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Biomedical subjects

R Stahlmann

Publications and source records attributed to R Stahlmann.

At least 19 recordsLinked to original sources
PubMed2006

[New antibiotics for the therapy of respiratory tract infections].

The need for new antibiotics is ongoing in view of manifold resistance developments. The resistance of Streptococcus pneumoniae against macrolides and penicillins in the USA already amounts to more than 30 %. The approval of new antibiotics, particularly those with a new mode of action, has been decreasing over the past years which is anticipated to result in a lack of resourceful therapy options in the future. Some new substances with good in vitro activity against S. pneumoniae have turned out to raise safety issues as shown for a number of quinolones. Likewise daptomycin, a lipopeptide with a new mechanism of action, did not show satisfying results due to its inactivation by surfactant. Established quinolones are levofloxacin and moxifloxacin, the latter being available as i. v. formulation since 2002. For ketolides, telithromycin (oral) and for azalides azithromycin (since 2005 as i. v. formulation) are available for antimicrobial therapy. Linezolid is the only approved oxazolidinone. Tigecycline, a tetracycline derivate, will be approved in 2006 in Germany. The latest approval regarding carbapenems was ertapenem in 2003, while doripenem, a new antibiotic from this group, is still under clinical development.

Anti-Bacterial Agents↗
PubMed2002

Children as a sensitive subgroup and their role in regulatory toxicology: DGPT workshop report.

There is increasing discussion that children might be considered as a specific subgroup in public health regulations which could be more sensitive than the average "adult" human being. Differences between children and adults, with regard to susceptibility towards toxicants, may result from a combination of toxicokinetic, toxicodynamic and exposure factors. Kinetic factors are of importance mainly in the early postnatal period, largely as the result of immature elimination systems, i.e. metabolising enzymes and/or renal function. Specific vulnerability may prevail during several time periods, related to the development and maturation of organs (for example, brain, bone, endocrine system). For some substances, it has been shown that children at a specific age are less sensitive than adults. Specific exposures of toddlers to environmental chemicals may be high due to their moving behaviour and hand-to-mouth activities. Existing scenarios and models for exposure of children should be improved, in particular with respect to different ages. The outcome of model calculations must be verified by human biomonitoring analysis. At present, there is ongoing discussion of toxicological test models suitable to delineate human postnatal development. Experience with infant-orientated test systems is scarce (for example in developmental neurotoxicity). In general, tools for predicting toxicological sensitivity of children must be further improved. Regulators should also be aware that reduction of lifestyle-related toxic exposures such as smoking and drug abuse in children and adolescents is now an increasing public health problem in many countries.

Adolescent↗
PubMed2002

Attitudinal classification of patients receiving antibiotic treatment for mild respiratory tract infections.

The aim of this study was to determine patients' perceptions of antibiotic therapy and the doctor's skill in the management of ambulatory respiratory tract infections. Standardized face-to-face interviews were used with more than 3000 randomized patients or parents from four European countries. Attitudinal dimensions relating to their doctor identified four patient types: Involved (30%), Deferent (23%), Ignored (13%) and Critical (17%). Involved and Deferent patients were the most satisfied by the information received from their doctor (43%/39% compared with 17%/16% for Ignored/Critical, respectively, P < 0.01). They also scored more highly on the accurate use of antibiotics, with 80%/80% vs. 38%/62%, respectively (P < 0.01), understanding dosing intervals and 77%/77% vs. 36%/60% (P < 0.01), understanding the course length. Involved and Deferent patients showed better compliant behaviour, with 91% of both groups vs. 86% of the Ignored and Critical claiming to have taken every dose (P < 0.001) and 92%/87% vs. 84%/85% claiming to have finished the course (P < 0.001 for Involved only). Involved and Deferent patients were less prone to save part of a course of antibiotics than the Ignored and Critical (46%/41% vs. 20%/31%, P < 0.001), and they perceived the antibiotics prescribed to be more effective (36%/31% vs. 21%/15%, P < 0.001). By analysing patient perceptions, this study identifies an important mirror effect, whereby a more sympathetic attitude from the doctor should increase the patient's involvement in disease management, for a more appropriate use of antibiotics in common infections.

Adolescent↗
PubMed2001

Ultrastructure of Achilles tendon from rats after treatment with fleroxacin.

