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R Stahlmann

Publications and source records attributed to R Stahlmann.

At least 37 records · Page 2Linked to original sources
PubMed1998

Effects of fluoroquinolones and magnesium deficiency in murine limb bud cultures.

Quinolone-induced arthropathy is probably caused by a lack of functionally available magnesium in immature joint cartilage. We used an in vitro assay to study the effects of fluoroquinolones on cartilage formation in mouse limb buds from 12-day-old mouse embryos in regular and in magnesium-deficient medium. Omission of magnesium from the medium had no adverse effect on the outcome of the culture: limb buds grew and differentiated well in regular and in magnesium-deficient Bigger's medium. Lack of calcium, however, severely impaired the development of the explants; this result was even more enhanced when both minerals (magnesium and calcium) were omitted. Electron microscopy revealed cell necrosis and deposition of electron-dense material in the vicinity of chondrocytes from limb buds after 6 days in a magnesium-free medium. A series of seven fluoroquinolones was tested at 30, 60, and 100 mg/l medium. At a concentration of 30 mg/l sparfloxacin only had a slight effect on limb development. At concentrations of 60 and 100 mg/l sparfloxacin, temafloxacin and ciprofloxacin impaired limb development in vitro concentration-dependently. The effects were enhanced in a magnesium-deficient medium (concentration of magnesium <10 micromol/l). Fleroxacin, lomefloxacin and ofloxacin impaired limb development only slightly; no significant differences were recognizable between the outcome in regular and in magnesium-deficient medium. Pefloxacin did not show any effect on limb development in both media. Using electron microscopy, very similar alterations as described above for the limbs cultured in magnesium-deficient medium were observed with ofloxacin at a concentration of 30 mg/l, which had no effect on the growth of the explants when evaluated macroscopically. The affinity of six fluoroquinolones to magnesium was determined by the use of a fluorescence assay. The affinity to magnesium correlated with the activity of the drugs in the limb bud assay. We conclude that fluoroquinolones have no effect on murine limb development in vitro at concentrations that are achieved under therapeutic conditions (peak concentrations approx. 1-5 mg/l in plasma). Effects at higher concentrations (60 and 100 mg/l) are slightly enhanced (factor 2) if the magnesium concentration in the medium is low. Macroscopically, limbs develop regularly in a magnesium-free medium, but ultrastructurally typical alterations are exhibited (e.g. cell necrosis and pericellular deposition of electron-dense material).

Animals↗
PubMed1998

Chondrotoxicity and toxicokinetics of sparfloxacin in juvenile rats.

Sparfloxacin is a fluoroquinolone with improved antibacterial activity against gram-positive pathogens. Like other quinolones, use of this drug is contraindicated in children and adolescents because of its potential chondrotoxicity in juveniles. We performed histological and immunohistochemical studies on the knee joint cartilage in 5-week-old rats after treatment with 600 or 1,800 mg of sparfloxacin/kg of body weight. Treatment with single or multiple oral doses of 600 mg of sparfloxacin/kg was not sufficient to induce joint cartilage lesions. However, five of eight rats treated with a single oral dose of 1,800 mg of sparfloxacin/kg of body weight showed typical cartilage lesions in the femoral part of the knee joint. The concentrations of the drug in plasma measured 0.25, 0.75, 1.5, 3, 6, 12, and 24 h after the administration of an oral dose of 600 mg of sparfloxacin/kg were 6.3 +/- 1.8, 9.2 +/- 1.7, 9.6 +/- 2.7, 13.0 +/- 1.8, 12.3 +/- 1.6, 3.4 +/- 0.4, and 0.30 +/- 0.20 mg/liter, respectively (mean +/- standard deviation [SD]; n = 5 to 6 per group). The concentrations in plasma measured 0.75, 1.5, 3, 6, 24, and 48 h after the administration of an oral dose of 1,800 mg of sparfloxacin/kg were 10.9 +/- 1.5, 15.9 +/- 1.6, 19.1 +/- 1.7, 14.9 +/- 3.1, 4.1 +/- 0.6, and 0.46 +/- 0.37 mg/liter, respectively (mean +/- SD; n = 3 to 4 per group). The concentrations of sparfloxacin in joint cartilage were significantly higher at all time points studied (114.8 +/- 80, 99.4 +/- 31.5, 84.9 +/- 16.8, 44.4 +/- 13.9, and 14.2 +/- 4.8 mg of sparfloxacin/kg at 1.5, 3, 6, 24, and 48 h after the administration of 1,800 mg/kg, respectively). The range of concentrations in bone were similar to the range of concentrations in cartilage (peak, 115 +/- 12 mg/kg after 3 h). Our data indicate that chondrotoxic doses of sparfloxacin in juvenile rats are approximately 300 times higher than the doses of sparfloxacin used therapeutically (1,800 versus approximately 6 mg/kg of body weight), but due to species differences in kinetics, concentrations in plasma differ by a factor of only approximately 15. More data on quinolone concentrations in cartilage from animals and humans could provide a better basis for a reasonable risk assessment.

