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Biomedical subjects

R Neubert

Publications and source records attributed to R Neubert.

At least 37 records · Page 2Linked to original sources
PubMed1995

Thalidomide and the immune system. 4. Down-regulation of the CD26 receptor, probably involved in the binding of HIV components to T cells in primates.

Thalidomide (Thd) is capable of down-regulating the CD26 receptor on CD4+ lymphocytes after treatment of healthy volunteers. Similar effects are observed when marmosets (Callithrix jacchus) are treated with Thd. The Ta1 epitope of the CD26 receptor has recently been shown to bind the HIV-1 Tat trans-activating protein, and CD26 has also been suggested to be a coreceptor for the binding of the V3 loop of the gp120 HIV envelope protein. This might provide a hint for possible therapeutic interventions.

Animals↗
PubMed1995

Chlorinated dibenzo-p-dioxins and dibenzofurans and the human immune system. 2. In vitro proliferation of lymphocytes from workers with quantified moderately-increased body burdens.

Lymphocyte proliferation responses were studied in workers with moderately increased body burdens of 2,3,7,8-tetrachlorodibenzo-p-dioxin and other polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs/PCDFs, calculated as International Toxicity Equivalencies [I-TE]). Mitogens (pokeweed mitogen [PWM], phytohemagglutinine [PHA], concanavalin A [Con A]), as well as an anti-human monoclonal antibody against CD3 were used as proliferation stimulators in vitro. Additionally, the feasibility of using the lymphocyte response to tetanus toxoid was assessed, and the response to this recall-antigen was included in this trial. No decrease in the capacity of 3H-thymidine incorporation was observed with any of the proliferation stimulators in the group of volunteers with the increased TCDD-body burden when compared with volunteers exhibiting TCDD-concentrations in blood fat within the reference range. Regression analysis revealed a slight trend towards an increase for 3H-thymidine incorporation during the stimulation with PHA only. It can be concluded from our data that moderate increases in the TCDD- or I-TE-body burdens do not induce any medically significant changes in the capacity for proliferation of lymphocytes, measured as 3H-thymidine incorporation.

Adult↗
PubMed1995

Proliferative capacity of marmoset lymphocytes after tetanus vaccination and lack of 2,3,7,8-tetrachlorodibenzo-p-dioxin to reduce a booster effect.

Marmosets (Callithrix jacchus) were vaccinated with tetanus toxoid and boostered 3 months and 1 year following the initial immunization. During this period, the proliferative response of lymphocytes (3H-thymidine incorporation) to the recall antigen was measured in vitro in blood samples 7 times. The experimental procedure proved to be suitable to monitor a defined but complex function of the immune system, and to assess possible substance-induced alterations with minimal stress or discomfort for the non-human primates. As a first example, a possible interference by a single very small dose (100 ng/kg body weight) of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) given at the time of the second booster was evaluated. No reduction in the in vitro response of the lymphocytes to recall antigen was observed under the experimental conditions used, and the extent of the 3H-thymidine incorporation was not significantly different in the groups. When the ratio of the responses between the first and the second booster was taken as a measure, there was a slight but statistically significant increase in this ratio for the lymphocytes of the TCDD-treated marmosets over that of reference animals. The limitations of these attempts to develop a test system and evaluate a substance-induced effect, and possible improvements of the test, e.g. with multivaccination, are discussed. It is suggested to use this approach also after routine multivaccination in children to assess possible substance-induced effects on immunological variables. This would allow an excellent comparison of experimental and clinical data obtained in primates with an identical technology.

Animals↗
PubMed1995

Modelling of drug penetration into human skin using a multilayer membrane system.

In this article, a new in vitro model system is presented with a multilayer membrane system serving as acceptor. Matrix-stabilized membranes are applied with dodecanol as lipid and collodion as matrix. Using the drug dithranol it was shown that the acceptor system can be varied over a wide range by changing the dodecanol content of the membranes and by addition of the hydrophilic substance propylene glycol to the membranes. It was demonstrated that the variability of the acceptor system can be used to adapt the penetration profiles of dithranol in a six-layer membrane system to those in excised human skin. It is shown that it is possible to study the penetration of dithranol from different semisolid formulations using the 'adapted' model system.

