Survey on ART and IUI: legislation, regulation, funding, and registries in European countries-an update.

STUDY QUESTION: How are ART and IUI regulated, funded, and registered in European countries, and how has the situation changed since 2018? SUMMARY ANSWER: Of the 43 countries performing ART and IUI in Europe, and participating in the survey, specific legislation exists in only 39 countries, public funding varies across and sometimes within countries (and is lacking or minimal in four countries), and national registries are in place in 33 countries; only a small number of changes were identified, most of them in the direction of improving accessibility, through increased public financial support and/or opening access to additional subgroups. WHAT IS KNOWN ALREADY: The annual reports of the European IVF-Monitoring Consortium (EIM) clearly show the existence of different approaches across Europe regarding accessibility to and efficacy of ART and IUI treatments. In a previous survey, some coherent information was gathered about how those techniques were regulated, funded, and registered in European countries, showing that diversity is the paradigm in this medical field. STUDY DESIGN, SIZE, DURATION: A survey was designed using the SurveyMonkey tool consisting of 90 questions covering several domains (legal, funding, and registry) and considering specific details on the situation of third-party donations. New questions widened the scope of the previous survey. Answers refer to the situation of countries on 31 December 2022. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: All members of the EIM were invited to participate. The received answers were checked and initial responders were asked to address unclear answers and to provide any additional information considered relevant. Tables resulting from the consolidated data were then sent to members of the Committee of National Representatives of ESHRE, requesting a second check. Conflicting information was clarified by direct contact. MAIN RESULTS AND THE ROLE OF CHANCE: Information was received from 43 out of the 45 European countries where ART and IUI are performed. There were 39 countries with specific legislation on ART, and artificial insemination was considered an ART technique in 33 of them. Accessibility is limited to infertile couples only in 8 of the 43 countries. In 5 countries, ART and IUI are permitted also for treatments of single women and all same sex couples, while a total of 33 offer treatment to single women and 19 offer treatment to female couples. Use of donated sperm is allowed in all except 2 countries, oocyte donation is allowed in 38, simultaneous donation of sperm and oocyte is allowed in 32, and embryo donation is allowed in 29 countries. Preimplantation genetic testing (PGT)-M/SR (for monogenetic disorders, structural rearrangements) is not allowed in 3 countries and PGT-A (for aneuploidy) is not allowed in 10; surrogacy is accepted in 15 countries. Except for marital/sexual situation, female age is the most frequently reported limiting criterion for legal access to ART: minimal age is usually set at 18 years and the maximum ranges from 42 to 54 with some countries not using numeric definition. Male maximum age is set in very few countries. Where third-party donors are permitted, age is frequently a limiting criterion (male maximum age ranging from 35 to 50; female maximum age from 30 to 37). Other legal restrictions in third-party donation are the number of children born from the same donor (or, in some countries, the number of families with children from the same donor) and, in 12 countries, there is a maximum number of oocyte donations. How countries deal with the anonymity is diverse: strict anonymity, anonymity just for the recipients (not for children when reaching legal adulthood age), a mixed system (anonymous and non-anonymous donations), and strict non-anonymity. Inquiring about donors' genetic screening showed that most countries have enforced either mandatory or scientific recommendations that exclude the most prevalent genetic diseases, although, again, diversity is evident. Reimbursement/compensation systems exist in more than 30 European countries, with around 10 describing clearly defined maximum amounts considered acceptable. Public funding systems are extremely variable. One country provides no financial assistance to ART/IUI patients and three offer only minimal support. Limits to the provision of funding are defined in the others i.e. age (female maximum age is the most used), existence of previous children, BMI, maximum number of treatments publicly supported, and techniques not entitled for funding. In a few countries reimbursement is linked to a clinical policy. The definitions of the type of expenses covered within an IVF/ICSI cycle, up to which limit, and the proportion of out-of-pocket costs for patients are also extremely dissimilar. National registries of ART are in place in 33 out of the 43 countries contributing to the survey and a registry of donors exists in 19 of them. When comparing with the results of the previous survey, the main changes are: (i) an extension of the beneficiaries of ART techniques (and IUI), evident in nine countries; (ii) public financial support exists now in Albania and Armenia; (iii) in Luxembourg, the only ART centre expanded its on-site activities; (iv) donor-conceived children are entitled to know the donor identity in six countries more than in 2018; and (v) four more countries have set a maximum number of oocyte donations. LIMITATIONS, REASONS FOR CAUTION: Although the responses were provided by well-informed and committed individuals and submitted to double checking, no formal validation by official bodies was in place. Therefore, possible inaccuracies cannot be excluded. The results presented are a cross-section in time, and ART and IUI frameworks within European countries undergo continuous modification. Finally, some domains of ART activity were deliberately left out of the scope of this survey. WIDER IMPLICATIONS OF THE FINDINGS: Our results offer a detailed updated view of the ART and IUI situation in European countries. It provides extensive answers to many relevant questions related to ART usage at the national level and could be used by institutions and policymakers at both national and European levels. STUDY FUNDING/COMPETING INTEREST(S): The study has no external funding, and all costs were covered by ESHRE. There were no competing interests.

