Effect of lindane on pregnancy in the rabbit and rat.

There was no evidence of any teratogenic effect of lindane when administered during pregnancy at levels equivalent to 5, and 15 mg/kg body weight to New Zealand White rabbits from days 6 to 18 inclusive, or to CFY rats from days 6 to 16 inclusive. These findings are consistent with the negative teratogenicity results in mice mutagenicity studies and 3-generation rat reproduction studies already reported.

International Commission for Protection Against Environmental Mutagens and Carcinogens. ICPEMC publication No. 18. Review of the genotoxicity and carcinogenicity of antischistosomal drugs; is there a case for a study of mutation epidemiology? Report of a task group on mutagenic antischistosomals.

One of the interests of ICPEMC is to identify situations in which the possible induction of inherited defects in man by mutagen exposure could actually be studied. The large-scale use of mutagenic drugs in field programmes against schistosomiasis, mainly during the 1970's, was considered a possible case. An ICPEMC task group approached the problem by (1) updating the genetic toxicology data base for antischistosomal drugs, and (2) reviewing possible study areas. Expertise was combined from genetic toxicology, mutation epidemiology and tropical medicine. It was considered that: (a) if any, hycanthone would be the most appropriate candidate drug for study; (b) it would be virtually impossible to meet the basic requirements of an appropriate mutation epidemiology study, in endemic countries; (c) as more defined genetic endpoints would be selected (e.g. sentinel phenotypes) the required large sample sizes would seem prohibitive, since documentation on past programmes is limited and local demography would render the reliable tracking of substantial numbers of offspring of treated persons an almost impossible task; (d) in most endemic countries proper diagnosis and registration of inherited defects is largely lacking; (e) the problems encountered in demonstrating inherited effects in humans after heavy or chronic exposure to established animal mutagens such as ionizing radiation and cancer chemotherapy, in combination with the ambiguous nature of the animal germ cell data with hycanthone, do not particularly warrant large expectations; (f) since non-mutagenic antischistosomal drugs are now in use, the problem is academic and of low priority in the endemic countries whose medical and research resources are often limited. Thus, studying offspring of hycanthone-treated people to demonstrate the mutagenic potential of the drug in man is not a viable enterprise.

[Automated mammary sonography and mammography: the differentiation of benign and malignant breast lesions]. / Automatisierte Mammasonographie und Mammographie: Differenzierung benigner und maligner Mammaläsionen.

PURPOSE: A prospective study on the differentiation of breast lesions was carried out using experimental combination schemes of mammography and automatic sonography. MATERIALS AND METHODS: X-ray mammograms and a B image from automatic sonography of 39 malignant and 41 benign lesions as well as 40 cases without lesions were separately examined by four experienced diagnosticians. The observers differentiated the findings mammographically and by measurement in the B images. RESULTS: For two examiners the combination of mammography and automatic sonography gave with regard to the differentiation of breast lesions an improvement in sensitivity of 3 or 5% and in specificity of 31 and 18%, respectively, as compared to mammography alone while for the other two examiners an improved specificity of 21 and 36%, respectively, was accompanied by an 8 and 10% decrease in sensitivity as compared to mammography alone. CONCLUSIONS: The differentiating criteria from automatic sonography and mammography can, in principle, be used to evaluate the dignity of breast lesions. However, an optimization is necessary since the improvement in specificity does not compensate the loss in sensitivity.

[Three-dimensional breast biopsy and surgery]. / Dreidimensionale Mammabiopsie und Chirurgie.

