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S Hess

Publications and source records attributed to S Hess.

At least 37 records · Page 2Linked to original sources
PubMed2001

Profiling indomethacin impurities using high-performance liquid chromatography and nuclear magnetic resonance.

The anti-inflammatory drug indomethacin was investigated regarding new related impurities. Therefore, related substances 2-9 were prepared by independent synthesis and physicochemically characterized. To determine indomethacin and its related substances, a new HPLC-UV method was developed and validated. Indomethacin and its impurities were eluted on a C(18) column with a mobile phase consisting of methanol and an aqueous solution of 0.2% phosphoric acid at a flow rate of 1.5 ml/min and were quantified by UV detection at 320 nm. Overall, the HPLC-UV method was simple and reliable for the detection of eight impurities in indomethacin. In addition to the HPLC-UV method, 1H nuclear magnetic resonance (NMR) was used to investigate indomethacin regarding impurities. For that purpose, related substances 2-9 were systematically added to indomethacin and investigated. The NMR method was found to be very useful for the identification of impurities in bulk substance without prior separation. Both HPLC-UV and NMR were used to analyze 38 batches of indomethacin available on the European market. The outcome was that 42% of the batches did not meet the compendial requirements although they met the specifications of current compendial methods. Some batches contained the previously undescribed impurity 8, while other batches contained by-products from two distinct synthetic routes. The methods presented herein are important contributions to the ongoing efforts to reduce impurities and therefore the risk of adverse side-effects in drugs that are no longer under patent protection.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Synthesis and immunological activity of water-soluble thalidomide prodrugs.

A series of new water-soluble thalidomide prodrugs was prepared. All compounds were derivatized on the nitrogen of the glutarimide ring. Esters of natural amino acids and succinic acid derivatives have been introduced by reaction with the hydroxymethyl thalidomide 2. Nicotinic acid derivatives were prepared from halomethyl derivatives. Additionally, a methoxymethyl derivative and a carboxymethyl derivative were prepared directly from thalidomide. Most compounds showed a very large increase in water solubility compared to thalidomide itself (0.012mg/mL). The amorphous hydrochlorides of the N-methylalanine ester 8, valine ester 9, and glycylglycine ester 10, respectively, were the most soluble compounds showing solubility greater than 300mg/mL, which equals an increase greater than 15,000-fold. The lipophilicity of the prodrugs has been determined by their HPLC capacity factors k'. The stability of selected compounds was determined. The hydrolysis rates follow pseudo-first order kinetics. In order to assess the immunological activity, the prodrugs were tested using tumor necrosis factor-alpha and interleukin-2 inhibition assays. Selected compounds were additionally investigated on their abililty to inhibit the local Shwartzman reaction, an assay to determine the vascular permeability. The prodrugs retained high effectiveness in the inhibition of TNF-alpha release. Our results indicated that the more stable prodrugs exhibited higher activity in the immunological assays. Some compounds showed higher activity than thalidomide itself, suggesting a high affine binding to the pharmacophore. In conclusion, the prodrugs exhibited high water solubility and high activity and might therefore be used in therapeutic applications.

Animals↗
PubMed2001

Toward a consensus on reference values for thyroid volume in iodine-replete schoolchildren: results of a workshop on inter-observer and inter-equipment variation in sonographic measurement of thyroid volume.