Assisted reproduction trends in Czech Republic National Assisted Reproduction Register 2007-2017.

OBJECTIVE: Find trends in assisted reproduction (AR) in Czech Republic (CR) in years 2007-2017. DESIGN: Retrospective national epidemiologic study. SETTINGS: Department of Obstetric and Gynaecology, 1st Faculty of Medicine, Charles University and Genereal University Hospital, Prague. METHODS: Data analysis of Czech Republic National Assisted Reproduction Register (NRAR) in years 2007-2017. RESULTS: Analyses of NRAR show mild, but permanent growth of AR cycles in CR (42 773 in 2017), as well as the nubmer of AR centers (43 in 2017). Important part of AR in CR are Egg Donation cycles (5003 in 2017) and Oocyte Receipt cycles (6057 in 2017). Fertilisation by ICSI is permanently growing (96% cycles in 2017). CR succeeded in decreasing in the number of transferred embryos (average1, 18 embryo in 2017 for women up to 35 years) with the aim to prevent multiple pregnancies. AR efficacy can be evaluated by several indicators, and the age is the main parameter - since 32 years the fertility of women is diminishing. CONCLUSION: Czech national assisted reproduction register provides detailed information about AR treatment and enables qualified decisions for Ministry of Health, health insurances, treatment doctors and patients.

[Mutations in genes affecting fertility of men - current routine laboratory genetic diagnostics and searching for more DNA segments and genes influencing spermatogenesis]. / Mutace v genech ovlivnujících plodnost muzu - soucasná rutinní laboratorní genetická diagnostika a hledání dalsích úseku DNA a genu, ovlivnujících spermatogenezi.

OBJECTIVE: To present the results of molecular genetics analysis in men with reproductive disorders focusing on the DNA segments and genes which affect spermatogenesis. DESIGN: Original article. SETTING: Institute of Biology and Medical Genetics of the First Faculty of Medicine and General Teaching Hospital, Prague. METHODS: One hundred and twenty-three patients identified with a fertility disorder were screened for mutations of the CFTR gene. In all patients were performed cytogenic analysis and assessment of Y-chromosome microdeletions. In 107 patients where the fertility was not detected by routine examination we performed an analysis for X-chromosome microdeletions (CNV64, CNV67, CNV69) and in certain genes necessary for normal spermatogenesis (AGFG1, CAPZA3, CNTROB, HOOK1, GOPC, SPATA16). RESULTS: Our results did not reveal any negative efffects of X-chromosome microdeletion on spermatogenesis. Analysis of six genes showed in two patients in gene SPATA16 a homozygotic haplotype [1526C>T + 1577T>C] which can be most probably responsible for the fertility in two examined patients. CONCLUSION: According to our results we do not recommend introduction of X-chromosome microdeletions assays in areas CNV64 , CNV67 and CNV69 into routine diagnostic. Regarding the selected genes affecting spermatogenesis, our results showed that homozygotic haplotype [ 1526C>T + 1577T>C] in SPATA16 gene is very likely responsible for infertility in two of our patients. The above mentioned haplotype deserves attention in the investigation of male infertility.