For the histological verification of suspicious non-palpable small breast tumors, the three-dimensional breast biopsy applied as cylindrical extirpation using the ABBI system is the optimal solution at present. Because of the possibility of performing mammography during the operation, errors of localization can be corrected and incorrect incisions avoided. Taking the three radiomorphologically leading symptoms into consideration--suspicious microcalcification, focal shadow and structural irregularity--it can be stated that the digital mammography of the ABBI system is more sensitive than the conventional one for detecting microcalcification, but focal shadow and structural irregularity are detected less well by digital technique. These structures should be preoperatively marked by using sonography. After the complete removal of suspicious microcalcification checked by digital mammography during the operation, residual tumor might be found in a second excision when histologically invasive or intraductal tumor terminations reach the excision margin (R1 resection). Thirteen invasive and 8 intraductal carcinomas were found in 80 cases of cylindrical extirpation using the ABBI system. In 7 procedures carried out to exclude an in-breast recurrence, 3 intraductal carcinomas and 1 invasive carcinoma were observed. In 8 of 12 invasive carcinomas and in 1 of 5 intraductal carcinomas, breast-conserving therapy was indicated. Two cases of invasive carcinoma fulfilled the criteria applied (minimal tumor-free margin > 2 mm, no extensive intraductal component) to use the ABBI cylinder as lumpectomy without a second excision to follow.

The toxicological profile of praziquantel in comparison to other anthelminthic drugs.

The toxicity data on praziquantel, effective against trematodes and cestodes, on the schistosomicides hycanthone, metrifonate, niridazole, and oxamniquine, and on albendazole, effective against cestodes and nematodes, are discussed. Praziquantel's efficacy in neurocysticercosis treatment has been well established. Recently, therapy of brain cysticercosis with albendazole was reported as well. For hycanthone, metrifonate, niridazole, and oxamniquine a mutagenic potential was demonstrated, at least in bacterial systems. Hycanthone and niridazole affect reproductive functions and are carcinogenic in animals. As not many safety data on albendazole have been published, it is possible only to deduce a teratogenic risk and--in rare cases--a hepatotoxic potential. Its capacity to induce cytochrome P-448 needs further elucidation, because the activation of drugs and chemicals by this monooxygenase isozyme may produce toxic or even carcinogenic metabolites. Likewise, it needs to be established, how possible effects on the intracellular tubulin system, which are known to occur with related benzimidazoles, affect the safety profile of this drug. From the toxicological point of view, praziquantel is the most promising drug, because it lacks systemic toxicity after repeated administration of daily doses of up to 1000 or 180 mg/kg to rats and dogs, respectively, and after lifetime bioassays with rats and Syrian hamsters. It does not affect reproduction, and is devoid of any mutagenic or carcinogenic potential.

[Preclinical research--toxicology]. / Präklinische Untersuchungen--Toxikologie

The different steps of the toxicological testing of new drugs are shortly described. Furthermore it is discussed that only 60-70% of the drug induced adverse reactions in man can be predicted by the experimental methods being available at present. Special problems exist in evaluating the results of reproductive-toxicological, carcinogenicity and mutagenicity tests. These problems are illustrated by some experimental and clinical examples.

PIP: Toxicological testing of new drugs is briefly described. Only 60-70 % of the adverse drug reactions in human beings can be predicted by presently available experimental methods. Special problems exist in the evaluation of reproductive-toxicity, carcinogenicity, and mutagenicity tests. The example of the carcinogenic effect of chlormadinone acetate, when given to beagles at doses 2-25x greater than the human therapeutic dose, is cited, in addition to several examples of antineoplastic agents .

Results of toxicological studies on praziquantel.

Praziquantel (2-cyclohexylcarbonyl-1,2,3,6,7, 11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one, EMBAY 8440, Biltricide) is an anthelminthic drug with activity against all species of schistosomes pathogenic to man and a wide range of cestodes, including the cysticerci of Taenia solium in human tissues and organs, also the CNS. Praziquantel does not reveal any undesired pharmacodynamic effects. After oral administration praziquantel is quantitatively and rapidly absorbed, metabolized and excreted as a variety of metabolites predominantly via the kidneys. The acute toxicity in rats, mice, rabbits and dogs is very low. Rats tolerated by oral administration doses of up to 1000 mg/kg repeated daily for four weeks, and dogs up to 180 mg/kg for 13 weeks without any organ damage. Praziquantel did not disturb reproduction in rats (up to F2-generation), nor did it reveal teratogenic effects in mice, rats and rabbits. In extensive mutagenicity trials performed by different laboratories worldwide, in a variety of test systems, no induction of point mutations, gene conversion, DNA-repair, sister chromatid exchanges (SCEs), or X-linked recessive lethals was detected. Besides, Salmonella tests with urines of praziquantel treated mice, rats, healthy and Schistosoma-infected persons gave no indication of a mutagenic effect. In different in vivo mammalian assays praziquantel not mutagenic either. Low toxicity of praziquantel was not mutagenic either. Low toxicity of praziquantel was demonstrated also in the combined chronic toxicity and carcinogenicity tests which were performed in rats and Syrian hamsters. In none of these species praziquantel exerted a carcinogenic action, and both doses were tolerated.

