Impact of the COVID-19 outbreak on the reporting of adverse drug reactions associated with self-medication.

OBJECTIVES: The primary objective of the present study was to describe the characteristics of adverse drug reactions (ADRs) linked to self-medication that were notified to the French Pharmacovigilance Database (FPVD) during the COVID-19 outbreak in 2020 first wave. The secondary objective was to compare the characteristics of these ADRs in 2020 with those notified during the same calendar period a year previously. MATERIAL AND METHODS: We analyzed ADRs recorded in the FPVD between March 15th and May 31st, 2020 vs. the same dates in 2019. Only ADRs linked to self-medication were analyzed. Descriptive statistics were used to obtain an overview of the types and characteristics of these ADRs. RESULTS: Of 3114 ADRs notified to the FPVD during the COVID-19 period in 2020, 114 (3.7%) were linked to self-medication. The equivalent proportion in 2019 was 1.6% (113 out of 7097). Half of the ADRs notified in 2020 were "serious". The median age of affected patients was 30.5, and 22% of the ADRs concerned children. Of the 114 ADRs linked to self-medication, 107 (66%) were for prescription-only drugs. The three mostly frequently suspected ATC classes were analgesics, psycholeptics, and antibacterials for systemic use. The most frequent ADRs were general disorders, gastrointestinal disorders, and nervous system disorders. The main difference between the non-COVID-19 period and the COVID-19 period was the higher proportion of medication errors during the latter. CONCLUSION: The present study is the first to have reported on ADRs linked to self-medication and notified during a COVID-19 outbreak. Further studies of self-medication patterns and their consequences in a pandemic context are mandatory and effective information on medication use (including self-medication and its dangers) during a pandemic is essential.

Assessment of the effect of grape seed cake inclusion in the diet of healthy fattening-finishing pigs.

Modulatory capacity of bioactive compounds from different wastes has been scarcely investigated in pigs. This study aimed to evaluate the effects of dietary inclusion of grape seed cakes (GS diet) on performance and plasma biochemistry parameters as health indicators, as well as on several markers related to inflammation and antioxidant defence in the liver of fattening-finishing pigs. Twelve cross-bred pigs (TOPIG) were randomly assigned to one of two experimental diets: control and 5% grape seed cake diet during finishing period (24 days). No effect of GS diet on pig performance and blood biochemistry was observed. However, GS diet decreased significantly (-9.05%, p < .05) the cholesterol concentration (85.71 ± 0.94 mg/dl vs 94.24 ± 2.16 mg/dl) and increased IgA level (+49.90%, p < .05) in plasma (5.04 ± 0.5 mg/ml vs 3.36 ± 0.7 mg/ml). GS cakes decreased the inflammatory response in the liver of pigs fed with GS diet by lowering the Gene expression and protein concentration of pro-inflammatory cytokines (IL-1ß, IL-8, TNF-α and IFN-γ) as well as the mRNA abundances of NF-κB signalling molecules. The antioxidant status was not increased by GS diet. The gene expression and activity of catalase decreased significantly. The gene expression of Nrf2, superoxide dismutase, glutathione peroxidase and heat-shock protein decreased, and no effect on their activity was observed with the exception of catalase activity which decreased. However, TBARS was reduced significantly. GS diet showed a modulatory effect on antioxidative status as well as anti-inflammatory and hypocholesterolic properties without effect on pig performance.

Repair of the dorsal capsuloligamentous scapholunate septum during arthroscopic resection of painful dorsal wrist ganglion cyst: Comparative analysis of two techniques.

We compared arthroscopic cyst resection (ACR) of dorsal ganglia of the wrist, either associated to reconstruction of the dorsal capsuloligamentous scapholunate septum (ACR-DCSS) in 66 cases in which the ganglia were painful on exertion, or isolated ACR in 15 pain-free cases. A single-center retrospective study analyzed data for the period April 2013 to May 2021. The main aim was to compare pre- and post-operative functional results (pain at rest (on a numerical rating scale: NRS), pain under effort (NRS), range of motion (°), grip strength (kg)) and recurrence rate between the two techniques. The study hypothesis was that DCSS repair improves recurrence of dorsal ganglion cyst and functional outcome. The ACR-DCSS group showed significant improvement in extension, pronation, supination, radial inclination, ulnar inclination, grip strength, pain at rest and pain on exertion. The ACR group showed significant improvement in pronation, ulnar inclination and pain on exertion. There was a significant difference in recurrence rate, in favor of ACR-DCSS. Recovery was also significantly better for the ACR-DCSS group in terms of extension, supination and pain at rest. Arthroscopic treatment of wrist ganglion cyst is a reliable, minimally invasive and reproducible technique that produces good results in terms of pain and recovery of range of motion, with significantly lower recurrence rate in case of DCSS repair. Level of evidence: Therapeutic III.