Animals↗
PubMed1997

In vitro evidence for a Donnan distribution of Mg2+ and Ca2+ by chondroitin sulphate in cartilage.

Fluoroquinolones are known for their ability to form chelate complexes with magnesium. Cartilage lesions observed in juvenile animals after quinolone treatment very probably are a consequence of the lack of functionally available magnesium. In cartilage, which contains high amounts of negatively charged proteoglycans, a Donnan distribution can be expected leading to an inhomogeneous distribution of ions (such as magnesium), which may support the toxic effects of magnesium deficiency or quinolone treatment of cartilage. We performed in vitro experiments using dialysis tubes to simulate the unequal distribution of proteoglycans in cartilage and measured the distribution of magnesium, calcium and ofloxacin. We found that the concentration of free magnesium is significantly reduced with the chondroitin sulphate-free solution due to a Donnan effect. For example, using a 3% chondroitin sulphate solution (outside the tubing) dialysed against a chondroitin sulphate-free solution (inside the tubing) the magnesium concentration decreased by 24% from 0.55 +/- 0.02 to 0.42 +/- 0.04 mmol/l inside the tubing during 48 h observation (P < 0.01). Under physiological conditions this unequal distribution of magnesium probably will be much more pronounced because chondroitin sulphate concentrations in cartilage are higher; nevertheless, magnesium concentration is sufficient for regular function of the tissue. During the sensitive phase of quinolone toxicity, magnesium in juvenile cartilage is lower than at other time points during postnatal development. Moreover, additional complexation by quinolones may further reduce the concentration of functionally available magnesium below the critical level.

Animals↗
PubMed1997

Quinolone-induced arthropathy: exposure of magnesium-deficient aged rats or immature rats, mineral concentrations in target tissues and pharmacokinetics.

Quinolone treatment or magnesium deficiency induce identical cartilage lesions in juvenile rats and show additive arthropathogenic effects. It has been shown previously that neither condition is arthropathogenic in 8-week-old rats. Joint cartilage from aged individuals is rather prone to pathological alterations but information on prolonged quinolone treatment and/or dietarily induced magnesium deficiency in aged animals is not available. We treated magnesium-deficient (n = 9) aged Wistar rats (age 15 months) and age-matched controls with daily doses of 600 mg ofloxacin/kg body wt. by gastric intubation for 28 days. Further groups of magnesium-deficient and control rats (n = 9 and n = 10, respectively) received the vehicle only. Peak plasma concentrations of ofloxacin in adult rats were 20.5 +/- 5.6 mg/l (mean +/- SD) following treatment with a single dose of 600 mg/kg body wt. At the end of the experiment the degree of magnesium deficiency was most pronounced in plasma (Mg2+-def., 0.33 +/- 0.12 mmol/l; control, 0.97 +/- 0.08 mmol/l) and less pronounced in sternal cartilage (Mg2+-def., 10.8 +/- 3.6 mmol/kg dry wt; control, 13.3 +/- 2.8 mmol/kg dry wt), whereas the magnesium concentration in femoral bone remained unchanged (Mg2+-def., 201 +/- 13 mmol/kg dry wt; control, 204 +/- 11 mmol/kg dry wt). Histological investigation of the knee joints revealed no cartilage lesions following ofloxacin treatment, magnesium deficiency or a combination of both conditions. By contrast, cartilage lesions such as scars and erosions of the joint surface, chondrocyte clusters within acellular areas of the cartilage matrix and persisting clefts were detectable in knee joints from 7 of 10 adult rats (age 9 months) which had been treated with 4 x 600 mg fleroxacin/kg body wt. at 5 weeks of age. Mean plasma concentration of fleroxacin in juvenile rats was approx. 50 mg/l between 1.5 and 6 h after dosing and the drug was still detectable in plasma 48 h after dosing (0.4 +/- 0.1 mg/l). Our data indicate that joint cartilage in aged rats is not altered by a 4-week quinolone treatment, even during magnesium deficiency. Cartilage lesions in adult rats were only detectable if the animals had been treated during the sensitive phase at 5 weeks postnatally.

Age Factors↗
PubMed1997

Effects of magnesium deficiency on magnesium and calcium content in bone and cartilage in developing rats in correlation to chondrotoxicity.