[Current issues of reproductive medicine in the Czech Republic]. / Soucasná témata reprodukcní medicíny v Ceské republice.

INTRODUCTION: During the 25th symposium of assisted reproduction in Brno was lunch time organised as the lunch table discussion on the selected topics of assisted reproduction. More than 150 specialists reviewed themes related to gynecology and embryology.Discussed topics: Lunch table discussion covered the following topics: (1) Cross-border health care in assisted reproduction; (2) Indication for PGS (preimplantation genetic screening) in the context of actual information; (3) Does ovarian stimulation belong to the ambulance of registering gynecologists? (4) Therapy with clomifen - only for IVF specialists? (5) How and with whom should psychological support be directed during IVF? (6) Stimulation in women with low ovarian reserve; (7) Is basic semen analyses sufficient? (8) Time-lapse systems as relevant markers of embryonic development; (9) How to be oriented with choices of media and consumables in the IVF lab, and (10) "Freeze All" - is this new trend in cryopreservation suitable for all? CONCLUSIONS: Panel conclusions were presented during the afternoon session, which had great attendance, featured lively commentary, and produced some definitive consensus. Certain issues remained inconclusive, and these matters will be the subject of further discussion in the future. Specific summation of all deductions is presented in this paper.

[Current issues of assisted reproduction in the Czech Republic]. / Aktuální otázky asistované reprodukce v Ceské republice.

INTRODUCTION: Participants of the lunch table discussion held during the 22nd symposium of assisted reproduction in Brno discussed some current topics of assisted reproduction. DISCUSSED TOPICS: More than 150 participants at round tables discussed 10 topics: 1. IVF in native AR cycle,2. observation of the embryo development dynamics, 3. evaluation and support of endometrial receptivity,4. increased number of elective single embryo transfers (eSET), 5. transport of gametes and embryos in the Czech Republic and between the Czech Republic and abroad, 6. National registry of assisted reproduction,7. new view on sperm pathology, 8. problems with the SAR membership records, 9. surogacy motherhood and 10. preimplantation genetic diagnosis and preimplantation genetic screening. CONCLUSIONS: All findings were presented in the afternoon session. Some of the topics brought concrete results. Some topics could not be clearly concluded and will be the subject of further discussions. A brief summary of those discussion conclusions presents this paper.

[In vitro fertilization - analysis of data in Czech National Assisted Reproduction Register from years 2007-2011]. / In vitro fertilizace - rozbor údaju Národního registru asistované reprodukce za roky 2007-2011.

OBJECTIVE: Analysis of IVF cycles (excluding donor oocytes programs) in Czech National Assisted Reproduction Register (NRAR). DESIGN: Retrospective study. METHODS: We analyzed NRAR data from 1. 1. 2007 to 31. 12. 2011 (107 529 cycles) concerning IVF cycles, according standards of European IVF monitoring - European Society of Human Reproduction and Embryology (EIM ESHRE). RESULTS: Yearly in Czech Republic there is 10 000-14 000 initiated IVF cycles. In agreement with common experience, IVF results differ depending the age of woman. The completeness of data in NRAR decreases significantly during the cycle course; data concerning the delivery after the cycle are missing in more than 50% of cycles in some years. So, parameters of cycle effectiveness are not possible to evaluate yet. CONCLUSION: Number of IVF centers in Czech Republic is still growing. Number of IVF cycles (and similarly frozen embryo transfer cycles) in Czech Republic is in general yearly very similar. In the subgroup of the age under 34, the number of cycles slightly diminishes, in the age group 34-40 increases. Number of cycles in Oocyte donation cycles and in Oocyte reception cycles is increasing. The effectiveness of IVF treatments is not possible to evaluate due to an important part of cycles with missing data concerning pregnancies and deliveries. It is necessary to stimulate centers to send missing data, but also to create the interconnection with the Deliveries register and the Abortions register, to reach data in cases, where it is really difficult to reach them by centers.