The pedestrian behaviour of Spanish adolescents.

Adolescent pedestrians are a particularly vulnerable group of road users. This research tested the applicability of the recently developed Adolescent Road user Behaviour Questionnaire (ARBQ) amongst a sample of 2006 Spanish adolescents. Confirmatory Factor Analysis of the full scale found that the original three factors did not adequately fit the data, but an acceptable fit was obtained for the shortened 21-item version of the scale. In line with research from the UK, the present study found that males reported more unsafe road crossing behaviour and playing on the roads, but there was no gender difference for engaging in planned protective behaviour. This research also confirmed that unsafe road crossing behaviour increased with age, while dangerous playing on the road and planned protective behaviours both decreased with age. The present study also confirmed that the ARBQ is a useful tool for investigating the safety-related behaviour of adolescents on the road.

[Telemedicine for prostate cancer during long-term radiotherapy follow-up: An opportunity for digital innovation in oncology]. / La téléconsultation pour le suivi après radiothérapie du cancer de la prostate : une place à l'innovation numérique en cancérologie.

PURPOSE: The annual follow-up in radiotherapy for prostate cancer consists of an oral interview with a radiation oncologist. The present study aimed at surveying the target population on their knowledge and perceptions of telemedicine. MATERIALS AND METHODS: A prospective study was conducted at the Lucien Neuwirth Cancer Institute (France) that included patients with prostate cancer undergoing treatment or in follow-up, during spring 2019 (n=158). A specific questionnaire was designed for the study. Patient's self-evaluation of satisfaction and enthusiasm was assessed through visual analog scale (VAS) (0/10 to 10/10). RESULTS: One hundred and fifty-eight patients completed the survey. The vast majority of the population commonly used phone for communication and 56% of patients owned internet connexion. Around 56% of patients declared telemedicine knowledge without having ever experienced telemedicine. If 60.8% of patients would not be against telemedicine with a median enthusiasm VAS of 6/10, patients' opinions were divergent: 48.7% of patients would like to keep a classical follow-up and 48.7% of patients would envision to alternate classical consultation with telemedicine. CONCLUSION: This feasibility study with an aged cohort showed that telemedicine is a valuable option for long-term radiotherapy follow-up, even if therapeutic education and information will be necessary to supervise this novel approach.

[Is muscle the best coverage for leg Gustilo IIIb fractures? A retrospective comparative study]. / Le muscle est-il la meilleure couverture pour les fractures ouvertes de jambe Gustillo IIIb ? Etude rétrospective comparative.

UNLABELLED: Well-vascularized muscle flaps have been the traditional gold standard for coverage of open fracture of the lower extremity. The last 15 years have brought the fasciocutaneous and perforator flaps and raised the issue of the type of coverage required for open fracture of the lower extremity. In recent years, in selected compromised patient, we have been using nonmuscular flaps for reconstruction. The goal of this study is to compare the results of fasciocutaneous reconstruction to those of classical muscular flaps. PATIENTS AND METHODS: A comparative retrospective study, including all patients from 2002 to 2006 requiring a coverage of a Gustillo III b fracture of the lower extremity, is done. The type of flaps, the fracture localization, the infection rate, the time required for consolidation of the fracture and the complication rate are reviewed. An independent university laboratory verified the statistical analysis. RESULTS: Twenty patients have experienced coverage by muscular flaps and 18 by fasciocutaneous flaps. We found a skin fistula and a chronic infection in the muscular-flap group, and two skin fistulae in the fasciocutaneous flaps group. The overall surgical results were comparable, except the bony union delay shorter in the fasciocutaneous flaps group. CONCLUSION: Muscle coverage is not mandatory to cover bone in the lower leg. The fasciocutaneous flaps can provide a good alternative for muscle-flap coverage. There is no significant difference as far as consolidation and infection are concerned, between the coverage by muscular or fasciocutaneous flaps.