OBJECTIVE: Interpretation of thyroid ultrasonography for assessing goiter prevalence requires valid reference criteria from iodine-sufficient populations. Reports have suggested the current reference criteria for thyroid volume (T(vol)) of WHO/ICCIDD (International Council for the Control of Iodine Deficiency Disorders) may be too high. Our objective was to determine if inter-observer and/or inter-equipment variability contributes to the disagreement in sonographic T(vol) in children reported from iodine-sufficient areas. DESIGN: A 2-day workshop in which four experienced ultrasound examiners from around Europe measured T(vol) in 45 6--12-year-old Swiss schoolchildren using four different portable ultrasound machines. One of the participating examiners (observer A) had generated the T(vol) data in European children that are the basis for the WHO/ICCIDD reference criteria. METHODS: Sonographic T(vol) was measured in each child by all four examiners on all four machines. Six hundred and eighty-four examinations were completed, with examiners having no knowledge of one another's results. Inter-observer and inter-equipment variation was calculated. RESULTS: Mean inter-equipment variation in T(vol) was 15.2% (95% CI: 14.1, 16.3%). There were no significant differences in T(vol) between equipment (P=0.51). For all observers, the mean inter-observer variation in T(vol) was 25.6% (95% CI: 23.9, 27.2%). At all ages and all body surface areas, there was a large systematic measurement bias (+30% volume) between the mean T(vol) of observer A and the mean Tvol of observers B, C and D. Reanalysis using data from observers B, C and D reduced the mean inter-observer variation in T(vol) to 13.3% (95% CI: 11.9, 14.7%). A correction factor for the systematic difference of operator A for the P50 and P97 of T(vol) was estimated using analysis of covariance. When applied to the WHO/ICCIDD reference data, it sharply reduced the discrepancy between the WHO/ICCIDD criteria and those from other iodine-sufficient children around the world. CONCLUSIONS: Inter-equipment error contributes minimally to reported differences in sonographic T(vol). Even among experienced examiners, inter-observer variation in sonographic T(vol) in children can be high, and probably contributes to the current disagreement on normative values in iodine-sufficient children. A systematic bias at least partially explains why the WHO/ICCIDD reference data differ from those reported from other iodine-sufficient children around the world. The findings argue strongly for the standardization of methods used for sonographic measurement of T(vol) in children.

Child↗
PubMed2001

Separation, analyses and syntheses of trimethoprim impurities.

The analysis of several impurities of the chemotherapeutic agent trimethoprim with various methods, including thin layer chromatography, gas chromatography, capillary electrophoresis as well as nuclear magnetic resonance is described. These methods were used to identify new impurities in trimethoprim batches. The main impurities were separated by column chromatography. To ensure the identity of the impurities, de novo syntheses were successfully carried out. With the methods described, it was possible to detect, separate and identify new impurities in trimethoprim batches.

Anti-Infective Agents, Urinary↗
PubMed2000

7-Deazaadenines bearing polar substituents: structure-activity relationships of new A(1) and A(3) adenosine receptor antagonists.

A series of 28 new pyrrolo[2,3-d]pyrimidine-4-amines, pyrimido[4, 5-b]indole-4-amines, and tetrahydropyrimido[4,5-b]indole-4-amines was synthesized and their adenosine receptor affinity determined in radioligand binding assays at rat A(1) and A(2A) adenosine receptors (ARs). Selected compounds were additionally investigated in binding assays at recombinant A(3) ARs. The 2-phenyl residue in (R)-7-(1-methylbenzyl)-2-phenylpyrrolo[2,3-d]pyrimidine-4-amine (ADPEP, 1) and in the corresponding pyrimido[4,5-b]indole (APEPI, 3) could be bioisosterically replaced by heterocyclic rings, such as 2-thienyl and 4-pyridyl. The resulting compounds retained high affinity and selectivity for A(1) ARs. Judging from the investigation of selected compounds, it appears that they are also potent at human A(1) ARs and selective not only versus A(2A) ARs but also highly selective versus A(2B) and A(3) ARs. The p-pyridyl-substituted derivatives 11 and 27 (APPPI) may be interesting pharmacological tools due to their fluorescent properties. Pyrrolo[2,3-d]pyrimidine-4-amine derivatives which were simultaneously substituted at N7 and N(4), combining the substitution pattern of ADPEP (1) and DPEAP (2), showed very low affinity for A(1) ARs. This finding supports our previously published hypothesis of different binding modes for pyrrolopyrimidines, such as ADPEP (1) and DPEAP (2). DPEAP (2), a pyrrolo[2,3-d]pyrimidine-4-amine substituted at the amino group (N(4)), was found to exhibit high affinity for human A(3) ARs (K(i) = 28 nM), whereas N(4)-unsubstituted analogues were inactive. DPEAP (2) and related compounds provide new leads for the development of antagonists for the human A(3) AR.

Adenine↗
PubMed2000

Loss of IL-6 receptor expression in cervical carcinoma cells inhibits autocrine IL-6 stimulation: abrogation of constitutive monocyte chemoattractant protein-1 production.