Anthralin↗
PubMed1995

Optimization of topical erythromycin formulations by ion pairing.

Erythromycin (ERY) is used in the topical treatment of acne vulgaris. In order to decrease the amount of microorganisms markedly, the antibiotic must penetrate into the sebaceous follicles. Firstly, the aim of this study was to improve the lipophilicity of ERY by ion pairing. Secondly, a formulation with optimized penetration of the ion pair was developed. Thirdly, the optimized formulation was compared with formulations containing ethanol and with the commercial product Zineryt. The determination of lipophilicity was based on partition coefficients (PC) and on the penetration of ERY into a modified multilayer membrane system (MMS). It was shown that the penetration of ERY into a lipophilic acceptor system was three times higher when ion pairing between ERY and octadecansulfonate was used in comparison with the penetration of the ERY base alone. The dosage of the antibiotic used can be markedly reduced by optimizing a vehicle for the ion pair.

Acne Vulgaris↗
PubMed1995

Interactions between food components and drugs. Part 3. Interactions between pectin and propranolol.

Bioavailability of drugs can be affected distinctly by interactions with food components. Effects of structural parameters of the soluble dietary fiber pectin on lipid-membrane transport of propranolol (1) was investigated in vitro using a two-compartment model with a dodecanol-collodium membrane at pH 7.2 and 37 degrees C. Starting from practically fully esterified citrus pectin two series of defined and in their structural parameters gradually varied pectins were prepared. In presence of pectins with a blockwise distribution of free COOH-groups the portion of permeated 1 is significantly diminished with a decreasing degree of esterification (DE). On the other hand, only in the smallest DE pectins having statistically distributed free COOH-groups seemed to affect the transport rate of 1. The viscosity of the tested pectins possessed no significant influence on the passage of 1.

Biological Availability↗
PubMed1994

Long-term interleukin-6 administration stimulates sustained thrombopoiesis and acute-phase protein synthesis in a small primate--the marmoset.

Interleukin-6 (IL-6) has been ascribed significant roles in both hematopoiesis and the immune response, although its contribution to host defence as a whole is poorly understood. Because short-term IL-6 treatment was previously shown to stimulate megakaryocytopoiesis, we investigated the effect of long-term administration of IL-6 on megakaryocytopoiesis and other systemic parameters in nonhuman primates. We chose a small primate, the marmoset (Callithrix jacchus), which enabled long-term administration at high doses. Recombinant human IL-6 (rhIL-6) administered at doses of up to 1,000 micrograms/kg/d over 4 and 9 weeks caused a sustained twofold to threefold increase of thrombocyte counts, peaking at 4 weeks. Thrombocyte counts declined thereafter, despite continuing IL-6 administration. The number of bone marrow megakaryocytes at 4 and 9 weeks was not increased compared with controls, but the ploidy grade was augmented, suggesting that IL-6 effects are restricted to mature megakaryocytes in vivo. An acute-phase protein response was observed within 24 hours after the first IL-6 administration and reached a maximum after 1 week of IL-6 administration at 25 micrograms/kg. Serum C-reactive protein, haptoglobin, and ceruloplasmin were increased, whereas albumin and transferrin levels declined. The acute-phase protein response was not associated with any morphologic evidence of hepatocellular damage. The increased levels of Ig and soluble IL-2 receptor in the serum levels reflected systemic immunostimulation. There was no evidence of renal mesangioproliferative pathology. Antibodies against rhIL-6 developed within 2 weeks, continuously increasing during the course of the study. High titers of neutralizing antibodies appeared concomitantly with the decrease in platelet counts and decline in acute-phase proteins. Therefore, despite the pleiotropic effects of IL-6 observed in vitro, long-term administration of IL-6 caused a selective and sustained stimulation of thrombopoiesis in marmosets that was only ablated by the appearance of neutralizing antibodies, and high doses were well tolerated in marmosets. A long-term targeting of IL-6 to cells of the megakaryocytic lineage, without evoking general toxicity, confirms the potential therapeutic usefulness of rhIL-6 for the chronic treatment of thrombocytopenic patients.