Quinolone therapy can be associated with tendon disorders (tendinitis, ruptures), but little is known about possible ultrastructural changes in tendons after exposure to these antimicrobials. We studied the Achilles tendons from fleroxacin-treated adult rats by electron microscopy. Wistar rats were treated orally with single oral doses of 0, 30, 100, 300 or 600 mg fleroxacin/kg body weight (n = 6 per group). The animals were killed 4 weeks after treatment. Achilles tendon samples were collected and tangential sections were made from the distal part of the tendon. Subsequently, tendons were cut crosswise for preparation of ultrathin sections. Samples were fixed by using glutaraldehyde, osmium tetroxide, tannic acid and finally contrasted with uranyl acetate/lead citrate before they were examined by transmission electron microscopy. The rats did not show any general effects such as behavioural changes or body weight changes which could be attributed to the treatment. However, we were able to detect pathological changes even at the lowest dose level (30 mg/kg), which increased in incidence and severity with increasing doses. Tenocytes exhibited degenerative changes such as multiple vacuoles and large vesicles in the cytoplasm that resulted from swelling and dilatation of cell organelles (mitochondria, endoplasmic reticulum). The nucleus became dense and the chromatin had clumped to form rough plaques. The cells detached from the extracellular matrix. Other important findings were a general decrease of the fibril diameter and an increase in the distance between the collagenous fibrils. The finding that these rather low single dose of a fluoroquinolone induce ultrastructural changes in Achilles tendons from rats, which were not associated with clinical symptoms and which were still present 4 weeks after treatment, is of concern. Further toxicological as well as clinical studies are needed to characterize the conditions under which quinolone-induced tendon lesions develop.

Achilles Tendon↗
PubMed2001

Effects of fluoroquinolones on the locomotor activity in rats.

During therapy with fluoroquinolones adverse CNS reactions such as dizziness, light-headedness, insomnia or sleepiness are observed in up to 20% of patients. Using a device developed at our institute for the simultaneous registration of the activity of rats housed in single cages, we have investigated the effects of trovafloxacin, fleroxacin or ofloxacin on the locomotor activity of juvenile and adult rats (11 per group) after oral administration of 600 mg/kg for 5 consecutive days. The effects were most pronounced after fleroxacin, which induced a reduction in activity to 36 +/- 9% (mean +/- SD) of the values measured in juvenile rats before treatment and to 60 +/- 21% (mean +/- SD) in adult rats. HPLC analysis of the plasma concentrations in juvenile rats showed that the concentrations of trovafloxacin were considerably lower than those of the other fluoroquinolones that had been studied previously in our laboratory: the peak concentration of trovafloxacin was 14 +/- 2.9 mg/l (mean +/- SD) after a single dose of 600 mg/kg in juvenile rats. Overall, we showed that the locomotor activities of juvenile and adult rats were significantly depressed during treatment with fluoroquinolones. The effects were more pronounced in juveniles. Monitoring of the locomotor activity of rats is a suitable approach to study CNS effects of fluoroquinolones in animals, but pharmacokinetics have to be taken into account.

Administration, Oral↗
PubMed2001

Biochemical changes in Achilles tendon from juvenile dogs after treatment with ciprofloxacin or feeding a magnesium-deficient diet.

Quinolones are antibacterial agents that have the potential to induce Achilles tendon disorders - such as tendinitis or even ruptures - in patients treated with these drugs. We studied the effects of ciprofloxacin on several proteins of Achilles tendons from immature dogs, 10- to 11-weeks-old. The dogs were treated orally for 5 days with 30 or 200 mg ciprofloxacin/kg body weight or with the vehicle alone. Since quinolone-like alterations in joint cartilage were observed in magnesium-deficient animals, another group was fed a magnesium-deficient diet for 6 weeks. At necropsy, tendons (n=3 from each group) were frozen and stored until analysis when they were homogenized in a lysis buffer to release a soluble fraction of the tendon proteins. Densitometric analysis of the immunoblots with anticollagen type I, anti-elastin, anti-fibronectin, and antiintegrin antibodies showed a significant reduction of all proteins. For example, collagen type I concentrations (mean +/-SD, arbitrary densitometric units) were 3190+/-217 (controls), 1890+/-468 (30mg/kg), 1695+/-135 (200mg/kg) and 2053+/-491 in the magnesium-deficient dogs. The differences between concentrations in controls and all treated groups were statistically significant (P<0.01, t-test). Similarly, compared with control samples, relative concentrations of other proteins in tendons from ciprofloxacin-treated dogs (30 mg/kg) decreased by 73% (elastin), 88% (fibronectin), and 96% (beta1 integrin) (data from low-dose group only). A very similar pattern of protein alterations was detected in samples from magnesium-deficient dogs. In conclusion, rather low doses of a fluoroquinolone or a diet-induced magnesium deficiency caused similar biochemical alterations in the soluble fraction of proteins from canine tendons. These findings support our hypothesis that quinolone-induced toxic effects on connective tissue structures are due to the magnesium-antagonistic effects of these antibacterial agents. They also indicate that patients with a latent magnesium deficiency could be at an increased risk of quinolone-induced tendon disorders.

