Final results of the real-life observational VICTOR-6 study on metronomic chemotherapy in elderly metastatic breast cancer (MBC) patients.

Nowadays, treatment of metastatic breast cancer (MBC) has been enriched with novel therapeutical strategies. Metronomic chemotherapy (mCHT) is a continuous and frequent administration of chemotherapy at a lower dose and so whit less toxicity. Thus, this strategy could be attractive for elderly MBC patients. Aim of this analysis is to provide insights into mCHT's activity in a real-life setting of elderly MBC patients. Data of patients ≥ 75 years old included in VICTOR-6 study were analyzed. VICTOR-6 is a multicentre, Italian, retrospective study, which collected data on mCHT in MBC patients treated between 2011 and 2016. A total of 112 patients were included. At the beginning of mCHT, median age was 81 years (75-98) and in 33% of the patients mCHT was the first line choice. Overall Response Rate (ORR) and Disease Control Rate (DCR) were 27.9% and 79.3%, respectively. Median PFS ranged between 7.6 and 9.1 months, OS between 14.1 and 18.5 months. The most relevant toxicity was the hematological one (24.1%); severe toxicity (grade 3-4) ranged from 0.9% for skin toxicity up to 8% for hematologic one. This is a large study about mCHT in elderly MBC patients, providing insights to be further investigated in this subgroup of frail patients.

Metronomic chemotherapy (mCHT) in metastatic triple-negative breast cancer (TNBC) patients: results of the VICTOR-6 study.

PURPOSE: Triple-negative breast cancer (TNBC) represents a subtype of breast cancer which lacks the expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2): TNBC accounts for approximately 20% of newly diagnosed breast cancers and is associated with younger age at diagnosis, greater recurrence risk and shorter survival time. Therapeutic options are very scarce. Aim of the present analysis is to provide further insights into the clinical activity of metronomic chemotherapy (mCHT), in a real-life setting. METHODS: We used data included in the VICTOR-6 study for the present analysis. VICTOR-6 is an Italian multicentre retrospective cohort study, which collected data of metastatic breast cancer (MBC) patients who have received mCHT between 2011 and 2016. Amongst the 584 patients included in the study, 97 were triple negative. In 40.2% of the TNBC patients, mCHT was the first chemotherapy treatment, whereas 32.9% had received 2 or more lines of treatment for the metastatic disease. 45.4% out of 97 TNBC patients received a vinorelbine (VRL)-based regimen, which resulted in the most used type of mCHT, followed by cyclophosphamide (CTX)-based regimens (30.9%) and capecitabine (CAPE)-based combinations (22.7%). RESULTS: Overall response rate (ORR) and disease control rate (DCR) were 17.5% and 64.9%, respectively. Median progression free survival (PFS) and overall survival (OS) were 6.0 months (95% CI: 4.9-7.2) and 12.1 months (95% CI: 9.6-16.7). Median PFS was 6.9 months for CAPE-based regimens (95% CI: 5.0-18.4), 6.1 months (95% CI: 4.0-8.9) for CTX-based and 5.3 months (95% CI: 4.1-9.5) for VRL-based ones. Median OS was 18.2 months (95% CI: 9.1-NE) for CAPE-based regimens and 11.8 months for VRL- (95% CI: 9.3-16.7 and CTX-based ones (95%CI: 8.7-52.8). Tumour response, PFS and OS decreased proportionally in later lines. CONCLUSION: This analysis represents the largest series of TNBC patients treated with mCHT in a real-life setting and provides further insights into the advantages of using this strategy even in this poor prognosis subpopulation.

Association of tumor-infiltrating lymphocytes with distant disease-free survival in the ShortHER randomized adjuvant trial for patients with early HER2+ breast cancer.

BACKGROUND: There is the need to identify new prognostic markers to refine risk stratification for HER2-positive early breast cancer patients. The aim of this study was to evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free survival (DDFS) in patients with HER2-positive early breast cancer enrolled in the ShortHER adjuvant trial which compared 9 weeks versus 1-year trastuzumab in addition to chemotherapy, and to test the interaction between TILs and treatment arm. PATIENTS AND METHODS: Stromal TILs were assessed for 866 cases on centralized hematoxylin and eosin-stained tumor slides. The association of TILs as 10% increments with DDFS was assessed with Cox models. Kaplan-Meier curves were estimated for patients with TILs ≥20% and TILs <20%. Median follow-up was 6.1 years. RESULTS: Median TILs was 5% (Q1-Q3 1%-15%). Increased TILs were independently associated with better DDFS in multivariable model [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.59-0.89, P = 0.006, for each 10% TILs increment]. Five years DDFS rates were 91.1% for patients with TILs <20% and 95.7% for patients with TILs ≥20% (P = 0.025). The association between 10% TILs increments and DDFS was significant for patients randomized to 9 weeks of trastuzumab (HR 0.60, 95% CI 0.41-0.88) but not for patients treated with 1 year of trastuzumab (HR 0.89, 95% CI 0.71-1.12; test for interaction P = 0.088). For patients with TILs <20%, the HR for the comparison between the short versus the long arm was 1.75 (95% CI 1.09-2.80, P=0.021); whereas, for patients with TILs ≥20% the HR for the comparison of short versus long arm was 0.23 (95% CI 0.05-1.09, P = 0.064), resulting in a significant interaction (P = 0.015). CONCLUSIONS: TILs are an independent prognostic factor for HER2-positive early breast cancer patients treated with adjuvant chemotherapy and trastuzumab and may refine the ability to identify patients at low risk of relapse eligible for de-escalated adjuvant therapy.