[What may be learnt from short- and long term tests and from studies on cancerogenicity, teratogenicity and mutagenicity (author's transl)]. / Was lehren toxikologische Kurz-und Langzeittests sowie Prüfungen auf Kanzerogenität, Teratogenität und Mutagenität

During the last 15 years the transferability of results from animal experiments to humans has been improved so that today certainly more than 70% of possible side effects can be predicted. Systemic hypersensitivity reactions cannot be predicted, however, since to date there are no safe animal experimental methods available. In spite of many decades of research in the field of animal experimental cancerogenesis the value of investigations of this kind for humans can be limited by the selection of unsuitable animal species, use of inadequate modes of administration or excessive doses. Similar aspects apply to reproduction toxicology; there are many examples in cancerology and teratology for false-positive and -negative results from animal experiments. In chemomutagenesis comparisons of in vivo cytogenetic investigations in somatic cells of animals and humans have revealed largely concurring results. However, only stable mutations found in generative cells are signs of a genetic danger. It will therefore have to be clarified which conclusions for generative cells should be drawn from changes in somatic cells. Furthermore, the elaboration of methods for the determination of the mutation of genes in the organism of mammals still requires intensive research.

Mutagenicity studies with praziquantel, a new anthelmintic drug: tissue-, host-, and urine-mediated mutagenicity assays.

Praziquantel, a new anthelmintic drug with activity against all species of schistosomes pathogenic to man, and against a wide range of Cestodes, was tested for mutagenic potential. For the detection of both base substitutions and frameshift mutations, Salmonella typhimurium TA 100 and TA 98 were used as tester strains. Using the plate assay with and without added S-9, host-mediated assay and urine-mediated assay without and after incubation with beta-glucuronidase/arylsulfatase, no mutagenic activity could be detected.

Toxicological profile of praziquantel, a new drug against cestode and schistosome infections, as compared to some other schistosomicides.

2-Cyclohexylcarbonyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a] isoquinolin-4-one (praziquantel, EMBAY 8440, Biltricide), a new anthelminthic drug with activity against all species of schistosomes pathogenic to man, and against a wide range of cestodes, did not reveal any undesired pharmacodynamic effects. After oral administration praziquantel is quantitatively and rapidly absorbed, metabolized and excreted as a variety of metabolites predominantly via the kidneys by all species tested, including man. Its acute toxicity tested in rats, mice, rabbits and dogs is very low as compared with other schistosomicidal drugs. After repeated oral administration rats tolerated daily doses of up to 1000 mg/kg for four weeks, and dogs up to 180 mg/kg for thirteen weeks without any organ damage. In contrast to some other schistosomicidal drugs praziquantel did not disturb the whole reproductive process (up to F2-generation) in rats, nor did it reveal teratogenic effects in mice, rats and rabbits. In extensive mutagenicity trials performed in different European laboratories in a variety of test systems no induction of point mutations, nor of gene conversion, nor of DNA-repair, nor of sister chromatid exchanges (SCEs), nor of X-linked recessive lethals was detected. Besides, Salmonella tests with urines of praziquantel-treated mice, rats, healthy and Schistosoma-infected persons gave no indication of a mutagenic effect. In different in vivo mammalian assays praziquantel was not mutagenic either. In contrast to these findings other schistosomicidal drugs demonstrated mutagenic potential, in bacterial tests at least. According to the results available so far from carcinogenicity studies with oral doses of 100 and 250 mg praziquantel/kg, given once weekly to Syrian hamsters for 80 weeks and to rats for 104 weeks, there is no hint of a carcinogenic potential of praziquantel in small rodents, while hycanthone had cancerogenic effects in mice and niridazole was carcinogenic in mice, rats and Syrian hamsters.