Achilles Tendon↗
PubMed2000

Developmental toxicity of the HIV-protease inhibitor indinavir in rats.

BACKGROUND: Indinavir is an antiviral agent used for the treatment of HIV infection. We studied its developmental toxicity in rats. METHODS: Pregnant animals were treated orally with 500 mg indinavir/kg body weight (bw) from day 6 to 15 of gestation (once daily) or from day 9 to 11 (twice daily). Fetuses were evaluated for external and skeletal anomalies on day 21 of gestation. In addition, 19 rats were treated from day 9 of gestation to day 24 postnatally with 500 mg indinavir/kg bw once daily; a control group of 17 rats was treated with the vehicle accordingly. Developmental landmarks were recorded. Sixteen offspring each were studied on postnatal days 7, 14, 21, and 35 for hepatic enzyme activity. Liver tissue was examined by electron microscopy. RESULTS: Fetal examination on day 21 of pregnancy showed no treatment-related effects on number, weight, and viability of the fetuses; however, an increased incidence was noted in the supernumerary ribs and variations of the vertebral ossification centers in both indinavir-treated groups. Postnatal evaluation showed delayed fur development, eye opening, and descensus testis. The most striking finding was unilateral anophthalmia, observed in 7 pups (3%) from 2 out of 19 litters exposed to indinavir, but not in controls. Only minor changes in hepatic monooxygenase activities occurred in dams. Electron microscopy of liver samples showed hepatocellular inclusions of lipids and myelin figure-like structures in maternal livers and infiltration with granulocytes in offspring livers. CONCLUSIONS: Further studies on reproductive toxicity, including combinations of three or more antiretroviral agents as used therapeutically, are needed to determine the hazards of such a treatment.

Abnormalities, Drug-Induced↗
PubMed2000

Chondrotoxicity of ciprofloxacin in immature beagle dogs: immunohistochemistry, electron microscopy and drug plasma concentrations.

The systemic effects of ciprofloxacin in immature Beagles were studied. Dogs of 10-11 weeks were dosed orally for 5 days with 0 (n=3), 30 (n=5) and 200 (n=5) mg ciprofloxacin/kg body wt. Plasma concentrations were measured by high-performance liquid chromatography (HPLC) 1 h after dosing (assuming to be peak concentrations). In view of the high doses used, the plasma concentrations were rather low and declined during the study period. For example, plasma concentrations in the high dose group were 6.6 +/- 0.9 mg/l (day 1), 3.9 +/- 1.4 mg/l (day 3), and 2.6 +/- 1.6 mg/l (day 5). In control dogs and in dogs treated with the low dose of ciprofloxacin no pathological changes were seen by light microscopy. However, cleft formation and erosions were observed in joint cartilage from two of five dogs treated with 200 mg/kg. It is noteworthy that despite the high dose used cartilage lesions were not detectable in all five dogs of this group by light microscopy. Using antibodies against cell membrane receptors (e.g. the alpha(5)beta(1)-integrin) or matrix components (fibronectin, collagen II) the articular cartilage effects were studied in detail by immunohistochemistry. The most sensitive alteration was an increase in fibronectin which was detectable in the vicinity of the lesions in cartilage samples from the group of dogs administered the high dose. No clear-cut changes were seen with the use of antibodies against other matrix components. Electron microscopy revealed typical alterations in chondrocytes from dogs treated with ciprofloxacin: e.g., swollen mitochondria and enlarged rough endoplasmic reticulum. These changes were much more pronounced in dogs from the high dose group than in dogs from the low dose group. Our main conclusion is that after oral administration ciprofloxacin exhibits rather low chondrotoxicity, even in the most sensitive species known to date. This correlates with the findings in humans that ciprofloxacin seems to be less chondrotoxic than pefloxacin or other quinolones.

