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Biomedical subjects

R Stahlmann

Publications and source records attributed to R Stahlmann.

At least 55 records · Page 3Linked to original sources
PubMed1992

Polyhalogenated dibenzo-p-dioxins and dibenzofurans and the immune system. 4. Effects of multiple-dose treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on peripheral lymphocyte subpopulations of a non-human primate (Callithrix jacchus).

Non-human primates (Callithrix jacchus) were treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) over a period of 30 weeks, and lymphocyte subpopulations of venous blood were monitored using monoclonal antibodies and flow cytometry (FACScan). There was no clear-cut change in the total lymphocyte population during this study. In the first part of the study the new-world monkeys (marmosets) were treated for 24 weeks with a weekly dose of 0.3 ng TCDD/kg body wt. At the end of this treatment period a level corresponding to an actual cumulative dose of about 2.5-2.7 ng TCDD/kg body wt was expected. The percentage and the absolute number of the CD4+CDw29+ cells ("helper inducer" or "memory" cells) surmounted the physiologically occurring increase. Concomitantly the percentage of the CD4+CD45RA+ cells ("suppressor-inducer" or "naive" cells) decreased. There was, at the same period, no change in the total T cell population (CD2+ cells) or in the cells carrying the CD8 or the CD4 epitope. When increasing the weekly dose to 1.5 ng TCDD/kg body wt, a transient increase in the percentage and the absolute number of the CD8+CD56+ cell population ("cytotoxic T cells") was observed 3 weeks after the increase in dosing. At this time the expected decrease in the percentage or the absolute number of CD4+CDw29+ cells was just detectable and this decline was at its maximum 6 weeks after switching to the higher weekly doses. The reduction in the percentage and the absolute number of CD4+CDw29+ cells persisted 5 weeks after discontinuation of the dosing, but this cell population was again within normal limits 7 weeks later. Because the two subpopulations are changed in opposite directions, the ratio CD4+CDw29+/CD4+CD45RA+ is a very sensitive measure of the effect induced by TCDD. There was a pronounced decrease in the percentage of the CD20+ cells (B1 cells), but their percentage and number rapidly normalized, in contrast to the CD4+CDw29+ cells, when the dosing was discontinued. At the end of the treatment period the apparent body burden was calculated to correspond to an actual dose of about 9-10 ng TCDD/kg body wt. Such an actual dose level might be assumed to be reached under steady-state conditions in chronic experiments with daily doses of about 135 pg TCDD/kg body wt (assuming a half-life for TCDD in the marmoset of 6-8 weeks). Extrapolations of the results obtained at higher doses to very low exposures is not justified with respect to the effects induced by TCDD on the immune system of marmosets. At lower doses the effect is clearly reversed.

Animals↗
PubMed1992

Influence of dexamethasone on the RM 3/1-positive macrophages in the peripheral blood and tissues of a New World monkey (the marmoset Callithrix jacchus).

Subcutaneous injection of the glucocorticoid dexamethasone in the primate Callithrix jacchus increased the proportion of the macrophage subtype RM 3/1 in the blood from a basic level of 16% positive monocytes to about 65%. The elevated numbers of RM 3/1-positive cells were seen 24 and 72 h after application and were independent of the dosages used (50 or 150 micrograms/kg). Oral administration had no effect. CD4-, CD14- and CDw14-antigen expression of monocytes was not influenced by the dexamethasone treatment. In tissues, e.g. spleen, thymus, liver, skin and kidney, RM 3/1-positive macrophages revealed a similar distribution as in human tissues but no differences in glucocorticoid treated to control animals could be observed. These results show that glucocorticoids induce in the monkey Callithrix jacchus a distinct monocyte subtype similarly as in man while other macrophage phenotypes were not influenced.

Animals↗
PubMed1991

[Cartilage-damaging effect of quinolones].