[Extended embryo culture in IVF does not improve pregnancy rate]. / Prodlouzená kultivace embryí pri IVF nezvysuje nadeji na otehotnení.

OBJECTIVE: Compare the effectiveness of the IVF extended embryo culture day 4 versus day 2. DESIGN: Retrospective analysis. SETTING: Assisted Reproduction centre Apolinar, Department of Obstetrics and Gynecology, 1st Faculty of Medicine, Charles University and General Faculty Hospital in Prague. METHODS: We compared pregnancy rate (PR) and implantation rate (IR) of all IVF and IVF/ICSI embryo transfers (ET) performed between August 2004 and July 2008, in which 2 embryos were transfered. All transfers were done by the same physician. Maternal age was < or = 35 years (from 22 to 35 years, mean 30.4 years, median 31.1 years). The group of embryos evaluated and transfered on the day 2 was compared with the embryos evaluated and transfered on the day 4. Based on the evaluation, each embryo was assigned to one of the following categories: Grade A (top quality embryo) or grade B (medium quality embryo). RESULTS: On the day 2, ET of A+A embryos led to PR 69.0%; A+B 53.3% and B+B 36.4% (IR 50.0%, 40.0% and 22.7%), where number of transfers was 42, 30 and 11 in every group. On the day 4, ET of A+A embryos led to PR 54.3%, A+B 48.7%, B+B 26.6% (IR 45.6%, 34.6%, 13.3%), where number of transfers was 46.39 and 15 in every group. CONCLUSION: In our group, we found no statistical significant difference (p < 0.05) in PR between day 2 and day 4 embryotransfers. Results of the day 2 transfers have a trend to be better than results of day 4 transfers. Regardless of the transfer day, the prognosis of grade A embryos was significantly better (p < 0.05) than for grade B embryos.

[A relation between the polycystic ovary syndrome and the status of ovarian hyperstimulation syndrome in IVF patients after controlled hyperstimulation]. / Do jaké míry je rozvoj ovariálního hyperstimulacního syndromu v prímé souvislosti se syndromem polycystických ovarií u IVF pacientek podstupujících rízenou hyperstimulaci ovarií?

OBJECTIVE: Ovarian Hyperstimulation Syndrome (OHSS) is a severe health complication observed in some patients undergoing hormonal stimulation during IVF. Some authors present that OHSS is associated with Polycystic Ovary (PCO) and with a high count of growing follicles (more than 18) responding to FSH hyperstimulation, although none of them is sufficient to predict the onset of OHSS. The aim of this study is to analyze the association between PCOS and OHSS the Inhibin B-based TFF/SBM index. DESIGN: Retrospective analysis. SETTING: Assisted Reproduction Center, Department of Obstetrics and Gynecology, 1st Faculty of Medicine, Charles University and General Faculty Hospital in Prague, Sigma-Aldrich, Prague, Immunotech, a.s., Prague. METHODS: Serum and follicular fluid of 36 women (high responders with more than 18 growing follicles) in IVF program were collected at the day of oocyte pick up and used for analysis of Inhibin B. Age: mean 30.2 years (24-35 years, median 31.0 years), BMI: mean 22.34 (18.3-29.7, median 21.6). For every patient, the TFF/SBM index was calculated as follows: [concentration in FF] x [growing follicle count]/ [concentration in serum] x [body mass]. A distribution of the following parameters were compared: OHSS status, TFF/SBM index based on Inhibin B, growing follicle count and the incidence of PCOS. RESULTS: Values of the TFF/SBM index showed an association with the severe form of OHSS but not with the incidence of PCOS. CONCLUSION: These observations suggested that the incidence of PCOS is not associated with the development of severe form of OHSS, but may be still associated with a high count of growing follicles.

[Follicular fluid and serum concentrations of PAPP-A in OHSS risk group of women undergoing IVF stimulation]. / Hladiny PAPP-A ve folikulární tekutine a krvi pacientek stimulovaných k IVF s hrozícím ovariálním hyperstimulacním syndromem.