Acute-Phase Proteins↗
PubMed1994

Effects of recombinant human interleukin 6 (rhIL-6) in marmosets (Callithrix jacchus). 1. General toxicity and hematological changes.

The physiological and toxicological properties of recombinant human interleukin 6 (rhIL-6) were assessed in marmoset monkeys (Callithrix jacchus). Two experimental series were performed with daily subcutaneous administration: (a) 5 or 1000 micrograms rhIL-6/kg per day for three weeks and (b) 25, 100 or 500 micrograms rhIL-6/kg per day for 3 months. RhIL-6 was well tolerated and did not induce fever or any other non-specific signs of toxicity. The main findings were: (1) A two- to threefold increase in platelet counts at 2-4 weeks, which decreased following further continuous rhIL-6 administration; (2) increase in total white blood cells between 1 and 4 weeks of administration, including an absolute increase in granulocytes (including band forms) and basophils. A change in the number of monocytes was not detected; (3) an increase in total red blood cells, which peaked at 4 weeks, sustained elevation of red cell distribution width and a slight decrease in hemoglobin between week 1 and 4, concurrent with a distinct decrease in mean corpuscular hemoglobin at 4 weeks. This effect persisted for 9 weeks in the 100 micrograms/kg and 500 micrograms/kg groups; (4) decrease in plasma AST activity and increase in plasma protein concentration after 2 weeks of treatment; (5) no clinical or biochemical signs of renal glomerular dysfunction; (6) RhIL-6 after s.c. administration was detectable in the plasma, peak levels (mean values +/- SD) of 9.4 +/- 6.3 and 72.4 +/- 7.7 ng/ml were measured after a single dose of 100 or 1000 micrograms/kg; (7) antibodies against rhIL-6 developed within 2 weeks, increased during administration and neutralized the biological effect of rhIL-6 progressively from 4 to 9 weeks. In conclusion, aside from a mild anemia, rhIL-6 was well tolerated in marmosets and had a profound and sustained effect on thrombopoiesis. Due to the formation of neutralizing antibodies, the chronic biological effect of rhIL-6 is lost in marmosets and studies beyond 4 weeks are rendered less meaningful. The analyses of antibody formation, induction of acute phase proteins, histological changes and alterations on lymphocyte receptors will be reported in two following publications.

Analysis of Variance↗
PubMed1994

Embryotoxic effects of thalidomide derivatives in the non-human primate Callithrix jacchus. 5. Lack of teratogenic effects of phthalimidophthalmide.

The teratogenic potency of the thalidomide (Thd) derivative phthalimidophthalimide (Phtpht) was assessed in the common marmoset (Callithrix jacchus), by oral administration of the relatively high daily dose of 50 mg Phtpht/kg body wt, during the susceptible period (days 48-61 of pregnancy). Since in this species daily doses of only 100 micrograms/kg body wt of the Thd derivative EM12 already induce typical gross structural abnormalities in nearly 100% of the fetuses, investigations with a small number of these New World monkeys allow a rough estimation of the teratogenic potency of Thd-type substances. Macroscopic inspection and skeletal evaluation of ten fetuses gave no indication of dysmorphogenesis following treatment with Phtpht. We conclude that Phtpht has little, if any, Thd-type teratogenic potency in this non-human primate.

Animals↗
PubMed1994

Thalidomide and the immune system. 3. Simultaneous up- and down-regulation of different integrin receptors on human white blood cells.