Quinolone-induced arthropathy has been described in juvenile rats between 3 and 6 weeks of age, but not in adult rats. The mechanism of this chondrotoxic effect is probably related to the Mg2+-chelating properties of the drugs, since identical cartilage lesions were observed in magnesium-deficient juvenile rats without quinolone treatment. However, the reasons for the phase-specificity of the effect are unknown. In the present study, we fed a magnesium-deficient diet to Wistar rats at different postnatal developmental stages. Cartilage lesions were only observed in magnesium-deficient rats between 3 and 5 weeks of age, but not in rats receiving the magnesium-deficient diet during weeks 5 to 8, weeks 8 to 11, or months 15 to 16. The formation of cartilage lesions was not related to the magnesium concentration in plasma, since magnesium concentrations in plasma were similarly reduced in rats with and without cartilage lesions. However, chondrotoxicity correlated with magnesium content in articular cartilage. In articular cartilage (articular and epiphyseal cartilage in immature rats) and bone, magnesium content was more reduced in rats receiving the magnesium-deficient diet between 3 and 5 weeks of age as compared with rats receiving the magnesium-deficient diet during weeks 8 to 11 postnatally. It was not possible to reduce the magnesium content in bone tissue of 15-month-old Wistar rats, which suggests a lower magnesium turnover in aged rats. Magnesium content in epiphyseal cartilage of 2-week-old rats (total femoral head) was 41.9 +/- 16.9 mmol/kg dry weight. The magnesium content in joint hyaline cartilage was significantly lower in 4-week-old rats (19.5 +/- 3.6 mmol/kg dry weight) and increased subsequently again to 48.5 +/- 9.2 mmol/kg dry weight (mean +/- SD; n = 8 to 16). Increase of the magnesium content in femoral bone between weeks 4 and 6 postnatally was less pronounced (139 +/- 10 and 175 +/- 15 mmol/kg dry weight, respectively). Taken together, these data show that in 4-week-old rats, magnesium concentration in joint hyaline cartilage is significantly lower than at other times during postnatal development. Only at this developmental stage can cartilage lesions be induced by feeding rats a magnesium-deficient diet. This period correlates well with the sensitive phase of immature rats toward the chondrotoxic action of quinolones.

Aging↗
PubMed1997

Safety profile of grepafloxacin compared with other fluoroquinolones.

Preclinical investigations with grepafloxacin showed that its toxicological profile is similar to that of other fluoroquinolones. The photosensitizing effect of grepafloxacin was relatively weak and similar to that of ciprofloxacin. Grepafloxacin did not cause convulsions in mice when administered in conjunction with the non-steroidal anti-inflammatory drug fenbufen. Intravenous injection of grepafloxacin caused transient dysrhythmias in rabbits at a dosage of 10 mg/kg and ventricular tachycardia at 30 mg/kg iv. Joint cartilage lesions were found in juvenile dogs after iv treatment with 100 mg/kg daily. Plasma concentrations (19-24 mg/L) under these conditions were approximately ten times above a therapeutic level. Data derived from patients who had been treated with grepafloxacin in phase II and phase III multiple-dose studies (400 mg, n = 1069; 600 mg, n = 925) were available for an analysis of the patients' tolerance of the drug. The most common adverse events observed for the 400 mg and 600 mg treatments during these studies were gastrointestinal reactions, such as nausea (11% and 15%, respectively), vomiting (1% and 6%) and diarrhoea (3% and 4%). In both groups a considerable number of patients (9% and 17%) reported an unpleasant taste; this was less common in the pooled controls (1%) after treatment with drugs such as doxycycline, ciprofloxacin, amoxycillin or cefixime. Headache occurred in 4% (400 mg) and 5% (600 mg) and insomnia in 1% (400 mg) or 2% (600 mg) of the patients. Similar incidences were found for photosensitivity (1% and 2%, respectively) and for rash (1% and 2%) in the 400 mg and 600 mg groups. So far, tolerance of the new compound seems to be similar to that of other fluoroquinolones. However, incidences of nausea, vomiting and unpleasant taste were rather high during the first clinical trials, particularly after treatment with 600 mg daily. Further data are necessary for a sound evaluation of the tolerance of grepafloxacin.

Animals↗
PubMed1996

Integrins on joint cartilage chondrocytes and alterations by ofloxacin or magnesium deficiency in immature rats.