In vivo cytogenetic investigations in bone marrow cells of rats, Chinese hamsters and mice treated with 6-mercaptopurine.

The chromosome-damaging effect of 6-mercaptopurine (6-MP) was investigated in bone marrow cells of rats, Chinese hamsters, and mice after single intraperitoneal injections of doses from 3.125 to 250 mg/kg, and after multiple applications of 10, 25, 50, and 125 mg/kg. The optimal time of investigation after single administration in these studies was 48 hrs after treatment for all 3 species. A nearly linear dose-response relationship with a low quadratic component was observed. The "critical dose" for all 3 species was 12.5 mg 6-MP/kg. However, mice generally demonstrated the highest sensitivity to the "clastogenic" effect of 6-MP. In agreement with results of acute toxicity studies, Chinese hamsters generally were less (and rats least) sensitive than the mouse to chromosomal damage induced by higher doses of 6-MP. After repeated treatment with low doses, the chromosome-damaging effect of 6-MP was less pronounced than after one single administration of a large dose equaling the total amount of substance applied in chronic treatment.

[Significance of interdisciplinary cooperation in surgical therapy of noninvasive breast carcinoma]. / Bedeutung der interdisziplinären Zusammenarbeit bei der chirurgischen Therapie nichtinvasiver Mammakarzinome.

Non-invasive mammary carcinoma can be surgically treated with preservation of the breast even without adjuvant radiotherapy, if all necessary conditions are provided, such as accurate indication, absence of multicentricity, no involvement of mamillae except of Paget's disease, tumour diameter not more than 20 mm as well as efficient and systematic performance of intraoperative diagnostic histology. An analysis of the author's own surgical findings revealed multicentricity in 16% of all cases of intraductal carcinoma. Breast-preserving operations could be performed on 63% of the patients. Local recurrences were recorded from 13% of all cases reviewed. The rate of breast-preserving operations with lowest possible rate of recurrence, by all accounts of experience, can be enhanced only by close interdisciplinary cooperation among radiologists, surgeons, and pathologists.

The incidence of spontaneous tumors of the central nervous system of Wistar rats.

The brains of 396 old albino rats of the breed Wistar-AF/Han-EMD were examined for spontaneous tumors of the CNS and the following tumors were diagnosed: 1 oligodendroglioma, 1 astrocytoma, 1 mixed glioma, 1 pleomorphic glioma, and 19 meningiomas. Thus the CNS tumor rate was 5.8%. In addition 6 micromeningiomas were found. Knowledge of the spontaneous tumor rate including the tumor incidence in the CNS of the animal strains used for these examinations is a necessary condition for the evaluation of the results of cancerogenicity tests. CNS tumors deserve particular attention because during recent years it was found that certain chemical compounds like for instance N-methyl-N-nitrosourea induce organ-specific tumors in the brain of rats. It is recommended, therefore, to always include the central nervous system in the autopsy and histologic examination of animals from cancerogenicity trials. For cerebral autopsy transversal sections through the different cerebral regions and histologic examination of transversal section surfaces of all tumors and suspected tumor areas are suggested.

[Lumpectomy with axillary lymph node excision and subsequent irradiation of the small breast cancer]. / Die Lumpektomie mit axillärer Lymphonodektomie und Nachbestrahlung beim kleinen Mammakarzinom.

The technique of lumpectomy with axillary lymphonodectomy and postoperative irradiation is discussed in this paper and is compared to quadrantectomy or bilaterally restricted subcutaneous mastectomy in cases of small-size mammary carcinoma. A critical appraisal is made of the authors' own concept of indication, with reference being also made to the problem of the non-invasive form.

[Possibilities and limits of diagnostic frozen section in breast carcinoma]. / Möglichkeiten und Grenzen der Schnellschnittdiagnostik beim Mammakarzinom.