The cartilage damaging effect of quinolones on juvenile experimental animals represents an unusual effect which is unknown, in this form, for other classes of substances. Since the damage is manifested at quite low doses the manufacturers and regulatory agencies have taken the consequence of declaring these preparations counter-indicated for children and adolescents up to the end of the growing period. Motor disturbances were observed only rarely, and only in individual cases, seen after therapeutic use of these drugs for the treatment of bacterial infections. In spite of long-term and sometimes high dose treatment with nalidixic acid during the 1960s and 1970s (the arthropathogenic effect on dogs was first described in 1977) no joint alterations could be demonstrated clinically or by x-ray. From this conclusion can be drawn that the effects seen in animal experiments under therapeutic conditions do not occur with the same intensity in humans. But, since many questions concerning this unusual toxic potential are still unanswered, quinolones continue to be counter-indicated for patients who are in the growing phase. Further experimental data and clinical observations are necessary to exclude with certainty the possible danger of joint damage to young patients. Even today it is still unclear whether the generally favourable clinical observations made with nalidixic acid also hold true for the other quinolones and whether differences in the possible risks exist. It will only become possible to define, with the necessary amount of certainty, indications for the use of quinolones in pediatrics when further information is available.

4-Quinolones↗
PubMed1991

In vitro and in vivo studies on the prenatal toxicity of five virustatic nucleoside analogues in comparison to aciclovir.

Several virustatic agents are known to be teratogenic in laboratory animals. Since routinely performed in vivo studies do not always offer the best conditions to detect the teratogenic potential of a drug, we used a combined in vivo/in vitro approach for comparative studies on the prenatal toxicity of five nucleoside analogues. Rat embryos were exposed for 48 h to various concentrations of vidarabine-phosphate (VAP), ganciclovir (GCV), 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxycytidine (ddC) and zidovudine (= azidothymidine, AZT) in a whole-embryo culture system. The steepness of the concentration-response curves as well as the induced abnormality pattern (head, neural tube, shape) were similar for these compounds. However, a wide range in embryotoxic potency was observed: VAP was the most potent compound (100% abnormal embryos at 25 microM) in this in vitro system, while AZT showed the lowest potency to interfere with normal embryonic development (40% abnormal embryos at 3000 microM). In addition to these experiments we treated rats on day 10 of gestation with three s.c. injections (8 a.m.; 12 a.m.; 4 p.m.) of 200 mg of each drug/kg body wt. The embryos were evaluated on day 11.5 of gestation, i.e. at a time of development corresponding to the developmental stage at the end of the whole-embryo culture. The same criteria were used as during the in vitro studies for the evaluation of these in vivo exposed embryos. With VAP and GCV we obtained similar results with both exposure routes (in vitro and in vivo), while no abnormalities were detectable with the other compounds after exposure in utero.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1991

Polyhalogenated dibenzo-p-dioxins and dibenzofurans and the immune system. 3. No immunosuppressive effect of 2,3,7,8-TCDD in the popliteal lymph node assay (PLNA) in rats.

We used a modified version of the popliteal lymph node assay in rats to investigate the immunosuppressive potential of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In 10 months we conducted 3 experimental series. Animals were treated with single s.c. injections of TCDD and 7 days later human red blood cells (HRBC) were injected s.c. into the right hind footpad of the rat. Another 7 days later, both popliteal lymph nodes were prepared, weighed, the cell number was counted and the quotients ("index") of these variables from the treated and the untreated side were determined. The doses applied in three experimental series were 600', 60, 6, 0.6, and 0.06 ng TCDD/kg body wt. In the first experimental series only the three highest doses were tested, in a second experimental series doses of 60, 6, 0.6, 0.006 ng TCDD/kg body wt were applied. Combining the results of these two experimental series, a statistically significant difference was found in the cell number index between the controls and the two highest doses tested (60 and 600 ng/kg body wt; p less than 0.01). This result was recently published as an abstract (Korte et al. 1990). However, with slight methodological changes in the third series of experiments (doses applied: 600, 60, 6, 0.6, and 0.06 ng TCDD/kg body wt) and using a greater number of animals we could not confirm these preliminary results. No difference was seen in the immune response to the antigen challenge in controls and in any of the treatment groups. We conclude that TCDD does not clearly influence the immune response as observed in the popliteal lymph node assay under our experimental conditions.

Animals↗
PubMed1991

Polyhalogenated dibenzo-p-dioxins and dibenzofurans and the immune system. 2. In vitro effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on lymphocytes of venous blood from man and a non-human primate (Callithrix jacchus).