A comparison between the effects of ochratoxin A and aristolochic acid on the inflammation and oxidative stress in the liver and kidney of weanling piglets.

Ochratoxin A (OTA) and aristolochic acid (AA) are toxins that can frequently contaminate cereals and cereals-based products. The present study has realized a comparison between the effect of OTA and AA on oxidative stress and inflammation in both the liver and kidney of pigs as major organs involved in the metabolism of xenobiotics. Fifteen pigs (five pigs/group) were randomly distributed in three groups (control, OTA, and AA) and were fed diets contaminated or not with 250 µg toxin/kg for 28 days. Consumption of a diet contaminated with OTA and AA increase the concentration of serum creatinine as compared with the control group. The exposure of piglets to AA decrease the activity of enzymes involved in the oxidative stress response: catalase (CAT), superoxide dismutase (SOD), and glutathione peroxydase (GPx) in the liver and kidney while OTA decrease only GPx activity and only in the kidney. The consumption of the diets contaminated with AA increase in the liver the synthesis of tumor necrosis factor (TNF) alpha, interferon (IFN) gamma, Interleukin (IL)-1 beta, IL-6, and IL-8 synthesis, while IL-4 was increase by OTA and decreased by AA. In the kidney, AA increase the TNF alpha and IFN gamma synthesis as compared with the control. In conclusion, our results have shown that beside the alteration of serum markers, much known indicators for nephropathy, OTA and AA can induce inflammation and oxidative stress. In conclusion, the inflammatory effects were more pronounced for AA and at the liver level, while oxidative stress was induced both in the liver and kidney.

Mobile phone use while driving in a sample of Spanish university workers.

A number of epidemiological studies have reported drivers who use a mobile phone while driving have an elevated risk of being involved in a crash. This is particularly concerning as a survey of drivers in the Spanish region of Catalunya found that approximately 87% own mobile phones. The present study investigated the reported frequency of mobile phone use on Spanish roads (for talking and using SMS), the characteristics of the drivers who use mobile phones while driving and whether they altered their driving behaviour when using a mobile phone. The research found that more than 60% use a mobile phone while driving and that the phone is mostly used for making calls, rather than using SMS. In general, males and females use mobile phones about the same reported frequency, although males were more likely to use a mobile phone to talk on the highway. The pattern for age was the same for both male and female participants, with the younger drivers using SMS more frequently than older drivers. On urban roads almost half of the drivers reported changing their driving behaviour when using a mobile phone, while on the highway this figure was slightly over 41%. The reported frequency of using a mobile phone to talk on urban roads was significantly correlated with crash involvement. However, this affect disappeared once the contributions of the demographic and descriptive variables had been partialled out.

Motivation for change and the pros and cons of smoking in a Spanish population.

Decisional balance and the stage of change have been used to understand the motivation for giving up the habit of smoking. The objective of this study was to find out whether the associations between the pros and the cons of smoking, taking into account the magnitude and delay parameters, and stages of change, can be demonstrated in a sample of Spanish smokers and ex-smokers using a cross-sectional design. The results are compared with the patterns of pros and cons of smoking found in samples of American, Swiss and Dutch smokers. The data confirms that amongst Spanish smokers it is also in the stages of contemplation and preparation that the crossover in the valuation of the pros and cons of smoking takes place: the cons hold more weight than the pros. On the other hand, unexpectedly, the pros of smoking are more highly valued in the stages of action and maintenance than in the rest of the stages.

[The metabolic syndrome: marker of cardiovascular risk in hypertensive patients? The importance of definition]. / Le Syndrome métabolique: marqueur de risque chez l'hypertendu? Importance de la définition utilisée.

