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H De Winter

Publications and source records attributed to H De Winter.

12 recordsLinked to original sources
PubMed2005

A new approach in the prediction of the dissolution behavior of suspended particles by means of their particle size distribution.

Though various attempts have been made in literature to model the particle size distribution of an active pharmaceutical ingredient (API) in function of the required release profile of the pharmaceutical product, so far one has not succeeded to develop a universal approach in the correlation of particle size distribution and in vitro dissolution data. In this publication, a new approach is presented on the use of particle size distribution data in the prediction of the in vitro dissolution profile of a suspension formulation. For this purpose, various theoretical experiments were done simply on paper and based on the Noyes-Whitney [A.A. Noyes, W.R. Whitney, J. Am. Chem. Soc. 19 (1897) 930-934] equation, the normalized dissolution profiles of various imaginary size distributions were calculated. For each size distribution, its weighted mean diameters were then calculated. Based on these theoretical data, a model could be developed which scientifically explains the dissolution profile of a suspension in function of its volume-weighted mean particle size (D[4, 3]). The applicability of this correlation model could experimentally be confirmed by evaluation of laser diffraction and in vitro dissolution data as they were obtained for different batches of a suspension formulation. This new approach in the correlation between particle size and dissolution may be an important analytical tool in the engineering of the particle size distribution of drug substance, and more precisely monitoring the D[4, 3] volume-weighted mean diameter may allow one to model the dissolution profile of a suspension formulation and thereby its in vivo release profile.

Algorithms↗
PubMed2005

Laser diffraction and image analysis as a supportive analytical tool in the pharmaceutical development of immediate release direct compression formulations.

Immediate release direct compression tablet formulations require a strict control of the particle characteristics (i.e. particle size (distribution) and shape) of both the active pharmaceutical ingredient (API) and the excipients. In this publication, the development of a dry dispersion laser diffraction (LD) method has been outlined. With this method, the chemical development of an API meant for the manufacturing of an immediate release direct compression tablet formulation can be supported. Comparison with static image analysis (SIA) and scanning electron microscopy (SEM) data often shows laser diffraction to generate different size data. However, since LD is fast and frequently shows an adequate precision over a wide particle size range, the technique is still considered as a valuable analytical tool in the screening of the particle size distribution of API batches. In the future, automated (static) image analysis and dynamic image analysis are believed to become more and more important, since these techniques will allow the fast analysis of large amounts of particles with a minimum intervention of the operator.

Chemistry, Pharmaceutical↗
PubMed2001

Fractional flow reserve in patients with prior myocardial infarction.

BACKGROUND: Fractional flow reserve (FFR), an index of coronary stenosis severity, can be calculated from the ratio of hyperemic distal to proximal coronary pressure. An FFR value of 0.75 can distinguish patients with normal and abnormal noninvasive stress testing in case of normal left ventricular function. The present study aimed at investigating the value of FFR in patients with a prior myocardial infarction. Methods and Results-- In 57 patients who had sustained a myocardial infarction >/=6 days earlier, myocardial perfusion single photon emission scintigraphy (SPECT) imaging and FFR were obtained before and after angioplasty. The sensitivity and specificity of the 0.75 value of FFR to detect flow maldistribution at SPECT imaging were 82% and 87%. The concordance between the FFR and SPECT imaging was 85% (P<0.001). When only truly positive and truly negative SPECT imaging were considered, the corresponding values were 87%, 100%, and 94% (P<0.001). Patients with positive SPECT imaging before angioplasty had a significantly lower FFR than patients with negative SPECT imaging (0.52+/-0.18 versus 0.67+/-0.16, P=0.0079) but a significantly higher left ventricular ejection fraction (63+/-10% versus 52+/-10%, P=0.0009) despite a similar degree of diameter stenosis (67+/-13% versus 68+/-16%, P=NS). A significant inverse correlation was found between LVEF and FFR (R=0.29, P=0.049). CONCLUSIONS: The present data indicate (1) that the 0.75 cutoff value of FFR to distinguish patients with positive from patients with negative SPECT imaging is valid after a myocardial infarction and (2) that for a similar degree of stenosis, the value of FFR depends on the mass of viable myocardium.