A short overview is given demonstrating the possibilities and limits of the frozen section technique in mammary carcinoma. The accuracy of this method in diagnostic pathology of the mammary gland is up to 97% when applied by experienced pathologists. In case of breast cancer it may be difficult to determine the maximum of tumor size and the minimum tumor-free distance to the resection margin which are significant for a breast-conserving operation. There are further limits when an atypical ductal hyperplasia (ADH) should be differentiated from a ductal carcinoma in situ (DCIS) and when in case of DCIS microinvasion is to be proven. Nevertheless, intraoperative frozen section technique is unrenunciable for breast cancer surgery. Mistakes can be avoided in most of the cases, if surgeon and pathologist will closely cooperate and if both are fully aware of the limitations of the method.

Toxicological study on pramiverine (author's transl). / Toxikologische Prüfung von Pramiverin

4,4-Diphenyl-N-isopropyl-cyclohexylamine-hydrochloride (pramiverine, Sistalgin) was investigated alone and in combination (1 + 1000) with N-methyl-N-(2,3-dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl)-aminomethanesulfonate (metamizole) in various species for acute toxicity after oral and intravenous administration, for local tolerance and subacute toxicity. In addition, long-term trials and reproduction toxicity studies were performed with pramiverine. Pramiverine was only slightly toxic and was well tolerated locally as an ampoule solution also in combination with metamizole. The acute trials of the two compounds in mice and rats like the subacute study in rats showed that the toxicity of metamizole was not increased by pramiverine. Rats tolerated in the long-term trial all pramiverine doses examined (0.5; 5.0; 50.0 mg/kg), while cholinolytic concomitant effects were observed in dogs under higher doses (5.0 and 20.0 mg/kg). Pramiverine did not have a foetotoxic and teratogenic effect in mice, rats and rabbits. In the perinatal and postnatal experiment in rats no effect on foetal development, viability and growth of the offspring as well as the course of labour and lactation ability of the dams was observed.

[Combination of mammography with automated ultrasound (Sono-X) in routine diagnosis?]. / Kombination der Mammographie mit einer automatisierten Sonographie (Sono-X) in der Routinediagnostik?

A new technique for breast imaging is presented. This technique combines radiographic mammography directly with automated ultrasound. The combined examination, which is performed without decompression of the breast, yields the conventional mammography films as well as a complete set of B-mode scans and ultrasound projections. These can be geometrically matched with each other in a definitive manner. A prototype of the device was first used in a pilot study of 50 patients followed by a study of an additional 450 patients with a total of 492 breast lesions, of which 269 were confirmed by histology or cytology. The results show that X-ray and ultrasound are complementary in the detection of cancer. The use of an experimental mode of image interpretation for combined mammography and automated ultrasound reduced the number of mammographically suspicious findings that ultimately turned out to be benign. These results were also confirmed in two blind studies including a total of 160 histologically or cytologically confirmed lesions and 40 cases without lesions. With further technical advancement of the technique aimed at rapid and easy application and confirmation of the results obtained so far, the combination of mammography and automated ultrasound might be introduced into a routine clinical setting.

Chromosome analysis of bone marrow in mammals after treatment with isoniazid.

Cytogenetic investigations in bone marrow from animals treated with isoniazid (INH) were performed in seven different laboratories according to a standard protocol. The experiments were carried out in the Chinese hamster, the mouse, and the rat. In short-term studies INH was administered twice at an interval of 24 h in doses of 5, 25, and 125 mg/kg, and the animals were sacrificed 6, 12, 24, and 48 h after the second dose. In long-term studies doses of 25 and 125 mg/kg were administered thrice weekly for 12 weeks. As a rule, each group consisted of at least four animals, and 100 metaphases per animal were counted. Statistical analysis of the data showed that the incidence of chromosomal aberrations including gaps lay in the critical range for two groups in one laboratory and was significantly higher than in the control in three groups in another of the seven laboratories. From the results of both the short-term and the long-term studies in all laboratories, however, it may be concluded, that isoniazid does not induce gross chromosomal aberrations.