The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on poke weed mitogen-stimulated proliferation and differentiation of peripheral lymphocytes was studied in vitro with cells from a non-human primate (marmoset monkey, Callithrix jacchus) and from man. Monoclonal antibodies and flow cytometry (FACScan) were used for analysis. The extent of the overall mitogen-stimulated proliferation of isolated lymphocytes in vitro from marmoset blood was only slightly reduced in the presence of TCDD compared to the solvent control (0.01% DMSO). However, incubation with TCDD in the culture medium together with the mitogen led to a pronounced decrease in the percentage of the lymphocyte subset with the surface marker CD4, and a concomitant increase in the percentage of CD8+ cells. The lowest concentration found to be effective in vitro was 1 x 10(-13) M TCDD (25 fg TCDD/ml). When culturing lymphocytes from human blood of different donors under identical conditions in the presence of TCDD and the mitogen, corresponding effects were observed to those seen with marmoset cells. A closer analysis of the T lymphocyte subsets affected revealed the CD4+ CDw29+ (helper-inducer cells) to be the main target for the action of TCDD. A clear-cut change in the percentage of this subpopulation was induced at concentrations as low as 1 x 10(-13) M TCDD. The development of the IL-2-marker in culture was only slightly affected by TCDD, and concentrations of 1 x 10(-12) M were required to slightly reduce the number of CD2+CD25+ cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Evaluation of safety and tolerance in clinical trials with antimicrobial agents.

In this review the general and specific difficulties encountered in the evaluation of safety and tolerance of antimicrobial agents in clinical trials are discussed. In addition to the usual pharmacological and toxicological effects (adverse drug reactions) occurring in individual patients, microbiologically induced side-effects also have to be considered. The different methods for registration of side-effects and their limitations are discussed. A system is proposed for evaluation of the cause/effect relationships of adverse drug reactions. A system is also discussed for the evaluation of the severity of adverse drug reactions, and different classifications are presented.

Anti-Bacterial Agents↗
PubMed1990

Polyhalogenated dibenzo-p-dioxins and dibenzofurans and the immune system. 1. Effects on peripheral lymphocyte subpopulations of a non-human primate (Callithrix jacchus) after treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Monoclonal antibodies were used to analyse the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on peripheral lymphocytes from marmosets (Callithrix jacchus) following injections of single low doses of TCDD. A reduction of the percentage and the total number of lymphocytes among the white blood cells was seen 3 weeks after a single administration of 300 ng TCDD/kg body wt, but not following 167 ng TCDD/kg or less. After treatment of marmosets with the single subcutaneous dose of 10 ng TCDD/kg body wt. we observed an average decrease of about 20% in the percentage of CD4+ cells in the venous blood of treated animals. This change was not seen at the time of maximum absorption (2 weeks after the injection), but was demonstrable after 4 weeks and reached its maximum 15 weeks after the injection. The time course of the changes suggests an indirect effect (possibly via the thymus). Due to the considerable inter- and intra-individual variability in the number of peripheral lymphocytes the effect was less convincing on the basis of the total CD4+ cells per microliter blood. There was a significant concomitant increase in the percentage of cells with the CD8+ marker. A closer analysis of the lymphocyte subpopulation involved revealed a predominant effect on the cells with the CD4CDw29 ("leu 3a+4B4+") surface marker ("helper-inducer cells"). Subsequent to a dose of 10 ng TCDD/kg body wt the percentage of these cells was reduced by 50% or more when compared with the (24) controls. On an absolute basis (number of cell/microliter blood) these CD4+CDw29+ cells were clearly reduced in only two out of four marmosets. There was no significant effect on the percentage of the CD4+CD45R+ ("leu3a+2H4+") subpopulation ("suppressor-inducer cells"). The ratios: CD4+CDw29+/CD4+CD45R+, or CD4+CDw29+/CD8+ appear to be convenient measures for monitoring the effect described. Since the difference between the percentage of CD2+ cells minus the sum of CD4+ plus CD8+ cells was found to be increased following rather high doses (167 ng TCDD/kg body wt or more), this suggests that immature cells (CD2+ CD4-CD8-) are released into the periphery as a result of the exposure to TCDD. Furthermore, a decrease in the percentage of CD20+ (B1+) cells (about 50% when compared with controls) was observed in the treated animals following a single dose of 10 ng TCDD/kg body wt or higher. Subsequent to a dose of 10 ng TCDD/kg body wt the percentage of CD56+ (NKH1+) cells seemed to be slightly increased. The dose-response for the effects observed was rather poor.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Ofloxacin in juvenile non-human primates and rats. Arthropathia and drug plasma concentrations.

