72% were hepatitis-C-positive. Some 43% of patients had deprivation scores in the worst category. ARF due to rhabdomyolysis from substance misuse is increasing in our area. Alcohol is frequently responsible. The introduction of the gel formulation of temazepam has contributed to the increase. Those at risk in this study were young, male, had a high incidence of hepatitis C and lived in the most deprived areas.

Acute Kidney Injury↗
PubMed2004

A one-layer recurrent neural network for support vector machine learning.

This paper presents a one-layer recurrent neural network for support vector machine (SVM) learning in pattern classification and regression. The SVM learning problem is first converted into an equivalent formulation, and then a one-layer recurrent neural network for SVM learning is proposed. The proposed neural network is guaranteed to obtain the optimal solution of support vector classification and regression. Compared with the existing two-layer neural network for the SVM classification, the proposed neural network has a low complexity for implementation. Moreover, the proposed neural network can converge exponentially to the optimal solution of SVM learning. The rate of the exponential convergence can be made arbitrarily high by simply turning up a scaling parameter. Simulation examples based on benchmark problems are discussed to show the good performance of the proposed neural network for SVM learning.

Journal Article↗
PubMed2003

Basic types of discontinuity in circular acoustic wave guide.

It is considered the interaction of acoustic waves with two basic discontinuities--"diameter step" and "diaphragm with coaxial opening"--in a cylindrical acoustic waveguide with a rigid wall. The problem is considered and solved in rigorous formulation for the case of axial symmetry and below first radial resonance (f(r1)) in the waveguide. Obtained data demonstrate that a one-dimensional (1-D) model provides good results for the "diameter step" if the frequency does not exceed 18%-50% of f(r1). Calculated data for the "diameter step" demonstrate that this discontinuity follows the reciprocity principle (below f(r1))--the parameter of nonreciprocity does not exceed calculation errors. Data for the "diaphragm" demonstrate good agreement with the Lamb formula for a rigid screen with parallel slots--a 2-D problem in the Cartesian coordinates. Calculation errors for the both discontinuities were evaluated with the energy conservation law. The difference between sum of power fluxes in reflected and transmitted waves and the power flux in the incident wave does not exceed 1%.

Journal Article↗
PubMed2003

The temporal prior in bioelectromagnetic source imaging problems.

The multiplicity of temporal priors proposed for regularization of the bioelectromagnetic source imaging problems [e.g., the inverse electrocardiogram (ECG) and inverse electroencephalogram (EEG) problems], is discordant with the fact that fundamental statistical principles sharply limit the choice. Thus, our objective is to derive the form of the prior consistent with the general unavailability of temporal constraints. Writing linear formulations of the inverse ECG and inverse EEG problems as H = FG + N (where the ith columns of matrices H, G, and N, are data, signal, and noise vectors at time step i, and F is the transfer matrix), and using the noninformative principle that features of the spatiotemporal prior not supplied a posteriori should be invariant under temporal transformations, we show that the implied spatiotemporal signal autocovariance matrix (of the vector formed by the entries of G) is given in block matrix form [equation in text] where Cg is a matrix of unit trace proportional to the autocovariance matrix of any column of G (representing supplied information regarding the spatial prior), epsilon[.] denotes expectation, superscript ' indicates transpose, [symbol in text] is the Kronecker product, [symbol in text] is Frobenius norm, and the "matrix scalar product" [symbol in text] indicates the inner product of the two vectors formed by the entries of the two adjacent matrices (i.e., A [symbol in text] B [triple bond] trace[A'B]). This result eliminates some uncertainties and ambiguities that have characterized spatiotemporal regularization methods--including eight methods previously introduced in this transactions. Ultimately, the result derives from an implied symmetry principle under which the form of a nontrivial noninformative temporal component of the prior can be identified. Among other things, separability of the spatiotemporal prior in terms of the above Kronecker product can be thought of as the expression of the lack of "entanglement" of the spatial and temporal contributions (a consequence of noninformativity). The approach is generalized to the important cases of non-Gaussian spatial priors, and signal and noise that are not independent (transfer matrix noise). We also demonstrate a means for computational complexity reduction, related to the application of a particular orthogonal transformation, having features dependent on whether or not the transfer matrix represents a surjective mapping.