Time-dependent changes in the surface receptor expression of various maturational and integrin receptors on peripheral blood cells were studied in two healthy human volunteers following oral applications of thalidomide (Thd). In each measurement the receptor density was quantified by prior calibration of the flow cytometer with latex beads bearing a determined number of fluorescence molecules. The effects observed in the course of the Thd-treatment were practically identical or at least very similar in both the volunteers during four different trials, and were in accord with previous results obtained in large-scale studies (68 treated animals) with non-human primates. It should be stressed that no clear-cut changes were observed in the percentage or absolute numbers of primary lymphocyte subsets such as CD3, CD4 and CD20. After the first two doses of 7 mg Thd/kg body wt the CD18 (the common beta-chain of the beta 2-integrins) marker already decreased in surface density or was no longer detectable on granulocytes, monocytes and lymphocytes. This effect persisted throughout the treatment period and slowly subsided after discontinuation of treatment. With a few days lag phase, the surface density of CD54 (ICAM-1) on granulocytes increased and many cells previously not bearing this receptor newly acquired such surface markers. On monocytes however, the CD54 receptor was lost on many cells. Within the lymphocyte fraction a loss of the CD54 marker could be noted on CD4 cells but not on CD8 cells, where an increase of the receptor expression could be observed. Other markers, such as the alpha chains of the beta 1 integrins CD49b (VLA alpha 2) and CD49d (VLA alpha 4) showed contrasting reactions to the Thd-treatment. Whereas a pronounced loss of the receptor density of CD49d was observed and only few cells with high epitope density were left in the blood at the end of the complete dosing schedule, no such effect was observable on cells bearing the CD49b epitope. A distinct reduction of the number of receptors was also noticeable on L-selectin (Leu8) bearing cells. On CD4 positive lymphocytes, the majority of the described effects on the integrin and adhesion receptors was seen on cells bearing the CD45R0 maturational epitope. This functional receptor is strongly down-regulated and the pathway of CD45RA to CD45R0 maturation is apparently altered by Thd-treatment. These multiple changes we observed may explain the large variety of therapeutic effects experienced in the treatment with Thd.

Carrier Proteins↗
PubMed1994

Changes in white blood cells during parturition in mothers and newborn.

Following spontaneous delivery (n = 12) a pronounced increase in the maternal total white blood cell count was found (to [mean +/- SD]: 20 +/- 6 x 10(9) total leukocytes/l), which would be considered highly 'pathological' in nonpregnant women. The alteration was predominantly due to an increase in polymorphnuclear cells and band forms. Simultaneously, a drastic decrease in the percentage and the absolute number of lymphocytes was noticed in venous blood (from 32 to 5%, or [mean +/- SD]: from 2.7 +/- 0.7 to 1.1 +/- 0.3 x 10(9) total lymphocytes/l). In this decrease nearly all lymphocyte subtypes were involved, although to differing extents. Following elective caesarean delivery (n = 6), no leukocytosis was found, however the percentage and absolute number of lymphocytes was also decreased, although not as pronounced as after spontaneous delivery. Again not all the lymphocyte subpopulations were affected to the same degree, and the effect was especially obvious for the suppressor T cells and B cells. Following emergency caesarean delivery (n = 5), no obvious effect on the absolute number of lymphocytes or on the pattern of lymphocyte subpopulations was observed. However, the total number of white blood cells was clearly increased, as after spontaneous deliveries. The possible significance of these findings, also for therapeutic consequences during the perinatal period, is discussed.

Adult↗
PubMed1994

Evaluation of possible effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and other congeners on lymphocyte receptors in Callithrix jacchus and man.

Using fluorescence-labeled monoclonal antibodies and flow cytometry (FACScan analysis) we measured surface receptors on peripheral lymphocytes in marmosets (Callithrix jacchus) treated with TCDD in the lower nanogram per kilogram range. Additionally, some polybrominated congeners were studied as well as a 2,3,7,8-substituted dioxin containing chlorine and bromine in the same molecule. Callithrix was found to be very sensitive to the action of TCDD and the other tetrahalogenated congeners; single doses of 10-30 ng/kg body weight reproducibly induced a decrease in the percentage and absolute number of 'memory' helper T cells [CD4+CD29(bright)] and of B cells (CD20+). Subsequently, according to the hypothesis based on the marmoset data, extensive analyses on surface receptors of white blood cells were performed in workers with moderately increased body burdens of TCDD, and for further hypothesis generation > 60 triple-labeling assays were performed with each of the blood samples. No decrease in typical surface receptors (CD4+CD45R0+CD45RA-CD29(bright) or CD20+) was found in the human adult volunteers studied, but a trend toward an increase was noted. It cannot be decided whether this may be a substance-related effect, or results from a confounder (possibly age differences between the groups).

Adult↗
PubMed1994

Risk assessment for possible effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related substances on components and functions of the immune system.