Arthropathia in juvenile animals is the most important toxic effect induced by quinolones. We conducted pharmacokinetic and morphological studies with ofloxacin on non-human primates (Callithrix jacchus, Marmosets) and rats. In the marmoset, electron microscopy and the application of immuno-morphological methods proved to be suitable for the detection of specific alterations in cartilage (e.g. loss of proteoglycans and altered chondrocytes). Subsequently performed electron microscopic examinations in rats showed similar specific alterations of the femur cartilage surface after multiple oral applications of 600 mg ofloxacin/kg body wt. These results were correlated with pharmacokinetic data obtained for the same species. After single oral application of 100, 300 or 600 mg ofloxacin/kg body wt to 5 week-old rats peak plasma levels were achieved 15-45 min after administration indicating a rapid absorption of the drug. The following peak concentrations were measured for the three doses applied (mean +/- SD): 8.9 +/- 2.1, 22.6 +/- 7.5 mg/l and 33.5 +/- 9.8 mg/l, respectively. After 360 min the concentrations were 1.1 +/- 0.4, 5.9 +/- 2.5 and 15.9 +/- 5.1 mg/l, respectively. After subcutaneous injection of 100 mg ofloxacin/kg body wt the mean peak concentration was 27.7 +/- 2.6 mg/l after 45 min (0.5 +/- 0.2 mg/l after 360 min). In the marmoset higher plasma concentrations were measured with comparable doses. One, 3, and 6 h after the last of nine administrations of 200 mg ofloxacin/kg body wt, the mean (+/- SD) plasma concentrations were: 42.7 +/- 16.7, 40.6 +/- 9.5, and 26.5 +/- 3.6 mg ofloxacin/l plasma. Typical alterations of the joint cartilage of juvenile rats (e.g. opened chondrocyte cavities, swelling of rough endoplasmic reticulum and mitochondrial swelling in the chondrocytes) were induced by oral administration of ofloxacin at doses that were approximately 100 times higher than therapeutic ones, but led to peak plasma concentrations which were only approximately 10 times above the therapeutic level.

Administration, Oral↗
PubMed1990

Safety profile of the quinolones.

The most important finding from preclinical evaluation of fluoroquinolones has been their arthropathogenic potential in young animals. This toxic effect is found with all quinolones known so far and has led to the decision not to use them in children and adolescents, despite the fact that the significance of the effect for humans is still unclear. The mutagenic potential of the drugs seems to be low although bacterial DNA-metabolism is a major target of their action. Newer in-vitro methods to study topoisomerases from bacterial and mammalian cells are suitable to detect differences in the derivatives with regard to their mutagenic potential. The major adverse effects observed clinically with the four most often used fluoroquinolones norfloxacin, ciprofloxacin, ofloxacin and enoxacin are gastrointestinal disturbances (1.8-5%), reactions of the central nervous system (0.9-1.6%) and skin reactions (0.6-1.4%). Higher incidences have been noticed during the clinical evaluation of fleroxacin at doses of 400 mg or more. A comparison of the adverse reaction frequencies of fluoroquinolones with those of other antimicrobial agents can most closely be made with the results from double-blind studies. Such results show that in most cases fluoroquinolones have been tolerated as well as or better than conventional drugs. Clinically relevant drug interactions have been observed with some quinolones that are metabolized primarily in the liver: enoxacin and ciprofloxacin reduce the theophylline clearance. Also, interactions of quinolones with Mg2(+)-containing antacids, which result in tremendous loss of bioavailability, are of therapeutic importance. Overall, fluoroquinolones are well tolerated and the incidences of side effects are similar to those of other antibacterials.

4-Quinolones↗
PubMed1990

[Successful treatment of flecainide (Tambocor) poisoning--effect of hemodialysis/hemoperfusion?].