IL-6 is synthesized in human papilloma virus (HPV)-transformed cervical carcinoma cell lines and is supposed to stimulate these cells in an autocrine manner. We studied IL-6 production and responsiveness in nonmalignant HPV-transformed keratinocytes and cervical carcinoma cells in detail. IL-6 was detected in cervical carcinomas in situ. Correspondingly, HPV-positive carcinoma cell lines expressed high IL-6 levels. However, these carcinoma cell lines showed low responsiveness to IL-6 as revealed by low constitutive STAT3 binding activity, which was not further enhanced by exogenous IL-6. In contrast, in vitro-transformed nonmalignant keratinocytes without endogenous IL-6 production strongly responded to exogenous IL-6 with activation of STAT3. STAT3 protein expression levels were comparable in both responsive and nonresponsive cell lines. Also, gp130, the upstream signal-transducing receptor subunit conveying IL-6 signals into the cell, was expressed in all tested cell lines. However, the IL-6 binding subunit gp80 was lost in the malignant cells. Addition of soluble gp80 was sufficient to restore IL-6 responsiveness in carcinoma cells as shown by enhanced activation of STAT3 binding activity. As a consequence of the restored IL-6 responsiveness, carcinoma cells strongly produced the chemokine monocyte chemoattractant protein-1 (MCP-1). Our data demonstrate that cervical carcinoma cells producing high amounts of IL-6 only weakly respond to IL-6 in an autocrine manner due to limited gp80 expression. While production of IL-6 might contribute to a local immunosuppressive effect, silencing an autocrine IL-6 response prevents constitutive production of the mononuclear cell-attracting chemokine MCP-1. Both mechanisms might help the tumor to escape the immune system.

Apoptosis↗
PubMed2000

One-pot synthesis and biological evaluation of aspergillamides and analogues.

A one-pot total synthesis of aspergillamide and analogues by a solution phase Ugi multi component reaction (MCR) is described. The reaction is easily performed in 96-well plates and offers a facile access to diverse aspergillamide analogue compound libraries. The antibiotic and cytotoxic activity of these compounds is measured. Several of them are more potent than the natural product.

Anti-Bacterial Agents↗
PubMed2000

Rheological evidence for a dynamical crossover in polymer melts via nonequilibrium molecular dynamics

A certain "critical" molecular weight controls rheological properties of the multibead finitely extensible nonlinear elastic (FENE) chain model polymer melt. The rheological crossover manifests itself in a change of power law behavior for the viscous properties at a critical number of beads per chain N(c) = 100+/-10. This finding confirms a newly proposed relationship between dimensionless critical weight, characteristic length, and flexibility which we obtain as a side result. Results further suggest that the entanglement molecular weight N(e) for the flexible FENE chain model could be comparable in size or even larger than its critical molecular weight N(c).

Journal Article↗
PubMed2000

The effect of additional brain injury on systemic interleukin (IL)-10 and IL-13 levels in trauma patients.

OBJECTIVE: Besides interleukin (IL)-10, accumulating evidence from in vitro studies has indicated a strong antiinflammatory capacity for IL-13. A prospective clinical study was undertaken to assess the influence of additional brain injury on systemic IL-10 and IL-13 levels as markers for the antiinflammatory state in trauma patients. MATERIAL AND METHODS: The course of IL-10 and IL-13 plasma levels from 32 patients with an isolated severe head trauma (SHT), 50 patients with multiple injuries and additional SHT and 39 patients with multiple injuries without SHT was detected using ELISA-technique. Blood samples from 37 healthy blood donors were analysed for control. RESULTS: IL-10 levels were significantly elevated in all 3 injury groups within 3 h after trauma. The lowest initial release was detected in patients with an isolated SHT (Injury severity score; ISS: 18.1 +/- 5.6). No difference could be demonstrated for the IL-10 levels from multiple injured patients with (ISS: 35.3 +/- 9.6) or without additional SHT (ISS: 25.5 +/- 11.7), though there were relevant differences in the ISS. In contrast, the IL-13 plasma levels were not elevated systemically after trauma. CONCLUSIONS: IL-10 but not IL-13 is a detectable antiinflammatory marker in trauma patients with or without brain injury and to a minor degree in patients with an isolated SHT.

Adult↗
PubMed2000

Pressure of fluids and solids composed of particles interacting with a short-range repulsive potential

A simple short range repulsive potential (SR), with an even smoother cut off than the Weeks-Chandler-Andersen (WCA)-Lennard-Jones potential, yields practically the same pressure, both in the fluid state and for the fcc solid, when the potential parameters are chosen such that the forces are the same at the distance where the the two potential curves are equal to k(B)T. The comparison of the pressure for the SR and the WCA systems is based on molecular dynamics computer simulations. The fluid branch of the equation of state is rather well described by a modified Carnahan-Starling expression.