Numerous reports have been published on the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on components and functions of the immune system of animal species, almost exclusively of rodents. Many of the data, obtained with very different dosing schedules, are conflicting or have not been confirmed. Since the overwhelming majority of evaluations were performed with rodents, it is not possible to perform a reliable quantitative or even qualitative risk assessment for TCDD in man based on immunological data obtained from these experiments and to extrapolate them to the situation in humans. In addition to the fact that the doses needed to induce measurable effects in the different species studied varies from 1- to 10,000-fold, there are intrinsic and general difficulties for extrapolations to human beings in the field of immunotoxicology due to the influence of different individual risk factors, e.g. smoking and drinking as well as the lack of experience and validation in this new field of toxicology. Some immunological variables were studied in populations highly exposed to dioxins. In comparison to the results obtained from nonhuman primates, no convincing evidence for substance-related effects was revealed, however, information on only a few immunological components and functions in exposed adults could be assessed so far. Except for one group of studied persons all other subjects were generally exposed to cocktails of several chemicals, vastly complicating the interpretation with respect to one isolated component of these mixtures. Results from studies on exposed children are not available yet.

Animals↗
PubMed1993

Effects of small doses of dioxins on the immune system of marmosets and rats.

There is no doubt that TCDD is capable of inducing effects on a variety of components and functions of the immune system in a variety of species. In fact, such changes seem to belong to the most sensitive variables affected by TCDD. Some of the biological effects, induced at rather high doses of TCDD exhibiting general toxicity (> 3 micrograms TCDD/kg body wt), may be considered unspecific or the result of the pronounced thymus involution. However, other effects (such as that on lymphocyte subtype patterns in marmosets or a reduced resistance of mice to influenza viruses) have been reported to occur at dose levels far from those leading to thymic involution or general toxicity. It should be remembered that the pathognomonic relevance for man of subtle modifications in the pattern of lymphocyte surface receptors is largely unknown. Until now, such deviations are considered rather as biological phenomena than indications or causes of specific diseases. Nevertheless, such changes represent clear-cut biological effects induced by TCDD. Since effects of TCDD on components and defined functions of the immune system have been revealed in several species, it would be surprising if humans were largely resistant to such effects, but reliable data in humans with high exposures to defined dioxins verified by an appropriate quantification of the exposure are scarce as of now. Data published so far have not revealed pronounced alterations of such variables. However, no studies of well-defined human populations with quantified body burdens have been performed with modern methods (such as flow cytometry) analyzing a wide variety of surface receptors. Performance of such studies is essential for a better and reliable risk assessment, and the technology is available. Some of the effects observed (such as the changes in the pattern of lymphocyte subpopulations) must certainly be considered as biological effects induced by TCDD, and the situation is similar to the induction of hepatic monooxygenases, which are also observable in this dose range. However, the relevance of such changes with respect to adverse health effects in humans is presently difficult to judge in the absence of clear-cut functional deficits demonstrated so far either in vivo or in vitro.

Animals↗
PubMed1993

Thalidomide derivatives and the immune system. I. Changes in the pattern of integrin receptors and other surface markers on T lymphocyte subpopulations of marmoset blood.