After suicidal ingestion of 3 g flecainide a 34-year-old woman showed somnolence, cerebral convulsion, disturbances of atrioventricular and intraventricular conduction and ventricular asystole. The maximum flecainide plasma level was 4900 ng/ml; this level is extremely high and exceeds the maximum therapeutic level by five times. After initial cardiopulmonary resuscitation and stabilization by intensive care treatment we performed a combined hemodialysis/hemoperfusion therapy (with activated charcoal). This procedure led to a rapid decrease of flecainide plasma levels and simultaneous improvement of ECG-alterations. The initial decrease in flecainide plasma levels during extracorporeal elimination occurred much quicker (4.5-8.5 h plasma halflife) than the spontaneous decrease rate of flecainide in humans (12-20 h plasma half-life). We conclude that, perhaps, hemodialysis/hemoperfusion therapy is an efficient method for decreasing toxic plasma levels of flecainide and for improvement of the clinical course of this intoxication.

Adult↗
PubMed1990

Enzyme histochemical and histological changes in the adult rat kidney after prenatal gentamicin exposure.

Treatment of rats between day 15 and 20 of gestation with gentamicin caused histological as well as enzyme histochemical lesions in the kidney of the one year old offspring (F1 generation). Other organs were not significantly affected. Primarily in the female kidney dilated convoluted proximal tubulus with reduced or absent staining for brush border and lysosomal proteases, phosphatases and glycosidases and mitochondrial dehydrogenases were observed. In comparison, glomeruli were less frequently damaged and contained fewer capillary loops or irregularly arranged tissue elements with lowered or no activities for plasma membrane-associated proteases as well as specific and non-specific phosphatases. In addition, the activities of proteases and phosphatases in cortical and medullary endothelial cells of capillaries were reduced or even abolished in the kidney of the female and male F1 generation after treatment of their mothers with gentamicin.

Animals↗
PubMed1989

Immuno-toxicology and -pharmacology.

1. The new field of immunotoxicology may be expected to gain considerable importance in the assessment of possible toxic risks of chemicals. It is an applied science based on the considerable experience gained in basic immunological research within the last decades. 2. Some possibilities are discussed and procedures suggested for evaluating toxic effects induced by chemicals (including drugs) in experimental animals and man. 3. Original data are presented on thymus atrophy induced in the offspring of rats treated on day 10 of pregnancy with the virostatic drug acyclovir. 4. Experimental data are presented on the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the distribution of lymphocyte populations (peripheral blood) in primates in vivo and in vitro, as determined with monoclonal antibodies as probes.

Acyclovir↗
PubMed1988

Prenatal toxicity of acyclovir in rats.

Pregnant rats were treated during organogenesis with s.c. injections of acyclovir and the embryos were evaluated on day 11.5 of gestation (crown-rump length, somites, protein content, score, abnormalities, histological examination). After eight injections of 50 mg/kg body wt on days 9, 10, and 11 of pregnancy a reduction of the crown-rump length was noticed. After 100 mg/kg this effect was more pronounced. With two or three applications of this dose on day 10 specific embryonic abnormalities were visible: the shape of the head was abnormal, the width of the skull had decreased resembling a beak-like visceral cranium. With a single administration of 200 mg/kg on day 10 we found a similar but slightly more pronounced outcome. A drastic change of all variables was obtained after eight injections of 100 mg/kg on days 9, 10, and 11. Comparatively we measured maternal plasma concentrations of acyclovir 1 h after the administration of 50, 100 or 200 mg/kg body wt. After an injection of 50 mg/kg on days 9, 10, and 11 of gestation (three injections/day) the plasma levels ranged from 19.1 to 40.0 mg/l (1 mg/l = 4.44 microM). No cumulation was observed. In contrast, a cumulative effect was detected following a dose of 100 mg/kg. After the first injection of this dose a mean value (+/- SD) of 60.3 +/- 14.7 mg/l (n = 16) was obtained. In this case a third injection increased the mean plasma level to 124.6 +/- 16.6 mg/l (n = 5). Further injections, however, led to decreasing levels. One hour after administration of 200 mg/kg body wt acyclovir levels ranged from 120.0 to 163.9 mg/l. We conclude that acyclovir, at doses leading to plasma concentrations well above the therapeutic level in the dam, interferes with the embryonic development in the rat. Acyclovir induces typical gross structural abnormalities which have been first observed using a whole embryo culture system.

Acyclovir↗