Animals↗
PubMed2000

Effects of magnesium deficiency on joint cartilage in immature beagle dogs: immunohistochemistry, electron microscopy, and mineral concentrations.

Quinolone-induced chondrotoxicity is possibly associated with the magnesium-chelating properties of quinolones. This toxic effect seems to be restricted to a rather short time period during postnatal development as shown in rats and dogs. We studied developmental changes of the integrin pattern on canine chondrocytes (e.g. the alpha(v)beta(3)- or alpha(5)beta(1)-integrin), because integrin function depends on divalent cations, as well as the matrix composition (e.g., collagen type II, fibronectin), in 11-, 18-, and 55-week-old Beagles (n=8) by immunohistochemistry. We also analyzed the magnesium and calcium content by atomic absorption spectroscopy in cartilage and bone and studied the effects of a magnesium-deficient diet on joint cartilage in four immature Beagles (18 weeks old at necropsy). The dogs were fed the magnesium-deficient diet for 40 to 46 days. All dogs exhibited gait alterations ('limping') after 4 weeks on the magnesium-deficient diet. Male, magnesium-deficient dogs exhibited pronounced weakness in their front legs; in one of these dogs the front legs were hyperextended to a 90 degrees angle. We observed no significant differences in the integrin pattern in samples from dogs at different developmental stages or in magnesium-deficient dogs in comparison to age-matched controls. Localization of fibronectin in the joint cartilage was found to vary with the age of the dogs as well as with the site of collection. In the middle zone of immature joint cartilage, corresponding to the predilective site of quinolone-induced cartilage lesions, we observed a slight increase in staining with the fibronectin antibody in some samples from magnesium-deficient dogs. Electron microscopy revealed alterations in chondrocytes from the magnesium-deficient dogs (e.g., swollen mitochondria and enlarged endoplasmic reticulum) which are also seen after treatment with quinolones. In summary, we found no significant differences of the integrin pattern on chondrocytes from joint cartilage of dogs at various developmental stages. However, magnesium deficiency in immature dogs induced similar clinical symptoms as quinolone treatment as well as distinct alterations in chondrocytic fibronectin staining and their ultrastructure. This corroborates our findings in rats where magnesium chelation is an important event in quinolone-induced chondrotoxicity.

Animals↗
PubMed2000

Cross-reactivity of antibodies on thymic epithelial cells from humans and marmosets by flow-cytometry.

Callithrix jacchus, the common marmoset, is particularly suitable for immunological studies in vivo and in vitro since many antibodies directed against epitopes of human cells do also react with their analogues from this non-human primate. We studied the reactivity of antibodies against human epitopes on primary cultures of thymic epithelial cells from marmosets and humans by flow-cytometry after different culture periods. The antibodies against integrins, including CD61, reacted with thymic epithelial cells from both humans and marmosets, as did anti-CD44 and anti-CD106. Antibodies specific for thymic epithelial cells (TE-3, TE-4, TE-8, TE-15, TE-16, TE-19) also bound to cells from marmosets but expression of all epitopes was not observed in all cultures studied. The expression of CD51, CD54, CD58 and CD106 on human cells declined after 4 weeks of culture. Our findings indicate that marmosets are a valuable model for immunological studies of effects of xenobiotics on the thymic epithelium.

Animals↗
PubMed2000

Test systems to identify reproductive toxicants.

Experience with drugs and other xenobiotics indicates that both animal testing and epidemiological studies are necessary to provide adequate data for an estimation of risks that might be associated with exposure to a chemical substance. In this review, the pros and cons of test systems for reproductive toxicity are discussed. Usually, several studies are performed to cover the different phases of the reproductive cycle. In the preclinical development of drugs, the three so-called 'segment testing protocols' have been used for several decades now. More recently, new testing concepts have been accepted internationally which include more flexibility in implementation. Several examples of compounds with the potential for reproductive toxicity are presented in more detail in a discussion of some pitfalls of the tests for fertility (phthalates and fluoroquinolones), teratogenicity (acyclovir and protease inhibitors) and postnatal developmental toxicity (fluoroquinolones). In addition, important aspects of kinetics and metabolism as a prerequisite for a rational interpretation of results from toxicological studies are briefly discussed. In vitro assays are useful for supplementing the routinely used in vivo approaches or for studying an expected or defined effect, but they are not suitable for revealing an unknown effect of a chemical on the complex reproductive process.