Angioplasty, Balloon, Coronary↗
PubMed2000

Membrane lymphotoxin is required for the development of different subpopulations of NK T cells.

The development of lymphoid organs requires membrane-bound lymphotoxin (LT), a heterotrimer containing LTalpha and LTbeta, but the effects of LT on T cell function have not been characterized extensively. Upon TCR cross-linking in vitro, splenocytes from both LTalpha-/- and LTbeta-/- mice failed to produce IL-4 and IL-10 due to a reduction in NK T cells. Concordantly, LTalpha-/- and LTbeta-/- mice did not respond to the lipoglycan alpha-galactosylceramide, which is presented by mouse CD1 to Valpha14+ NK T cells. Interestingly, both populations of NK T cells, including those that are mouse CD1 dependent and alpha-galactosylceramide reactive and those that are not, were affected by disruption of the LTalpha and LTbeta genes. NK T cells were not affected, however, in transgenic mice in which LT signaling is blocked, beginning on day 3 after birth, by expression of a soluble decoy LTbeta receptor. This suggests that membrane-bound LT is critical for NK T cells early in ontogeny, but not for the homeostasis of mature cells.

Animals↗
PubMed1999

Mucosal immunity and inflammation. II. The yin and yang of T cells in intestinal inflammation: pathogenic and protective roles in a mouse colitis model.

Inflammatory bowel disease (IBD) is a multifactorial immune disorder of uncertain etiology. The advent of several mouse models of mucosal inflammation that resemble IBD has provided insight into the mechanisms governing both normal and pathological mucosal immune function. In a widely used adoptive transfer model, the injection into immunodeficient mice of a subset of CD4(+) T lymphocytes, the CD4(+)CD45RBhigh cells, leads to inflammation of the intestine. Pathogenesis is due in part to the secretion of proinflammatory cytokines. The induction of colitis can be prevented by cotransfer of another CD4(+) subpopulation, the CD4(+)CD45RBlow T cells. This population behaves analogously to the CD4(+)CD45RBhigh population in terms of the acquisition of activation markers and homing to the host intestine. However, their lymphokine profile when activated is different, and anti-inflammatory cytokines secreted and/or induced by CD4(+)CD45RBlow T cells prevent colitis. In this themes article, a description of the adoptive transfer model is given, the factors that promote and prevent colitis pathogenesis are discussed, and some controversial aspects of the model are addressed.

Animals↗
PubMed1998

Real-life radiation burden to relatives of patients treated with iodine-131: a study in eight centres in Flanders (Belgium).

In view of the EURATOM 96/29 [1] regulations, a prospective multicentre study was performed to evaluate the present guidelines given to relatives of patients treated with iodine-131 for both thyroid carcinoma and thyrotoxicosis, based on the real-life radiation burden. This study comprised 166 measurements carried out on a group of 94 relatives of 65 patients. All relatives wore a thermoluminescent dosemeter (TLD) on the wrist for 7 days. Sixty-one relatives agreed to wear another TLD for an additional 7 days. TLD were placed on nine patients' bedside tables. The eight participating centres were arbitrarily divided into three groups according to the period of time they advised their patients to sleep separately. Groups I, II and III respectively advised their patients to sleep separately for 0, 7-10 and 14-21 days. The median dose received by in-living relatives of thyroid carcinoma patients during the 14 days following hospital discharge was 281 microSv (doses to infinity not calculated); the median dose to infinity received by in-living relatives of ambulatory treated thyrotoxicosis patients was 596 microSv, as compared with 802 microSv for in-living relatives of hospitalised thyrotoxicosis patients. In general the children of patients received a significantly (P < 0.1) lower mean dose than their partners. For thyroid carcinoma patients, only two relatives out of 19 (10%) exceeded the EURATOM 96/29 limit of 1 mSv/year. For thyrotoxic patients, 28% of relatives exceeded the EURATOM 96/29 limit, but none of them were relatives of patients who followed guidelines for 21 days. The results of this study indicate that sleeping separately for 7 days, after a period of hospitalisation of 2-3 days, will usually be sufficient for thyroid carcinoma patients. For thyrotoxicosis patients, up to 21 days of sleeping separately could be necessary in order to strictly abide by EURATOM 96/29. Therefore, the authors propose the implementation of a non-rigid dose constraint for people who "knowingly and willingly" help patients treated with 131I, while still following the ALARA principle.