OBJECTIVE: Ovarian Hyperstimulation Syndrome (OHSS) is a serious complication of In Vitro Fertilisation (IVF) treatment. It is estimated that 3-5% of treated women suffer of severe form of OHSS. OHSS pathogenesis remains unknown and its treatment is only symptomatic. It is difficult to predict the risk of OHSS of an individual woman, since a current criterion--the number of punctured follicles--is not very reliable. Our aim was to find, whether in patients with a high risk of OHSS (more than 18 follicles punctured for oocyte pick-up) is possible to predict the individual risk of OHSS. As a marker we tested concentrations of Pregnancy Associated Plasma Protein-A (PAPP-A) in follicular fluid (FF) and blood serum (S). STUDY DESIGN: Prospective study. SETTINGS: Assisted Reproduction Center, Clinic of Obstetrics and Gynecology, First Faculty of Medicine, Charles University in Prague and General Teaching Hospital in Prague. METHODOLOGY: Follicular fluid and serum of 118 female patients undergoing IVF treatment was collected at the day of oocyte pick-up and analysed for PAPP-A concentration. The resulting data were then correlated with the OHSS status of individual patient. RESULTS: Mean concentration of PAPP-A in FF was 0.81 +/- 0.29 IU/l, while in S it reached only 0.0017 +/- 0.0003 IU/l. Patients with subsequent OHSS grade 1, 2 and 3 reached FF levels of PAPP-A 0.81; 0.52; and 0.73 IU/l, respectively 0.0017; 0.0017 a 0.0017 IU/l in blood serum. No correlation was found between PAPP-A FF or PAPP-A serum concentrations and the degree of OHSS. No correlation was found between PAPP-A serum concentrations and the number of follicles. CONCLUSION: 1. Pathological response on hormonal stimulation leading to OHSS is not related to the concentrations of PAPP-A in either FF or in blood serum. 2. PAPP-A does not pass from follicles to blood in a significant amount.

[Ovarian hypertimulation syndrome: a review]. / Ovariální hyperstimulacní syndrom--shrnutí soucasných poznatku.

OBJECTIVE: Discuss prevalence, risk factors, pathophysiology, symptoms, complications and therapy of OHSS. DESIGN: A review article. SETTING: Department of Obstetrics and Gynaecology, 1st Faculty of Medicine and General faculty Hospital, Charles University, Prague. SUBJECT AND METHODS: A review from literature and bibliographic databases. RESULTS: OHSS is an iatrogenic complication of ovarian stimulation. We still can not completely explain the pathophysiology of OHSS. The therapy is based on symptomatic approach. To prevent OHSS, the hCG should not be given to induct the ovulation, or we should not transfer embryos during the IVF-stimulated cycle.

[Assisted reproduction in patients with food intake disorders--clinical and ethical aspects]. / Asistovaná reprodukce u pacientek s poruchou príjmu potravy--klinické a etické aspekty.

Fertilization treatment is established therapy of infertility in the cases, where other approaches have failed or were impossible. In eating disorders, majority of fertility problems has been secondary and so fully reversible if appropriately treated. Fertilization treatment should not be used in patients refusing the psychological treatment of the illness. In patients in active phase of the illness fertility treatment at fertility are contra-indicated. Two cases of negative impact of fertility treatment in patients with anorexia nervosa are presented.

[Single embryo transfer does not compromise the pregnancy rate in patients with good IVF/ICSI prognosis]. / Transfer jednoho embrya u pacientek s dobrou prognózou lécby pomocí IVF/ICSI nesnizuje pravdépodobnost otehotnení.