Action Potentials↗
PubMed2004

An efficient algorithm for optimizing whole genome alignment with noise.

MOTIVATION: This paper is concerned with algorithms for aligning two whole genomes so as to identify regions that possibly contain conserved genes. Motivated by existing heuristic-based software tools, we initiate the study of an optimization problem that attempts to uncover conserved genes with a global concern. Another interesting feature in our formulation is the tolerance of noise, which also complicates the optimization problem. A brute-force approach takes time exponential in the noise level. RESULTS: We show how an insight into the optimization structure can lead to a drastic improvement in the time and space requirement [precisely, to O(k2n2) and O(k2n), respectively, where n is the size of the input and k is the noise level]. The reduced space requirement allows us to implement the new algorithm, called MaxMinCluster, on a PC. It is exciting to see that when tested with different real data sets, MaxMinCluster consistently uncovers a high percentage of conserved genes that have been published by GenBank. Its performance is indeed favorably compared to MUMmer (perhaps the most popular software tool for uncovering conserved genes in a whole-genome scale). AVAILABILITY: The source code is available from the website http://www.csis.hku.hk/~colly/maxmincluster/ detailed proof of the propositions can also be found there.

Algorithms↗
PubMedDate not supplied

Issues in contemporary drug delivery. Part VI: Advanced cardiac drug formulations.

OBJECTIVE: To identify and discuss the clinical utility of new delivery systems and formulations of cardiac drugs. DATA SOURCES: Studies describing or evaluating new drug delivery systems for cardiac drugs were identified through a MEDLINE literature search. STUDY SELECTION: All studies describing or evaluating new delivery systems for cardiac drugs were reviewed. DATA EXTRACTION: Data were abstracted and evaluated by each author independently. DATA SYNTHESIS: The most common oral sustained-release formulations include the wax-matrix system, the gastrointestinal therapeutic system (GITS), and the spheroidal oral drug absorption system (SODAS). The wax-matrix delivery system is limited by the occurrence of "dose-dumping." In a low-pH setting, the wax-matrix formulation may dissolve too rapidly, liberating the entire dose in a short period of time. The clinical relevance of this phenomenon is unknown. The GITS and SODAS formulations are less likely to be affected by pH and food. Nitroglycerin is available by many routes of administration. The topical patch forms are convenient to use, but are associated with the development of tolerance. A buccal formulation incorporates a relatively short onset of effect with a three- or four-times-daily dosing regimen. Although tolerance is less of a problem with buccal nitroglycerin than with topical nitrates, this formulation is less convenient to use because of buccal irritation and interference with eating and talking. A new spray formulation of nitroglycerin offers longer shelf-life storage stability and an easier mode of administration. The spray canister is stable for three years compared with 12 weeks for an opened bottle of sublingual nitroglycerin tablets. Sublingual administration of oral cardiac drugs offers the potential for a more rapid onset of effects. Although nifedipine is often given sublingually, objective data indicate that it is not absorbed buccally but rather in the stomach. It appears that the chew-and-swallow route is most appropriate for nifedipine. Captopril is absorbed sublingually but its efficacy has not been demonstrated. Transdermal clonidine improves compliance and is associated with fewer adverse effects than oral clonidine. Transdermal formulations of beta-blockers are currently being evaluated. CONCLUSIONS: Further advancements in the development of novel delivery systems for cardiac drugs are expected in the future.

Administration, Cutaneous↗
PubMed2004

ABI 007.

