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H J Verhaar

Publications and source records attributed to H J Verhaar.

34 records · Page 2Linked to original sources
PubMed1997

Solid phase microextraction as a tool to determine membrane/water partition coefficients and bioavailable concentrations in in vitro systems.

Solid phase microextraction (SPME) is an extraction technique that uses a polymer-coated fiber as the extraction device. After extraction, the compound of interest can be desorbed from the fiber and subsequently analyzed by GC or HPLC. One of the properties of SPME is that only the freely dissolved fraction of a chemical is available for partitioning to the extraction device. The method can be applied in a way that small amounts are extracted from the sample, which allows negligible depletion extraction. These two properties make SPME devices particularly suitable for measurements of free concentrations. In toxicological studies the free concentration is considered to be a more relevant parameter, concerning toxic effects, than the nominal concentration that is used most frequently. In the current study, the usefulness of this method to measure phospholipid/water partition coefficients and free concentrations in three different in vitro test systems (rat hepatocytes in primary culture, 9000 g and 100,000 g homogenate fractions of rainbow trout liver) was demonstrated. Results show separate relationships between phospholipid/water and n-octanol/water partition coefficients for a set of polar and nonpolar organic chemicals, respectively. These observations suggest that phospholipid/water partition coefficients may be a more suitable parameter in modeling the kinetic behavior of organic chemicals. Additionally, differences between the nominal and the actual free concentration in in vitro systems are more pronounced for more hydrophobic compounds, as was expected based on theoretical considerations. To our knowledge, the approach presented here is the first analytical method to measure toxicologically relevant concentrations in in vitro test systems in a fast and efficient way.

Animals↗
PubMed1997

A proposed approach to study the toxicology of complex mixtures of petroleum products: the integrated use of QSAR, lumping analysis and PBPK/PD modeling.

Mixture toxicity is a topic that has become a matter of concern during the last two decades. One of the major problems with assessing the toxicity of mixtures and the associated human and environmental risk is the large number of possible mixtures, as well as the fact that the actual mixture effect for a given set of constituents might strongly depend on the actual composition of the mixture, i.e., the ratios of the constituent, as well as their nature. This paper presents a possible approach to describe and thereby better understand the pharmacokinetics and dynamics of complex mixtures by combining quantitative structure-activity relationships to predict needed parameters, lumping to reduce the complexity of the problem, and physiologically based pharmacokinetic/pharmacodynamic modeling to integrate all this information into a complete toxicological description of the mixture. It is our hope that by presenting this conceptual approach we might be able to stimulate some criticisms and discussions in the toxicology community regarding this complex and yet very important area of research.

Animals↗
PubMed1995

[Intestinal pseudo-obstruction during use of baclofen].

In a 75-year-old man acute intestinal pseudo-obstruction was observed during treatment with baclofen 20 mg daily. After discontinuation of the baclofen he recovered completely. No other cause of intestinal obstruction could be demonstrated. Baclofen is an agonist of spinal GABA receptors. It is used in the treatment of spasticity caused by multiple sclerosis or other diseases of the spinal cord, in particular traumatic lesions. Physicians should be aware of this possible adverse effect of baclofen.

Aged↗
PubMed1995

Comparison of the action of 17 beta-estradiol and progestins with insulin-like growth factors-I/-II and transforming growth factor-beta 1 on the growth of normal adult human bone-forming cells.

Endogenous growth factors may be involved in the prevention of bone loss by estrogen and progestins in postmenopausal women. The present study was performed to compare the action of estrogen/progestins on bone-derived cells with the effects of exogenously added purified growth factors. Human osteoblast-like (HOB) cells were incubated with 17 beta-estradiol (E2), progesterone (P), dydrogesterone (DD), 20 alpha-dihydroxydydrogesterone (DHD), with and without the growth factors, insulin-like growth factors-I/-II (IGF-I/-II) or transforming growth factor-beta type 1 (TGF-beta 1) for 24 h under serum-free conditions. Cell growth and DNA synthesis were assessed by spectophotometrical analysis of total cell number and immunochemical detection of BrdU incorporation, respectively. Compared with the sex steroids, incubation of the cells with IGF-I or TGF-beta 1 resulted in at least a two-fold increase of total HOB cell numbers. No difference in stimulating HOB growth was observed between IGF-II and the female sex steroids E2 and P. Combining IGF-I/-II or TGF-beta 1 with either E2 or P did not result in a significantly further increase in the human osteoblast-like cell growth. In conclusion, the bone anabolic growth factors, IGF-I and TGF-beta 1, may be more important regulators of osteoblast proliferation than the female sex steroids. An interaction of estrogen/gestagens with the growth factors IGF-I/-II or TGF-beta 1 was not evident from the growth of human bone-forming cells in short-term cultures.