OBJECTIVE: Twin pregnancy is perceived as a suboptimal result of an IVF/ICSI cycle. The most effective way to reduce the number of twins in IVF/ICSI program is a single embryo transfer. The aim of our study was to compare the efficiency of elective single embryo transfer (eSET) and double embryo transfer (DET) in the couples with a very good prognosis of IVF/ICSI. DESIGN: Prospective case observational study. SETTINGS: Department of Obstetrics and Gynecology, Charles University, 1nd Medical Faculty and General Teaching Hospital, Prague, Czech republic. METHODS: A prospective study focused on eSET was performed between 1. 1. 2003 and 31. 12. 2004. We offered eSET or eDET to 331 IVF/ICSI couples who met the following inclusion criteria: age of the women < 35 years, 3 and more top quality embryos on day 4 after oocyte pick up. Fifty seven (17.2%) couples have chosen eSET and 274 (82.7%) couples preferred eDET. We compared clinical pregnancy rates in two groups of patients: In a group of patients who have chosen eSET versus patients who have preferred double embryo transfer (eDET). Student's t-test and F test were used to compare both groups. RESULTS: Patients in both groups were not significantly different in age, number of oocytes retrieved and total number of quality embryos. In the eSET group, we achieved 30 clinical pregnancies and the pregnancy rate (PR) was 52.6%. In the eDET group, 151 clinical pregnancies were observed and the PR was 55.1%. Although the pregnancy rate in the eDET group was higher than in the eSET group, the difference between the two groups was not statistically significant. We have not observed any twin pregnancy (0.0%) in the eSET group while 57 (37.7%) twin pregnancies and 1 pregnancy with 3 embryos (0.4%) have been observed in the eDETgroup. This difference is statistically significant (P < 0.00001). CONCLUSION: In the group with a very good IVF/ICSI prognosis (women < 35 years, 3 and more top quality embryos on day 4 after oocyte pick up), eSET did not significantly decrease the chance to achieve clinical pregnancy in comparison with DET. eSET seems to be a very efficient option to reduce the rate of twin pregnancy without compromising the pregnancy rate and should be recommended to these patients.

[Delivery of a healthy child from pregnancy after IVF complicated hyperstimulation syndrome, phlebothrombosis and resection of uterine horn. Case report]. / Porod zdravého plodu v gravidite po IVF komplikované hyperstimulacním syndromem, flebotrombózou a resekcí rohu delozního. Kazuistika.

OBJECTIVE: To evaluate the negative effect of uterine horn resection for heterotopic pregnancy in the uterine horn in the first trimester on the course of pregnancy and labor. To point out the increased incidence of other complications in pregnancy after IVF+ET (ovarian hyperstimulation syndrome, phlebothrombosis of the pelvic veins). DESIGN: Case study. SETTING: Department of Obstetrics and Gynecology, 1st Faculty of Medicine, Charles University and General Faculty Hospital, Prague. METHODS: In this study, the authors analyze their experience with the course of pregnancy of a patient who had uterine horn resection for a heterotopic uterine horn pregnancy after IVF+ET. The course of pregnancy was associated with further complications such as ovarian hyperstimulation syndrome and the resulting occurence of thrombosis in the 2nd trimester of pregnancy. The pregnancy was terminated by caesarean section for the indication of prior uterine surgery-resection of the uterine horn in the first trimester. A healthy infant was delivered. CONCLUSION: This case study demonstrates the multiple occurrence of serious complications in pregnancy after IVF+ET, which are associated with ovarian hyperstimulation and the transfer of multiple embryos. The pregnancy was terminated with the delivery of a healthy term infant.

Nidation inhibition by simple ergoline derivatives.

The ability of four ergoline-type compounds (elymoclavine, its O-benzoate and O-carbamate, and N-methyl-6,7-secoelymoclavine) to inhibit nidation in rats was determined and found to parallel their prolactin-inhibiting activity.

Absence of noxious effects of selected neuroleptics in dominant-lethal mutagenesis assay.

In a dominant-lethal assay in mice the following tricyclic neuroleptics were tested: prothiaden, imipramine, oxyprothepin decanoate and docloxythepin. No dominant-lethal effect was induced by these neuroleptics, even when administered at doses many times as great as clinical doses. The reduced percentages of pregnancies, in females who had copulated with males receiving docloxythepin, observed during and immediately after its administration, were directly connected with marked sedation induced in the males by this neuroleptic.

Reductive effect of lonazolac on lung metastasis formation in mice.