Adolescent↗
PubMed1997

Value of axillary ultrasonography and sonographically guided puncture of axillary nodes: a prospective study in 144 consecutive patients.

The value of axillary sonography in 144 consecutive patients was prospectively studied. Abnormal lymph nodes were demonstrated in 72 axillae, only half (36 of 72) of which were clinically detected. In comparison with intraoperative findings in 47 patients with breast carcinoma, the sensitivity of sonography in detecting malignant nodes was 92%, the specificity 95%, and the positive and negative predictive value 96% and 91%, respectively. In 42 patients a sonographically guided node puncture was performed. Evidence of malignancy was found in 38 (90.5%). In 14 (33%) of them, cyto-histology pointed to a clinically undetected primary malignancy.

Adult↗
PubMed1997

alpha-Amino acids derived from ornithine as building blocks for peptide synthesis.

Recently great interest has arisen in the synthesis of combinatorial libraries, and this technology provides a significant partner to contemporary strategies in rational design and lead discovery. By simple combination of a given set of building blocks, high numbers of different molecules are produced simultaneously, increasing the possibility of discovery of a lead compound in a limited time. One direction of research in this field focuses on the synthesis of libraries composed of modified amino acids. Here, the synthesis and characteristics of some building blocks derived from ornithine are described. The synthesis is based on the acylation/sulfonation of the copper complex of ornithine by aroyl and arylsulfonyl chlorides exemplified by 2-thiophenecarbonyl chloride, p-toluenesulfonyl chloride and 8-quinolinesulfonyl chloride. To evaluate the potential use of these modified alpha-amino acids as component in an oligopeptide library, all three derivatives were incorporated in a hexapeptide with a random sequence using a standard coupling procedure (DIC/HOBt/DIEA). Depending upon the acidity of the amido hydrogen on the delta-nitrogen, competition between intramolecular cyclization and peptide bond formation was observed. The higher the acidity, the more pronounced is this side reaction. Coupling conditions for peptide formation were optimized so that the newly described amino acid based building blocks are suitable for incorporation into libraries consisting of unnatural amino acids. The outlined procedures open up a broad avenue of possibilities for creation of diversity into peptidic libraries.

Amino Acids↗
PubMed1996

Understanding the binding of 5-substituted 2'-deoxyuridine substrates to thymidine kinase of herpes simplex virus type-1.

Thymidine kinase from HSV-1 (HSV-1 TK) is a key enzyme in the metabolic activation of antiviral nucleosides. High affinity of such compounds for the enzyme is required for efficient phosphorylation. In this study, affinity data from a series of 5-substituted 2'-deoxyuridine substrates in combination with the crystal structure of the viral enzyme were used to investigate the structural factors influencing the affinity of these compounds for the enzyme. Calculations showed that the binding energetics and conformations of thymidine and the 5-substituted 2'-uridine analogues are similar. The major part of the binding energy arises from interactions involving sugar and base moieties. Small differences in affinity for the enzyme are explained by the hydrophobicity of the 5-substituent or by its energetic complementarity with the active site pocket. In designing high-affinity nucleoside substrates of HSV-1 TK, care should be taken to maintain the geometry of the base moiety and sugar hydroxyl functionalities. Substitutions at the 5-position of the nucleobase should be lipophilic and characterized by well-defined geometrical properties. The present study represents a first quantitative explanation for HSV-1 TK affinity of 5-substituted 2'-deoxyuridines which are historically the first group of selective antivirals. The results may be used to design new and more potent compounds.

Antiviral Agents↗