INTRODUCTION: Metabolic syndrome (MetS) was defined by association of abdominal obesity, hypertension, glucose intolerance and/or dyslipidemia. The objective of this study was to compare the new International Diabetes Federation (IDF) definition and the National Cholesterol Education Program Adult Treatment Panel III (NCEP) definition and their association with cardio-vascular disease in hypertensive patients. POPULATION AND METHOD: Two hundred and thirty hypertensive patients were hospitalized successively for cardio-vascular disease exploration and hs-CRP measurement. The stratification of cardio-vascular risk was made according to the French recommendations. The IDF definition and the NCEP definition were compared according frequency of resistant hypertension and cardio-vascular disease extension. RESULTS: In our study, high cardio-vascular risk hypertension represented 68.5% of patients. Diabetes was present in 23.5% of them and obesity in 45.5%. Patients with cardio-vascular disease represented 60% of our study population. Prevalence of MetS was 38.5% according to the NCEP definition and 59% according to the IDF definition. The NCEP definition was allowed to select subjects with widespread vascular disease and resistant hypertension whereas the IDF definition did not. These results could be explained by lower waist circumference and glycaemia cuts offs according to the IDF criteria. When diabetic's patients were excluded, MetS was not associated with increase of resistant hypertension frequency. Moreover, hs-CRP was independently associated to the extension of the cardiovascular disease and smoking remained the most powerfully factor associated to the cardio-vascular disease extension. CONCLUSION: In hypertensive patients, the NCEP definition seems more adapted to the diagnosis of MetS than the IDF one. Abdominal obesity could be the indispensable element to the MetS diagnosis but according to the NCEP waist circumference cut off. The use of this syndrome seems to be relevant to select the patients presenting an intermediate cardio-vascular risk in order to adapt treatment.

Spasticity and hyperselective neurectomy in the upper limb.

Spasticity is a complex pathology, both in terms of assessment and treatment. This article focuses on the clinical examination (objective, capacity, performance and function), which is key for choosing a treatment and can be helped by botulinum toxin injections. The treatment involves physical therapy, occupational therapy, medications and surgery. Neurectomy has been used in the upper limb since 1912 and is one of the therapeutic options for spasticity. This treatment is usually reserved for nonfunctional hands. Cadaver studies have helped us better understand nerve anatomy and improve the hyperselective neurectomy (HSN) technique. This article describes the history of neurectomy, how anatomical dissections apply to surgery, the HSN technique in the musculocutaneous nerve, median nerve and ulnar nerve and results of preliminary prospective studies. Spasticity, mobility, performance and function were evaluated a few months after HSN and about 12 months later to assess the permanence of the results in children and adult spastic patients. No matter the nerve or function targeted (elbow extension, wrist extension, or supination), spasticity was reduced with improvements in the functional House score and appeared stable at the last follow-up. HSN seems to be a good, reliable therapeutic option for spasticity, including functional hands.

Quantification and kinetics of the residual brine generation during ham and shoulder pile salting.

Salting is one of the most important stages of the traditional process of cured ham manufacturing. During pile salting a saturated brine is formed and drips through the orifices located at the bottom of the salting containers. The objective of the present work was to quantify the released brine in the ham manufacturing industry in Spain and to relate the brine generation with the salt gained by hams in the process. The total released brine during ham and shoulder salting in Spain was determined theoretically and from the experimental values obtained from the industry (around 38,000 metric tons in 2002). In addition to that, an easy method for the estimation of the NaCl gained by hams and shoulders was developed by using the measurements of the released brine (the estimated NaCl gained differed 3.5% from the experimental data).

Differential effects of ellipticine and aza-analogue derivatives on cell cycle progression and survival of BALB/c 3T3 cells released from serum starvation or thymidine double block.

10-[Diethylaminopropylamino]-6-methyl-5H-pyrido[3',4':4,5] pyrrolo[2,3-g]isoquinoline (BD-40) (NSC-327471D) is an aza-ellipticine derivative with a promising antitumor activity (M. Marty, C. Jasmin, P. Pouillard, C. Gisselbrecht, G. Gouvenia, and H. Magdalainat, 17th Annual Meeting of the American Society of Clinical Oncology, C-108, 1981) and less toxicity than ellipticine. We have compared the effects of ellipticine, several of its analogues, and two aza-analogue ellipticine derivatives (BD-40 and BR-1376) on cell cycle progression of BALB/c 3T3 mouse cells under different growth conditions. Both drug series were found to stop cell growth and block cells in G2 phase in exponentially growing cultures and cultures released from a thymidine double block. Long-term viability of these cells was completely suppressed after a short exposure to the drugs. In contrast, while ellipticine and its derivatives caused identical effects in cells recovering from serum starvation, BD-40 and BR-1376 did not block cells in G2 phase and did not prevent the completion of the first division round occurring after serum addition to quiescent cells. This transient refractory state was accompanied by a total conservation of long-term viability of these cells at least for the next 6 h following serum and drug addition. This lack of effect was not related to an impaired drug uptake by cells recovering from serum starvation or by a dramatic change in drug distribution inside the cells. These results indicate that the nitrogen substitution in the ellipticine heterocycle is an important if not unique feature for the particular effect of the aza-analogues of ellipticine. Furthermore, they suggest that, in contrast to ellipticine derivatives, these compounds require an activation step before exhibiting cytotoxicity.