Abnormalities, Drug-Induced↗
PubMed2000

Ultrastructure of Achilles tendons of rats treated with ofloxacin and fed a normal or magnesium-deficient diet.

Fluoroquinolones can cause tendinitis and tendon rupture. However, toxicological as well as clinical information on quinolone-induced tendopathy is scarce. We performed extensive electron microscopic studies with Achilles tendon specimens from ofloxacin-treated rats. The drug was given at a dose of 1,200 mg/kg (body weight) orally. Juvenile Wistar rats received one or three oral doses each of 1,200 mg of ofloxacin/kg (body weight)/day. Three days after treatment, the tenocytes of their Achilles tendons showed degenerative alterations, such as multiple vacuoles and vesicles in the cytoplasm that had developed due to swellings and dilatations of cell organelles. Other indications of cell degradation were the occurrence of cell debris and cell detachment from the extracellular matrix accompanied by a loss of cell-matrix interaction. The tenocytes of juvenile Wistar rats that had been treated at day 36 with a single oral dose of 1,200 mg of ofloxacin/kg (body weight) and sacrificed either 3 or 6 months later exhibited similar degenerative alterations. The number of degenerative alterations of tenocytes after ofloxacin treatment was considerably higher in rats that had received a magnesium-deficient diet than in rats with normal magnesium status. Of the adult rats that had been treated once, 5 times, and 10 times with ofloxacin and killed 1 day later, only those with the 10-times treatment showed a significantly increased number of degeneratively altered tenocytes. In summary, effects observed in tendons show similar pathological features as described earlier in cartilage, indicating that quinolone-induced arthropathy and quinolone-induced tendopathy probably are different clinical manifestations of the same toxic effect on cellular components of connective tissue structures.

Achilles Tendon↗
PubMed1999

Toxicity of quinolones.

Reactions of the gastrointestinal tract, the CNS and the skin are the most often observed adverse effects during therapy with fluoroquinolones. At least for some of the newer fluoroquinolones a steep dose-response relationship of adverse effects seems to exist. Pathogenesis of the neurotoxic effects of fluoroquinolones is still unknown. Among the newer drugs, trovafloxacin caused mild CNS reactions such as dizziness and lightheadedness in a considerable proportion of patients. Young females seem to be especially sensitive to this effect, which diminishes during treatment or if taken together with food. Cardiotoxic potentials of sparfloxacin and grepafloxacin are higher than those of other fluoroquinolones, but during therapy no clearcut drug-related serious reactions have been reported, apart from a slight prolongation of the QT interval. However, to avoid risks these drugs should not be prescribed to patients with known prolongation of the QT interval (e.g. patients on antiarrhythmics). Phototoxicity has been described for all quinolones, but derivatives with a halogen atom at position 8 show the highest potential for such reactions. Fleroxacin, sparfloxacin, clinafloxacin and lomefloxacin belong to this group of fluoroquinolones. The phototoxic potential of the other new fluoroquinolones is considerably lower, but extensive exposure to UV light should generally be avoided during therapy with all quinolones. Chondrotoxicity of quinolones, as observed in immature animals, can affect articular cartilage and/or the epiphyseal growth plate, depending on the developmental stage. Pathogenesis of chondrotoxicity can probably be explained by the magnesium-chelating properties of these drugs. As juveniles are especially sensitive, use of these drugs in paediatrics should be restricted to carefully selected indications (such as the use of ciprofloxacin in cystic fibrosis). Another manifestation of the toxic effects of quinolones on connective tissue structures are tendopathies. Tendinitis and tendon ruptures have occurred as late as several months after quinolone treatment. Overall, quinolones are well tolerated drugs. Their specific toxic potentials have to be considered when they are chosen for treatment of bacterial infections.

4-Quinolones↗