Recently, we showed that magnesium deficiency induces lesions in knee joint cartilage from 5-week-old rats that are very similar to ofloxacin-induced cartilage defects. We concluded that quinolone-induced arthropathy is probably due to chelation of magnesium and thus a deficit in functionally available magnesium in joint cartilage (Stahlmann et al. 1995). As magnesium deficiency in joint cartilage could impair chondrocyte-matrix interaction which is mediated by cation-dependent integrin receptors of the beta 1-subfamily, we investigated integrin expression in joint cartilage from untreated, ofloxacin-treated and magnesium-deficient Wistar rats. With immunohistochemical methods using monoclonal and polyclonal antibodies, we showed that the integrin pattern in joint cartilage from rats corresponded largely to integrin expression described for human cartilage tissue: beta 1, alpha 1, alpha 3 and alpha v subunits and the alpha 5 beta 1 and alpha v beta 3 heterodimers were consistently expressed. Joint cartilage lesions were detected in ofloxacin-treated and magnesium-deficient rats. Lesions were more pronounced in the quinolone-treated group. Expression of several integrins was reduced in the vicinity of lesions after oral treatment with 2 x 600 mg ofloxacin/kg for 1 day. Gross-structural lesions (e.g., cleft formation, unmasked collagen fibres) in magnesium-deficient rats were very similar but changes in integrin expression were less pronounced. On the other hand, changes in cartilage matrix composition showed similar alterations in ofloxacin-treated and magnesium-deficient rats: fibronectin deposition in the cartilage matrix increased in both groups while glycosaminoglycan content decreased. In summary, similar defects occur in ofloxacin-treated and magnesium-deficient rats and with immunohistochemical methods subtle differences are demonstrable.

Animals↗
PubMed1996

Quinolone-induced cartilage lesions are not reversible in rats.

The reversibility of quinolone-induced cartilage lesions has not been studied in detail. We treated five groups of five to seven juvenile Wistar rats (male and female; age: 5 weeks) with 2 x 600 mg ofloxacin/kg by gastric intubation on 1 day only (9:00 a.m. and 5:00 p.m.) and studied the knee joints histologically 3 days, 1, 3, 8 and 17 weeks later. In addition, joint cartilage specimens from vehicle-treated control rats (n = 21) at corresponding age were examined. Cartilage lesions such as matrix swelling, loss of proteoglycans and horizontal clefts were found in nearly all knee joints (26 of 27 joints; incidence: 96%) of the ofloxacin-treated rats. Within the observation period of 4 months the size of these lesions in knee joint cartilage did not decrease significantly. The diameter of the lesions at the time points of evaluation was 1146 +/- 535, 1713 +/- 309, 1250 +/- 585, 1406 +/- 356, and 1542 +/- 467 microns, respectively (mean values +/- sd). Chondrocyte clusters producing glycosaminoglycans were observed 3 weeks after dosing and at later time points. They are considered to reflect the onset of repair but chondrocyte organization did not normalize during the study period, thus indicating the irreversibility of the effect under the experimental conditions. In principle, long-term joint cartilage damage has to be taken into account when the use of quinolones in children is considered. More detailed pharmacokinetic data are necessary for a reasonable risk assessment approach.

Animals↗
PubMed1995

Enoxacin is an inducer of CYP1A2 in rat liver.

The induction of cytochrome P450 by enoxacin, ciprofloxacin, and ofloxacin was investigated in female Wistar rats. Animals were treated orally with daily doses ranging from 10 to 400 mg enoxacin per kg body wt, 400 mg ciprofloxacin, or 400 mg ofloxacin per kg body wt for up to 7 days. Activities of methoxyresorufin O-demethylase (MROD) and ethoxyresorufin O-deethylase (EROD) were determined fluorimetrically in hepatic microsomes. MROD activity was increased 2.6-fold after treatment with 100 mg enoxacin per kg body wt for 7 days. Lower doses of enoxacin did not induce MROD activity significantly. Antipeptide antibodies directed specifically against different rat cytochrome P450 enzymes demonstrated that CYP1A2, but not CYP1A1, was induced in rats treated with enoxacin. After ciprofloxacin or ofloxacin treatment, no induction of MROD or EROD activity was observed. Neither ciprofloxacin nor ofloxacin caused any change in CYP1A1 or CYP1A2 apoprotein levels. Further investigations with antipeptide antibodies showed that there was no induction of CYP2B1, CYP2B2, CYP2E1, CYP3A1, CYP3A2, CYP4A1, or CYP4A2 following treatment with enoxacin, ciprofloxacin, or ofloxacin. It is concluded that enoxacin, but not ciprofloxacin or ofloxacin, is an inducer of CYP1A2 in rat liver.

Animals↗
PubMed1995

Magnesium deficiency induces joint cartilage lesions in juvenile rats which are identical to quinolone-induced arthropathy.