ABI 007 [Abraxane] is an albumin-stabilised nanoparticle formulation of paclitaxel designed to overcome insolubility problems encountered with paclitaxel. This then eliminates the need for toxic solvents like cremophor, which limits the dose of paclitaxel that can be administered and hence affect overall drug efficacy. Studies have shown that the albumin receptor-mediated paclitaxel-transport mechanism is analogous to the opening of a 'trapdoor' on the endothelial cell wall within blood vessels. This facilitates the passage of ABI 007 from the bloodstream via the blood vessels to the underlying tumour tissue. ABI 007 is being developed for the treatment of a variety of tumour types by American Pharmaceutical Partners. In addition to the standard infusion formulation of ABI 007, oral and pulmonary delivery formulations are also being investigated. American Pharmaceutical Partners, a subsidiary of American BioScience, secured exclusive North American marketing and manufacturing rights to ABI 007 from American BioScience in November 2001. In anticipation of product launch within the fourth quarter of 2004, the company formed Abraxis Oncology and recruited an experienced sales and marketing team. The company has also accumulated approximately 28 million US dollars of paclitaxel inventory. As such, American Pharmaceutical Partners anticipates pre-launch expenses to cost approximately 40 million US dollars, incurred over 2004. In addition, the company expects to make two milestone payments worth 10 million US dollars as well as 15 million US dollars, based upon US FDA acceptance of NDA filing in the second quarter of 2004 and subsequent US FDA approval, respectively. The milestone for US FDA approval would be capitalised and amortised over the estimated life of the product.Previously, American Pharmaceutical Partners reported that its rolling NDA submission for ABI 007 commenced in May 2003. In July 2003, the company announced that this was progressing on schedule and expected to have completed its entire NDA submission by the end of 2003. The company also began preparations to form a sales and marketing group in anticipation of product launch. In addition, production of commercial quantities of ABI 007 was expected to begin in the second half of 2003. The US FDA granted fast-track status to ABI 007 for this indication in January 2003. The decision for NDA filing was based on the successful completion of a phase III trial evaluating ABI 007 versus standard paclitaxel among 460 patients with metastatic breast cancer in the US. In September 2003, American Pharmaceutical Partners and American BioScience jointly announced positive interim results from the trial, which shows that the primary efficacy objective had been exceeded. American BioScience completed this phase III trial in early 2003 with the results unblinded in mid-2003. The phase III study directly compared the efficacy of ABI 007 260 mg/m(2) versus paclitaxel 175 mg/m(2). Both agents were administered every 3 weeks. ABI 007 was administered as a 30-minute infusion without steroid pretreatment. Paclitaxel-treated patients received steroid pretreatment and the drug was administered over 3 hours. Enrollment was completed in December 2002 with 460 first- and second-line metastatic breast cancer patients enrolled. A Data Monitoring Committee concluded in October 2002 that a sample-size adjustment of the phase III trial was not required and that the study could be continued to completion. A phase II trial of ABI 007 was also underway in metastatic breast cancer patients who have failed taxane therapy. The trial was evaluating a weekly rather than 3-weekly regimen of ABI 007. Also in February 2004, American BioScience initiated a multicentre phase II trial in patients with metastatic melanoma. The trial will evaluate both chemotherapy-naive patients (at a dose of 150 mg/m(2) administered weekly) and patients who have previously received chemotherapy (at a dose of 100 mg/m(2) administered weekly) as treatment for metastatic disease. In May 2003, American Pharmaceutical Partners reported that ABI 007 is also being evaluated for the treatment of non-small cell lung cancer, ovarian cancer, melanoma and cervical cancers. Phase I/II trials have also been conducted in other solid tumours, including squamous cell cancer of the head and neck, and pelvis. Phase I trials have also been conducted in patients with solid tumours to evaluate the administration of ABI 007 on a weekly schedule. In September 2003, American BioScience was issued US patent No. 6,506,405, which has 89 claims covering compositions of matter and unit dosage forms. In addition, the patent covers methods of use without the requirement for pretreatment with steroid therapy or growth factor support. In July 2003, the US Court of Appeals for the Federal Circuit in Washington DC unanimously ruled that American BioScience is the true and rightful owner of patent No. 5,780,653. This patent covers three next-generation taxane anticancer compounds. This ruling overturned a lower court decision in a lawsuit brought in 1998 by Florida State University (FSU) and FSU Prof. Robert Holton's privately held company, Taxolog. In the lawsuit, FSU and Taxolog alleged that Prof. Holton and others at FSU were the true inventors of the compounds claimed under American BioScience's patent.

Albumin-Bound Paclitaxel↗