The purpose of this study was to determine the antimetastatic potential of lonazolac. Intravenous inoculation of Lewis lung carcinoma (LLC) or melanoma B-16 (B-16) cells induced macroscopically detectable lung metastases on day 15 after inoculation. After pre- and post-treatment with lonazolac-Ca at oral doses of 1, 25, and 50 mg/kg, the numbers of animals with lung metastases and the score of metastases significantly decreased. Lonazolac-Ca had similar effects also on the formation of spontaneous lung metastases. After treatment with lonazolac-Ca at oral daily doses of 1, 25, and 50 mg/kg during 8 days (LLC) or 10 days (B-16) after inoculation of the tumor cells, the number of animals developing spontaneous lung metastases and the score of metastases also decreased. Intravenous injection of lonazolac natrium was effective in protecting the mice inoculated with 1 X 10(6) melanoma B-16 cells against acute pulmonary embolic death.

Hindering of tumor lung metastasizing with alpha-(4-cyclohexylphenyl)propionic acid in mice.

Alpha-(4-cyclohexylphenyl)propionic acid, a potent inhibitor of platelet aggregation, has appeared to reduce the quantity and size of Lewis lung carcinoma (LLC) tumor nodules in the lungs. The number of animals developing the tumor colonies in the lungs was decreased by 34% to 49% either when the tumor cells were injected i.v. and alpha-(4-cyclohexylphenyl)propionic acid was administered during 3 days, or when the tumor cells were transplanted i.m. The primary tumor was removed 6 days later and the drug administered during 8 or 21 days.

Antimetastatic effect of flurbiprofen and other platelet aggregation inhibitors.

In the present study, we have examined the antimetastatic effect of flurbiprofen, a nonsteroidal antiinflammatory drug, on spontaneous metastases formation in mice bearing Lewis lung carcinoma and these results were compared with effects of other inhibitors of platelet function (mopidamole, dipyridamole, pentoxifylline). Flurbiprofen decreased significantly spontaneous metastases formation in a dose-depending manner. From the results obtained, it appears that the treatment with flurbiprofen, either on days 1-8 or days 1-21, was similarly effective. In mopidamole treated groups the number of animals with lung metastases was significantly decreased. This effect was not observed after treatment with dipyridamole or pentoxifylline.

Biochemistry of drugs. XXIV. Substances with antineoplastic effect. LXII. Pharmacokinetics of gamma,gamma-bis-4-ethylphenyl-alpha,beta-dibromoisocrotonic acid-3H (Edikron-3H) in experimental animals.

After oral administration of Edikron-3H to mice with mammary gland adenocarcinoma HK, within 24 h after ingestion almost 50% of administered radioactivity was excreted (16% in urine, 33% in faeces), and within 4 day it was almost 80% (27% in urine, 50% in faeces). Like in mice, also in dogs the faecal excretion preponderated. In mice, the levels in most tissues and blood culminated at hour 6 after administration of the substance. Relatively high levels were found in the liver, the levels in other tissues and blood being substantially lower in comparison. The levels in the tumor were initially low, later on they rose, and culminated at hour 24. Besides, it was found that the transfer of radioactivity by milk into the sucklings' bodies was relatively low, and radioactivity penetration into fetuses was negligible. In urine, unchanged parent substance was present in very slight amounts only.

Derivatives of benzo(c)fluorene. XVI. Absorption, distribution and elimination of 3H-benflurone, 5-(2-N,N-dimethylamino)ethoxy)-7-oxo-7H-benzo(c)fluorene hydrochloride in rats after oral and intravenous administration.

3H-benfluorone administered orally to rats, persists for a long time in the stomach; it is absorbed only partly and eliminated mostly through the feces (about 80% within 7 days). The maximum levels in the blood and the organs were determined in the 1st and 9th hour after application. Benflurone penetrates through the placentary barrier. Within one week 13% of the administered radioactivity was eliminated through the urine and 8% through the bile within 12 h. It has been demonstrated that benflurone was excreted through the milk, as well. After being administered intravenously, benflurone moves quickly from the blood into the tissues. The high levels were recorded in the heart, the lungs, the kidneys, the brain and the liver. After intravenous application about 70% of the administered radioactivity was eliminated within one week through the feces and about 24% through the urine, almost 54% through the bile within 12 h.