Neuroendocrine regulation of frog adrenocortical cells by neurotensin.

We previously characterized the primary structure of neurotensin (NT) from an extract of the intestine of the frog Rana esculenta. In this study, we provide evidence for the involvement of NT in the neurocrine regulation of the secretory activity of frog adrenocortical cells. Immunohistochemical studies revealed that the adrenal gland of R. esculenta is innervated by a dense network of NT-immunoreactive fibers. Graded concentrations of frog NT induced a dose-dependent stimulation of corticosterone and aldosterone secretion by frog adrenocortical explants through activation of two receptors with pEC(50) of 9.8 and 6.9. These data support the view that NT, released by nerve fibers within the frog adrenal gland, acts locally to control corticosteroid secretion.

An observational study of driving distractions on urban roads in Spain.

The present research investigated the prevalence of driver engagement in secondary tasks and whether there were any differences by age and gender, as well as day of the week and time of the day. Two independent researchers observed 6578 drivers at nine randomly selected urban locations in Girona, Spain. Nearly 20% of the drivers observed were engaged in some type of secondary task, with the most common being: conversing with a passenger (11.1%), smoking (3.7%) and talking on a handheld mobile phone (1.3%). Surprisingly there were no differences by gender, but there were age-related differences with younger drivers being more frequently observed engaged in a number of different types of secondary tasks while driving (i.e. drinking, talking on a handheld mobile phone, and texting or keying numbers). Logistic regression showed that younger drivers, and to a lesser extent middle-age drivers, were significantly more likely to be observed engaged in a technological distraction than older drivers. Conversely, non-technological distractions were significantly predicted by day of the week, time of the day and location. A substantial number of the drivers observed in this study were putting themselves at an increased risk of becoming involved in a crash by engaging in non-driving related tasks at the same time as driving. Furthermore, the higher crash rate among young drivers may be partially accounted for by their more frequent engagement in some types of secondary tasks while driving.

HIV prevalence, sexual risk behaviour and sexual mixing patterns among migrants in Amsterdam, The Netherlands.

OBJECTIVE: To study (1) HIV prevalence; (2) sexual risk behaviour; (3) sexual mixing patterns; (4) determinants of disassortative (between-group) mixing among migrant groups in Amsterdam, the Netherlands and to gain insight into the potential for heterosexual spread of HIV/sexually transmitted diseases. DESIGN: Cross-sectional study among 1660 Surinamese, Antilleans and sub-Saharan Africans, mainly recruited on the streets. METHODS: Saliva was tested for HIV and questions were asked about sociodemographic characteristics, sexual behaviour and the ethnicity of sexual partners. Multivariate logistic regression analysis was used to find predictors for disassortative mixing. RESULTS: HIV prevalence was 1.1% (95% confidence interval: 0.6-1.7). Compared with the Dutch population in general, our study group reported having multiple partners, concurrent partnerships and a history of sexually transmitted diseases much more frequently. Sex in the country of origin during a visit occurred frequently and there was a considerable degree of sexual mixing between different ethnic groups in the Netherlands. For men, disassortative mixing was associated with hard drug use, recent immigration, a high number of partners, being from Nigerian or Hindu-Surinamese origin, a recent sexually transmitted disease and, for steady relationships, consistent condom use. For women, determinants included: hard drug use, low income, being a-religious and, for Antillean and Ghanaian women, consistent condom use. CONCLUSION: Our data suggest a potential for heterosexual spread of sexually transmitted diseases within and between ethnic groups in the Netherlands. The potential for HIV spread is however limited by the low HIV prevalence at present among these groups. This situation may change when HIV prevalence increases in the countries of origin, as bridges exist between those countries and the Netherlands. Culturally appropriate AIDS prevention programmes remain important for these groups.

Effects of BD-40, an ellipticine analogue (aza-ellipticine) on cell cycle traverse and DNA synthesis in cultures of synchronized mouse fibroblasts.