Aged↗
PubMed1994

Application of QSARs in risk management of existing chemicals.

QSAR-estimates of aquatic toxicity of relatively unreactive (narcosis-type) organic chemicals for 19 species were used to predict "no-effect-levels" (NELs) at the ecosystem level by means of several extrapolation models which were recently discussed by the Organisation for Economic Cooperation and Development (OECD). It appeared that the differences between the numerical results of these extrapolation methods, despite their different statistical assumptions, were small. Equilibrium-partitioning theory for sediment and water as well as biota and water was used to derive NELs for aquatic sediments and whole-body residues. Simple equations are given, from which NELs for water, and subsequently for sediments and whole-body residues, can be predicted on the basis of only the octanol-water partition coefficient. Actual application of the models presented absolutely requires the availability of methods to recognize chemicals that act by the unspecific mechanism of narcosis. To this end, a classification scheme, based on molecular structure, was developed. This classification scheme was applied to the approximately 2000 so-called High Production Volume Chemicals (HPVCs) listed in Annex 1 of the Council Regulation on the Evaluation and the Control of the Environmental Risks of Existing Chemicals of the European Communities. From the classification of these 2000 HPVCs it is concluded that, for a large portion of all existing chemicals, reliable QSAR estimates of aquatic toxicity can be made; this considerably speeds up the process of priority setting and risk assessment of existing chemicals. The validity of this (dual) approach was tested by a comparison of estimated NELs with actual FCC values for all compounds from the US-EPA Water Quality Guidelines list that classify as narcosis-type compounds. This comparison shows that for many existing chemicals QSARs may be used to derive quality guidelines for water, aquatic sediments and residues in aquatic biota.

Amphibians↗
PubMed1992

Stimulatory effects of estrogen and progesterone on proliferation and differentiation of normal human osteoblast-like cells in vitro.

Here we report that osteoblast-like cells derived from female and male adult human trabecular bone are able to directly respond to 17 beta-estradiol (E2) and progesterone (P). In short-term (1 day) cultures using serum-free and phenol red-free medium, both steroid hormones were found to stimulate DNA synthesis and growth of the human osteoblast-like cells. P was more potent in stimulating osteoblast growth compared to E2. On the other hand, E2 showed a stronger differentiation-inducing effect as determined by analysis of the number of cells displaying cytochemical alkaline phosphatase (AP) activity, a marker for the mature osteoblast phenotype. Combination of E2 and P resulted in a further increase in DNA synthesis, but did not further affect the number of cells expressing AP activity. In conclusion, female sex steroids may be involved in regulating bone mass in human adults via a direct anabolic action on the bone forming cells.

Alkaline Phosphatase↗
PubMed1991

The application of QSARs, extrapolation and equilibrium partitioning in aquatic effects assessment for narcotic pollutants.

QSAR estimates of toxicity of relatively unreactive organic chemicals for 19 species of bacteria, algae, fungi, protozoans, coelenterates, rotifers, molluscs, crustaceans, insects, fish and amphibians were used to predict 'no-effect-levels' (NELs) at the ecosystem level by means of a recently developed extrapolation model. Equilibrium-partitioning theory for sediment and water was used to derive NELs for aquatic sediments. A simple table is given from which NELs for water and sediments can be predicted on the basis of only the octanol-water partition coefficient and molecular weight.

Animals↗
PubMed1991

Bioconcentration of chlorinated anilines and benzene in fish: preliminary results.

1. Seven chlorinated anilines and one chlorinated benzene were tested for their ability to bioconcentrate in guppies (Poecilia reticulata) under different experimental conditions. 2. Interactions between compounds in a mixture influence the bioconcentration of some chlorinated anilines. These interactions result in either an increase or a decrease of bioconcentration, depending on the compound studied. 3. Exposure concentration can have an effect on the extent of bioconcentration of some chlorinated anilines.