Journal Article↗
PubMed2000

Thyroid ultrasound compared with World Health Organization 1960 and 1994 palpation criteria for determination of goiter prevalence in regions of mild and severe iodine deficiency.

OBJECTIVES: In 1994, WHO/International Council for the Control of Iodine Deficiency Disorders recommended replacing the WHO 1960 four-grade goiter classification with a simplified two-grade system. The effect of this change in criteria on the estimation of goiter prevalence in field studies is unclear. In areas of mild iodine deficiency disorders (IDD) where goiters are small, ultrasound is preferable to palpation to estimate goiter prevalence. However, in areas of moderate to severe IDD, goiter screening by palpation may be an acceptable alternative to thyroid ultrasound. To address these two issues, we compared WHO 1960 and 1994 criteria with thyroid ultrasound for determination of goiter prevalence in areas of mild and severe IDD in Morocco. DESIGN: A cross-sectional study of 400 six- to 13-year-old children from two mountain villages (Ait M'hamed and Brikcha) in rural Morocco was carried out. METHODS: Urinary iodine concentration (UI), whole blood TSH and serum thyroxine were measured. Thyroid size was graded by inspection and palpation by two examiners using both WHO 1960 and 1994 criteria. Thyroid volume was determined by ultrasound. Variation between examiners and examination methods was assessed. Sensitivity and specificity of the two classification systems compared with ultrasound were calculated. RESULTS: Median UIs in Aït M'hamed and Brikcha were 183 and 24 microg/l respectively. In Ait M'hamed, using 1960 and 1994 criteria, goiter prevalence was 21 and 26% respectively, compared with 13% by ultrasound. In Brikcha, with 1960 and 1994 criteria, goiter prevalence was 64 and 67% respectively, compared with 64% by ultrasound. Agreement between observers was better with the 1994 criteria than with the 1960 criteria in Ait M'hamed (kappa=0.53 and 0.47 respectively), while in Brikcha observer agreement was similar with the two systems (kappa=0.67). Using either the 1994 or 1960 criteria, agreement with ultrasound was only moderate in Ait M'hamed (kappa=0.41-0.44), but good in Brikcha (kappa=0.55-0.64). Overall, compared with ultrasound, sensitivity increased 3-4% using 1994 criteria, while specificity decreased 4-5%. CONCLUSIONS: The WHO 1994 criteria are simpler to use than the 1960 criteria and provide increased sensitivity with only a small reduction in specificity. Agreement between observers is better with the 1994 criteria than with the 1960 criteria, particularly in areas of mild IDD. Like the 1960 criteria, the 1994 criteria overestimate goiter prevalence in areas of mild IDD, compared with ultrasound. However, the 1994 palpation criteria provide an accurate estimate of goiter prevalence in areas of severe IDD, and may be an acceptable and affordable alternative to thyroid ultrasound in these areas.

Adolescent↗
PubMed1999

CD40 ligand-CD40 interaction induces chemokines in cervical carcinoma cells in synergism with IFN-gamma.

Cellular immunity plays a major role in controlling human papilloma virus infection and development of cervical carcinoma. Mononuclear cell infiltration possibly due to the action of chemokines becomes prominent in the tumor tissue. In fact, the macrophage chemoattractant protein-1, MCP-1, was detected in cervical squamous cell carcinoma in situ, whereas absent in cultured cells. From this, unknown environmental factors were postulated regulating chemokine expression in vivo. In this study, we show high CD40 expression on cervical carcinoma cells and CD40 ligand (CD40L) staining on attracted T cells in tumor tissue, suggesting a paracrine stimulation mechanism via CD40L-CD40 interactions. We therefore investigated chemokine synthesis in nonmalignant and malignant human papilloma virus-positive cell lines after CD40L exposure. Constitutive expression of MCP-1, MCP-3, RANTES, and IFN-gamma-inducible protein-10 was almost undetectable in all cell lines tested. CD40L was able to induce MCP-1 production; however, despite much higher CD40 expression in malignant cells, MCP-1 induction was significantly lower compared with nontumorigenic cells. After sensitization with IFN-gamma, another T cell-derived cytokine showing minimal effects on CD40 expression levels, CD40 ligation led to a more than 20-fold MCP-1 induction in carcinoma cell lines. An even stronger effect was observed for IFN-gamma-inducible protein-10. Our study highlights the synergism of T cell-derived mediators such as CD40L and IFN-gamma for chemokine responses in cervical carcinoma cells, helping to understand the chemokine expression patterns observed in vivo.