Quinolones accumulate in cartilage, and because they form chelate complexes with divalent cations, they possess the potential to induce a deficiency of functionally available magnesium. To test the hypothesis that quinolone-induced arthropathy is caused (or aggravated) by magnesium deficiency in cartilage, we induced magnesium deficiency by feeding juvenile rats a magnesium-deficient diet for 9 days and treated the rats with single oral doses of ofloxacin (0, 100, 300, 600, or 1,200 mg/kg of body weight) during this period. Additional groups of juvenile rats on a normal diet were treated with ofloxacin correspondingly. Typical cartilage lesions (e.g., swollen matrix, cleft formation) were found in knee joints of all magnesium-deficient rats, including those without ofloxacin treatment. Lesions in these groups were not distinguishable from lesions induced by a single dose of 600 mg of ofloxacin per kg of body weight or higher in rats on a normal diet. Ofloxacin levels in plasma after 600 mg/kg of body weight were approximately 10-fold higher than those in humans during therapy with this quinolone. Lesions in rats treated with ofloxacin plus magnesium deficiency were more pronounced than those in rats with normal magnesium concentrations. After intake of a magnesium-deficient diet for 9 days, the magnesium concentration in serum (mean +/- standard deviation) was 0.18 +/- 0.05 mmol/liter (control on normal diet, 0.82 +/- 0.10 mmol/liter). Magnesium concentrations in bone (femur) and cartilage (processus xiphoideus) samples were 64.7 +/- 10.5 and 14.3 +/- 3.9 mmol/kg of dry weight, respectively, which corresponded to approximately 50% of the concentrations measured in controls on a normal diet. It was concluded that quinolone-induced arthropathy is probably caused by a deficit of available magnesium in joint cartilage due to the formation of quinolone-magnesium chelate complexes. If juvenile patients must be treated with quinolones for serious infections, it seems prudent to ensure that these patients do not have a disturbed magnesium balance.

Animals↗
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↗
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

Significance of embryo culture methods for studying the prenatal toxicity of virustatic agents.

Culture methods have become important tools for elucidating the prenatal toxicity of drugs and other xenobiotics. In this paper we will review how we used in vitro as well as in vivo approaches to demonstrate the teratogenic potential of aciclovir and other related virustatic agents. In addition, some new data on this topic will be given. The teratogenic potential of the virustatic agent aciclovir was not recognized in routinely performed segment-II-studies, but the first indication came from experiments with the culture of rat embryos. Subsequently, the findings were confirmed in modified in vivo tests and it became clear that out of a group of six related drugs aciclovir exhibited the highest potential for prenatal toxicity. The effects of aciclovir on limb development were not pronounced--this has been shown with in vitro and in vivo experiments as well. In vivo experiments first indicated that the prenatal development of the thymus is disturbed by aciclovir. This effect was further studied with the culture of fetal thymuses and again the effect of aciclovir could be compared with related drugs. In summary, our work with virustatics during the last years has shown that in vivo and in vitro approaches are by no means competitive and that a combination of both approaches can provide a solid basis for a toxicologic evaluation.

Abnormalities, Drug-Induced↗
PubMed1992

Abnormal thymus development and impaired function of the immune system in rats after prenatal exposure to aciclovir.

Aciclovir (synonym: acyclovir) causes abnormal thymus development in rats. After treatment on day 10 of gestation a weight reduction of the organ is obvious in 21-day-old fetuses which persists postnatally. Adult male rats exposed in utero to one or three injections of 100 mg aciclovir/kg body wt given to the dam on day 10 of pregnancy showed a reduction of the thymus weight to 333 +/- 158 mg and 276 +/- 61 mg (control: 428 +/- 92 mg; n = 10). Corresponding alterations were detectable in female offspring. Liver weight was also decreased and spleen weight (in relation to body wt) was significantly increased in the offspring after the three exposures. In a host resistance model with Trichinella spiralis the function of the immune system of rats prenatally exposed to aciclovir was examined. Six weeks postnatally 10-12 randomly selected male rat offspring of one control and two treatment groups (1 or 3 injections of 100 mg aciclovir/kg body wt on day 10 of gestation) were infected orally with 500 Trichinella spiralis muscle larvae. Before and several times after the infection blood was taken from a tail vein or obtained by decapitation for examination of the antibody titers (IgM, IgG, IgA, IgE) to antigens of T. spiralis. Six weeks after the infection the weight of relevant organs was determined and tongue preparations were used for T. spiralis muscle larvae counting. Aciclovir exposed animals showed a different immune response than control rats. IgM titers in both treatment groups were higher than in controls two weeks after the infection but not different by the end of the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)

Acyclovir↗