Analysis of Variance↗
PubMed1988

1-Phenyl-5-vinyl-2-imidazolidinethione, a proposed causative agent of Spanish toxic oil syndrome: synthesis, and identification in one of a group of case-associated oil samples.

A method is described for the synthesis and characterization of N-(2-hydroxy-3-butenyl)-N'-phenylthiourea, and its cyclization product, 1-phenyl-5-vinyl-2-imidazolidinethione (PVIZT). Fourteen coded oil samples associated with toxic oil syndrome cases in Spain were examined by gas chromatography-electron impact mass spectrometry for the presence of PVIZT. Although these samples were obtained from households where cases of toxic oil syndrome had been recorded, they differed extremely with regard to their anilide and sulphur contents. In one sample PVIZT was detected at an estimated concentration of 1 mg/kg.

Anilides↗
PubMed1985

Isolation of intestinal mononuclear cells: factors released which affect lymphocyte viability and function.

Whether toxic or immunomodulatory factors are released during the collagenase digestion phase of the isolation of mononuclear cells from human intestinal mucosa was investigated by assessing the effect of the collagenase supernatant on the viability and natural killer activity of normal peripheral blood mononuclear cells. Three hours' incubation in collagenase supernatant suppressed natural killer activity by 25 +/- 4% and decreased the viability of peripheral blood mononuclear cells by 11 +/- 2%. The ability of collagenase supernatants to kill 51Cr-labelled peripheral blood mononuclear cells over four hours was assessed in 16 collagenase supernatants, eight of which produced lysis of 20 +/- 4%. There was no ultrastructural evidence of early degenerative changes in the viable intestinal mononuclear cells fresh from the isolation process or in peripheral blood mononuclear cells incubated in collagenase supernatant. Because prostaglandins are known to inhibit natural killer activity, PGE was measured in 20 collagenase supernatants by radioimmunoassay and found to be high at 27.5 +/- 4.0 ng/ml. Addition of indomethacin to the collagenase medium, however, failed to abolish the inhibitory effect of collagenase supernatant on natural killer activity and did not increase the natural killer activity of isolated intestinal mononuclear cells. The release of cytotoxic and immunomodulatory factors during the isolation of intestinal mononuclear cells indicates the necessity for careful assessment of the potential effects of the isolation process on any function being examined and casts doubt upon the relationship between in vitro findings and in vivo functional capabilities.

Cell Separation↗
PubMed1984

The mononuclear cells of human mesenteric blood, intestinal mucosa and mesenteric lymph nodes: compartmentalization of NK cells.

The proportions of T cell subsets and Leu 7+ cells and the spontaneous cell-mediated cytotoxicity (SCMC) of isolated mononuclear cells have been determined across the mesenteric vascular bed and along the intestinal mucosal-mesenteric lymph node (MLN) axis in patients undergoing abdominal surgery. Whereas the proportion of T4+ and T8+ cells were similar in simultaneously taken PVB and mesenteric venous blood (MVB), the proportion of Leu 7+ cells was higher in MVB in 16 of 17 studies (15.4 +/- 6.8%, 10.8 +/- 5.1%). Additional studies showed that the proportions of lymphocyte subsets in peripheral arterial blood are the same as those in PVB. Thus, an enrichment of Leu 7+ cells occurs across the mesenteric vascular bed. Isolated intestinal and MLN mononuclear cells contained similarly high proportions of T4+ and T8+ cells as in PVB but Leu 7+ cells made up a minority subpopulation in intestinal (1.3 +/- 0.8%) and MLN mononuclear cells (1.0 +/- 0.9%). The SCMC of intestinal and MLN mononuclear cells was low and paralleled the proportion of Leu 7+ cells. Despite the higher proportions of Leu 7+ cells in MVB, the SCMC was less than that of PVB in eight patients with inflamed intestine and not significantly different from PVB in seven patients with normal intestines. These paradoxical findings were at least in part due to inhibitory factors in mesenteric plasma. In conclusion, NK cells appear to be largely confined within the vascular system and the enrichment of Leu 7+ cells across the mesenteric vascular bed suggests that this compartmentalization may be due to differences in the traffic of lymphocyte subpopulations through the intestinal mucosa and MLN.