Treatment of marmosets (Callithrix jacchus) with thalidomide (Thd) or its derivative EM12 (which is also teratogenic, but more stable to hydrolysis) resulted in the lack of reaction of adhesion surface receptors (integrins) on T lymphocytes in venous blood. Lymphocyte subsets appeared, for example CD4+CD2-, which are not found under normal conditions. (a) There was no clear effect of the treatments on the total number of leukocytes or lymphocytes or on the total number of CD4+ or CD8+ T lymphocytes. (b) A decrease in the percentage of the cytotoxic T cells carrying the CDw29 marker (CD8+CD56+CDw29+) at a dose as low as 5 mg EM12/kg bw, and an increase in the percentage of suppressor cells carrying the CDw29 marker (CD8+CD56-CDw29+) at 10 mg EM12/kg bw were found. Similar effects were induced by Thd at somewhat higher doses, while supidimide (Sup) was less active even at the very high dose of 100 mg/kg bw. Especially at the lower doses these effects occurred with a lag phase and persisted after discontinuation of the dosing. Alterations induced in helper T cell subpopulations by Thd or EM12 were less impressive (no significant effect was observed with 5 mg EM12/kg bw). Some changes were observed at higher dose levels in the CD4+CD45RA+CDw29+ cells and the CD4+CD45RACDw29+ cells. (c) The most significant effect, reduction in the reactivity of CD2+, was detectable subsequent to daily oral doses as low as 10 mg Thd/kg or 1 mg EM12/kg bw. Peak plasma concentrations to be expected under these experimental conditions are less than 1 micrograms/ml. (d) The surface receptors found to be affected include among others: CD2 (LFA-2) and CD11a (LFA-1 alpha) and CD18 (LFA-1 beta). Clearly, CD4+ cells were found to be more susceptible to the loss of the integrin receptors than CD8+ cells. (e) The effect persisted for several weeks subsequent to the discontinuation of the dosing. (f) A rough estimate of the relative potency to reduce the CD2 receptor in the marmoset suggests EM12 to be five to ten times more potent than Thd. Sup, a Thd derivative reported to exhibit no or a low teratogenic potency, was found to be at least five times less potent than Thd. (g) The alterations of surface adhesion receptors by the substances studied in this investigation were not confined to T lymphocytes. We also observed similar effects on B lymphocytes, monocytes, and neutrophils, and many other cell types carrying such receptors might be affected.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Chlorinated dibenzo-p-dioxins and dibenzofurans and the human immune system. 1. Blood cell receptors in volunteers with moderately increased body burdens.

Using monoclonal antibodies (mAbs) and flow cytometry, we studied a variety of surface receptors on lymphocyte subpopulations of workers with moderately increased body burdens of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and of other polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/PCDF), expressed here as International-Toxicity Equivalencies (I-TE). The hypothesis to be tested was whether or not humans exhibit a similar susceptibility to PCDDs/PCDFs with respect to the surface receptors found previously to respond to small doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in Callithrix jacchus. These are: helper-inducer (memory) T cells (CD4+CD45R0+CD45RA-CD29highCD11a+), CD20+ B cells, and cytotoxic T cells (CD8+CD56+/CD57+). Furthermore, 68 triple-labellings with mAbs were performed on the cells of each volunteer to possibly generate further hypotheses. It was evaluated whether any of the variables might be used as a biomarker of effects for this class of compounds. There were two main goals: (1) to evaluate whether workers with a moderately increased PCDD/PCDF-body burden [25-140 ppt TCDD or 104-522 ppt I-TE in blood fat] exhibit changes in the surface receptors of white blood cells, as observed in previous studies in non-human primates, and (2) to clarify whether persons at the upper range [10-23 ppt TCDD or 30-90 ppt I-TE in blood fat] of the body burden reference values of a not particularly exposed population show detectable deviations in these immunological variables, when compared with persons at the lower and medium range [1-3 ppt TCDD or 9-29 ppt I-TE] of these body burden reference values. Regression analysis of our data revealed slight trends for some of the biomarkers (e.g. CD45R0+). With one exception, these were all increases. None of the alterations observed are of medical relevance. The slight increase in the percentage of CD4+CD45R0+ cells remained significant even after covariant analysis taking age-related changes into account. Altogether, the data do not provide any evidence to support an assumption that moderately increased body burdens of PCDDs/PCDFs in adults induce decreases in the cellular components of the human immune system. Adult humans certainly are less susceptible to this action of PCDDs/PCDFs than adolescent Callithrix jacchus.

Adult↗
PubMed1993

[Improvement of the absorption of the active substance 2'-hydroxy-5'-methyllaurophenoxamine (FLM 5011) with prodrugs and preparations].

Methods to improve the absorption of problem drugs are presented for the strongly lipophilic, poorly water-soluble, potential lipoxygenase inhibitor FLM 5011 (1). The water-solubility is improved by using prodrugs or by solubilizing. The characterization of solubility has been characterized with an suitable in vitro model system. The bioavailability of 1 in rabbits after oral administration is markedly increased using 1-prodrugs studied. The good correlation between the ABC measured in vitro and the AUC estimated in vivo demonstrates that it is possible to predict the bioavailability at the rabbit of highly lipophilic drugs such as 1 using the flow through model system.

Animals↗