BD-40 is a pyrido-pyrrolo-isoquinoline analogue of ellipticine, which possesses oncostatic in vivo activity on experimental tumors, and dose-dependent cytostatic and cytotoxic activities on mammalian cells in culture. In order to appreciate the effects of the drug on the replication of DNA, cultures of murine fibroblasts were synchronized by thymidine double block, and BD-40 was added at the time of the block release. The drug did not interfere with the entry of cells in S phase, but a delay in S-phase transit was observed, regardless of the dose employed. In agreement with these data, DNA synthesis started at the same time in control cells and in BD-40 treated cells, but a significant reduction of 3H thymidine incorporation was found in drug-treated cells. This inhibition was not likely to result from a diminution of the specific activity of 3H-dTTP, since nuclei, isolated from cells previously incubated with the drug, also presented a strong diminution of synthetic activity in the presence of the four nucleoside triphosphate precursors (dNTPs). Analysis by alkaline sucrose gradient centrifugation of DNA synthesized in the presence of BD-40 showed that primary fragments, probably corresponding to the duplication of initial replicons, were normally formed but were not further elongated in cells treated with cytotoxic doses, while they were normally processed (although at a slower rate than in control) with a cytostatic drug concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Possible relationship between pyrido-pyrrolo-isoquinoline derivative (BD-40) cell uptake and cell viability.

BD-40 is a pyrido-pyrrolo-isoquinoline derivative which possesses an heterocyclic nucleus very closely related to ellipticine and a diethylaminopropyl amino lateral chain (Rivalle et al., 1979). Cellular effects of the drug have been studied. Viability and morphology of the cells were irreversibly impaired by 24 hours drug treatments at concentrations exceeding 0.10 micro M. Spectrofluorimetric determinations of the drug repartition between cytoplasm and nucleus showed that 10 per cent of BD-40 was found in the nucleus for external drug concentrations lower than 0.10 micro M. On the other hand, for cytotoxic doses exceeding 0.10 micro M, 40 to 50 per cent of the total intracellular BD-40 were found in the nuclear fraction. Although possible exchange phenomena during the course of the cell fractionation cannot be excluded, these results suggest that a direct relationship exists between BD-40 nuclear content and cell lethality. Comparisons of intracellular drug contents in the absence and the presence of a metabolic inhibitor, sodium azide, indicated that drug content of azide-treated cells was approximately twice that of untreated cells. Besides, sodium azide blocked the release of the drug when previously loaded cells were placed in BD-40-free medium. These results are in agreement with the existence of an active outward transport (efflux), which is sodium azide-sensitive.

The in vitro involvement of topoisomerase II in the activity of aza-ellipticine analogues is not correlated with drug activity on isolated nuclei.

Aza-ellipticines are DNA intercalative ellipticine analogues with antitumor activity that induce protein-linked DNA breaks in NIH 3T3 cells in culture. The effects of two aza-ellipticine congeners (BD-40 and BR-76) on the activity of purified Calf Thymus type II topoisomerase were studied using pUC13 DNA as substrate. DNA cleavage was stimulated by both molecules at those doses required for inducing lethal effects in cells (DE5O). This effect was reversed by high salt treatment, indicating that it was actually mediated by Topo II. Mapping of cleavage sites on linearized and 3' end-labelled pUC13 DNA showed that ellipticine and aza-ellipticines stimulated the same sites, which differed from those stimulated by m-AMSA. Decatenating activity of Topo II on Trypanosoma cruzi kDNA was both inhibited by ellipticine and BD-40 at concentrations much higher than DE50 concentrations. Activity of aza-ellipticines was also investigated on isolated nuclei. Unlike ellipticine which promoted DNA-breaking activity, BD-40 and BR-76 were repeatedly inactive. Prior treatment of DNA by Proteinase K did not reveal hidden breaks which are formed in intact cells treated with BD-40 (Vilarem et al., 1984, Nucleic Ac. Res. 12, 8653). Concordant with these data, BD-40 did not impair DNA-synthetic activity in isolated nuclei, while Ellipticine largely decreased it. These results indicate that lesions induced in DNA by Aza-ellipticines are mediated by Topo II. The absence of effect of these drugs on isolated nuclei compared to that of Ellipticine may be due to some specific features of the association between Topo II and Aza-ellipticines or reflect a bioactivation step as a prerequisite for in vivo activity.