Cell Movement↗
PubMedDate not supplied

A comparison of the action of progestins and estrogen on the growth and differentiation of normal adult human osteoblast-like cells in vitro.

Estrogen/gestagen replacement therapy prevents excess bone loss in postmenopausal women. The mode of action by which these sex steroids exert their anabolic effects on bone has not been completely clarified yet. In this study, 17 beta-estradiol (E2), as well as progestins progesterone (P), dydrogesterone (DD), 20 alpha-dihydroxydydrogesterone (DHD), medroxyprogesterone acetate (MPA), and cyproterone acetate (CPA) were able to stimulate the mitogenesis and differentiation of normal adult human osteoblast-like (HOB) cells harvested from female trabecular bone explants. The different progestins exerted a more pronounced stimulatory effect on HOB proliferation than E2 did. The combination of E2 with P, DD, or DHD did not result in a statistically significant further increase of HOB proliferation, as compared with the progestins alone. In general, E2 showed a stronger differentiation-inducing effect than the progestins, as measured by histochemical staining of the HOB cells for alkaline phosphatase activity. Combining E2 and the progestins did not result in a further increase of the number of alkaline phosphatase positive cells, compared with E2 alone. The different progestins proved to be equally potent in stimulating HOB proliferation and differentiation. In conclusion, progestins as well as E2 exerted anabolic but differential effects on normal adult human osteoblasts in vitro.

Aged↗
PubMedDate not supplied

Relationship between circulating levels of sex hormones and insulin-like growth factor-1 and fluid intelligence in older men.

The relationship was investigated between baseline serum levels of total testosterone (T), free testosterone (FT), dehydroepiandrosterone sulfate (DHEAS), ESTRADIOL (E2), sex hormone-binding globulin (SHBG), insulin-like growth factor-1 (IGF-1) and cognitive functioning in 25 healthy older men (mean age 69.1 years). Cognitive tests concerned measures not sensitive to ageing (crystallized intelligence), and measures sensitive to ageing (fluid intelligence and verbal long-term memory). Partial correlation coefficients (controlled for level of education) revealed significant associations of total T (r = -.52, p = -.009), SHBG (r - .59, p = .002) and IGF-1 (r = .54, p = .007) with the composite measure of fluid intelligence test performance, but not with crystallized intelligence, nor verbal long-term memory. Stepwise hierarchical regression analysis with the composite measure of fluid intelligence as the dependent variable showed that the contributions of SHBG, total T, and IGF-1 were not additive.

Aged↗
PubMedDate not supplied

Quick titration of pergolide in cotreatment with domperidone is safe and effective.

The purpose of the study was to analyze efficacy and safety of quick pergolide titration combined with domperidone. In an open-label prospective study, pergolide was titrated in 16 days to a maximum of 3 mg/d doses as adjunctive treatment to L-Dopa in 10 elderly patients with Parkinson's disease. Sixty milligrams domperidone was started 2 days before and and continued during the pergolide titration period to prevent side effects. Adverse events were studied for 6 weeks. Efficacy was measured with the motor part ("on" condition) of the Unified Parkinson's Disease Rating Scale (UPDRS), the 2-minute walking test, the Timed Up and Go test, and the Postural-Locomotor-Manual test. After quick titration of pergolide with domperidone cotreatment, no symptomatic side effects were seen except for lightheadedness in one patient, which disappeared after dose reduction. The UPDRS motor score improved significantly from 21 +/- 8 at baseline to 16 +/- 7 and 12 +/- 7 after 1 and 2 weeks, respectively. The 2-minute walking distance improved significantly from 123 +/- 36 m at baseline to 136 +/- 41 m after 6 weeks. The Timed Up and Go and Postural-Locomotor-Manual test results, overall, did not show significant changes. Quick titration of pergolide to a maximum of 3 mg/d with domperidone cotreatment is safe and effective. Therefore, we recommend domperidone cotreatment in the titration period to prevent unnecessary failure of dopamine agonist treatment because of adverse effects.

Aged↗