CD40 Antigens↗
PubMed1999

Mediation of differentiating effects of butyrate on the intestinal cell line Caco-2 by transforming growth factor-beta 1.

BACKGROUND: Beside their role as the main energy source in the colonic mucosa, short chain fatty acids were found to act as potent antiproliferative and differentiation agents in various cancer cell lines. It has recently been shown that butyrate also induces TGF-beta 1 mRNA in human keratinocytes, suggesting that TGF-beta 1 may play a role in butyrate induced cell differentiation. AIM OF THE STUDY: The objective of our study was to investigate the possible role of exogenous and endogenous TGF-beta on butyrate induced differentiation of intestinal epithelium. METHODS: Studies were performed in Caco-2 cells, a cell line resembling functionally normal enterocytes. Cells, cultured in standard medium were studied over a 15-day period. Sodium butyrate (5 mM), TGF-beta 1 (2 ng/ml) or butyrate (5 mM) + anti-human TGF-beta 1 antibody (30 micrograms/ml) were added to the medium. At day 4, 8, 11 and 15 total protein content, alkaline phosphatase activity, lactate dehydrogenase activity and transepithelial resistance were measured. RESULTS: Under culture conditions both, butyrate and TGF-beta 1 inhibited growth accompanied by an induction of cell differentiation approved by increased alkaline phosphatase activity and transepithelial resistance. The differentiating effect of butyrate was accompanied by an increased endogenous TGF-beta 1, but not TGF-beta 2 expression in Caco-2 cells. Co-incubation of butyrate with anti-human TGF-beta 1 antibody suppressed at least in part the differentiating effects of butyrate. CONCLUSIONS: Our results directly implicate that the TGF-beta isoform TGF-beta 1 is necessary for butyrate-induced Caco-2 cell differentiation, but other molecular mechanisms may also play a role in the differentiation of this cell line.

Alkaline Phosphatase↗
PubMed1999

Soluble CD40 in the serum of healthy donors, patients with chronic renal failure, haemodialysis and chronic ambulatory peritoneal dialysis (CAPD) patients.

CD40 and its ligand CD40L are key players in T cell-B cell interaction and T cell-antigen-presenting cell (APC) interaction. Inhibition of CD40-CD40L interaction leads to severe humoral and cellular immunodeficiency. In this study we examined the presence of soluble CD40 (sCD40) in the serum of haemodialysis (HD) patients, CAPD patients, chronic renal failure (CRF) patients and healthy donors in order to evaluate the possible involvement of CD40 in uraemic immunodeficiency. Soluble CD40 was detected in the serum of healthy donors (n = 41) with a mean of 0.14 +/- 0.12 ng/ml and in the urine of healthy donors with a mean of 1.80 +/- 0.74 ng/ml. Soluble CD40 was highly elevated in all patients with impaired renal function. HD patients (n = 22) had up to 100-fold elevated sCD40 levels with a mean concentration of 8.32 +/- 4.11 ng/ml, whereas CAPD patients (n = 10) had considerably lower levels of sCD40 with a mean of 3.58 +/- 2.40 ng/ml. A strong correlation between sCD40 and serum creatinine levels was noted in CRF patients (n = 66). The highly elevated levels of sCD40 may point to the involvement of CD40 and its ligand CD40L in the clinical manifestation of uraemic immunodeficiency.

Animals↗
PubMed1999

Molecular reorientation of a nematic glass by laser-induced heat flow.

Laser-induced birefringence patterns which break the symmetry of the experimental setup have been observed in a low molar mass anisotropic glass with nematic orientational order under a polarizing microscope. It is shown that the observed spatial modulations in birefringence can be explained by laser-induced heat flow and stress, leading to molecular reorientation which is then frozen and stored in the glassy state if the optical excitation is switched off. The experimental findings can be regarded as a manifestation of heat-flow alignment caused by a spatially inhomogeneous temperature field.

Journal Article↗