Metformin plus chemotherapy versus chemotherapy alone in the first-line treatment of HER2-negative metastatic breast cancer. The MYME randomized, phase 2 clinical trial.

PURPOSE: To investigate the efficacy of metformin (M) plus chemotherapy versus chemotherapy alone in metastatic breast cancer (MBC). METHODS: Non-diabetic women with HER2-negative MBC were randomized to receive non-pegylated liposomal doxorubicin (NPLD) 60 mg/m2 + cyclophosphamide (C) 600 mg/m2 × 8 cycles Q21 days plus M 2000 mg/day (arm A) versus NPLD/C (arm B). The primary endpoint was progression-free survival (PFS). RESULTS: One-hundred-twenty-two patients were evaluable for PFS. At a median follow-up of 39.6 months (interquartile range [IQR] 24.6-50.7 months), 112 PFS events and 71 deaths have been registered. Median PFS was 9.4 months (95% CI 7.8-10.4) in arm A and 9.9 (95% CI 7.4-11.5) in arm B (P = 0.651). In patients with HOMA index < 2.5, median PFS was 10.4 months (95% CI 9.6-11.7) versus 8.5 (95% CI 5.8-9.7) in those with HOMA index ≥ 2.5 (P = 0.034). Grade 3/4 neutropenia was the most common toxicity, occurring in 54.4% of arm A patients and 72.3% of the arm B group (P = 0.019). M induced diarrhea (G2) was observed in 8.8% of patients in Arm A. The effect of M was similar in patients with HOMA index < 2.5 and ≥ 2.5, for PFS and OS. CONCLUSIONS: The MYME trial failed to provide evidence in support of an anticancer activity of M in combination with first line CT in MBC. A significantly shorter PFS was observed in insulin-resistant patients (HOMA ≥ 2.5). Noteworthy, M had a significant effect on CT induced severe neutropenia. Further development of M in combination with CT in the setting of MBC is not warranted.

Immunoglobulin G fragment C receptor polymorphisms and efficacy of preoperative chemotherapy plus trastuzumab and lapatinib in HER2-positive breast cancer.

Lapatinib enhances antibody-dependent cell-mediated cytotoxicity (ADCC) activity of trastuzumab. FcγR polymorphisms have been associated with both ADCC and clinical activity of trastuzumab in HER2+ breast cancer (BC) patients (pts). We analyzed FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms in the CHER-LOB trial population of HER2+ BCs treated with preoperative chemotherapy plus trastuzumab (arm A), lapatinib (arm B) or both (arm C). Genotyping was successfully performed in 73/121 (60%) pts. A significant improvement in pathological complete response (pCR) rate was observed for the combination arm C, but only in FcγRIIIa V allele carriers (C vs A, 67 vs 27%, P=0.043; C vs B, 67 vs 22%, P=0.012). An independent interaction between arm C and FcγRIIIa V allele was found for pCR (odds ratio=9.4; 95% confidence interval, 2.3-39.6; P=0.003). No significant associations were observed between pCR and FcγRIIa polymorphism, and between pre-treatment tumor-infiltrating lymphocytes and FcγR polymorphisms. Our study provides evidence for a FcγRIIIa V allele-restricted pCR benefit from neoadjuvant trastuzumab plus lapatinib in HER2+ BC.

Hypovitaminosis D and fat mass in healthy older people.

Prospective studies have suggested that hypovitaminosis D can predict the onset of obesity, but they relied mainly on body mass index, which could be scarcely reliable in older people. We investigated whether baseline hypovitaminosis D could predict higher fat mass (FM) levels using dual-energy X-ray absorptiometry in a sample of 116 fit and healthy older subjects. Although no significant differences in FM estimates emerged between subjects with and without hypovitaminosis D at the baseline, abdominal FM was found significantly higher in the former group (with hypovitaminosis D at the baseline) than in the latter after 3 years of follow-up. Adjusted logistic regression analysis confirmed these findings: hypovitaminosis D coincided with an approximately sixfold higher risk of subjects having higher abdominal FM levels at the follow-up. In conclusion, hypovitaminosis D predicts higher abdominal FM levels in the elderly.

Detection of blood pressure increments in active elderly individuals: the role of ambulatory blood pressure monitoring.

BACKGROUND AND AIMS: Physiological aging can lead to an increase in blood pressure (BP) over time even in regularly exercising elders. Office BP measurements (OBPM) might be unable to detect these BP variations. The aim of this study was to analyze BP changes over 3.5 years in active elders using ABPM. METHODS AND RESULTS: The study involved 80 active subjects ≥65 years old who exercised regularly. At baseline and again 3.5 years later, all subjects had lab tests, weight, body mass index (BMI), body composition, resting energy expenditure (REE) recorded; they underwent OBPM, ABPM and physical activity assessment. Over 3.5 years, our sample's mean weight, BMI, body composition, REE, albumin, and physical activity levels, did not change significantly. The prevalence of hypertension detected by OBPM dropped from 68.8% to 61.3%. ABPM revealed an increase in mean 24-h BP (Δsystolic: 5.3 ± 13.6 mmHg; p = 0.001; Δdiastolic: 1.8 ± 6.7 mmHg; p = 0.018) and mean daytime BP (Δsystolic: 5.8 ± 13.5 mmHg; p = 0.001; Δdiastolic: 1.9 ± 7.1 mmHg; p = 0.022); the prevalence of hypertension detected by ABPM increased from 50% to 65%, also due to an increase (from 8.8% to 16.3%) in masked hypertension. There was no correlation between BP changes and changes in body composition and REE. CONCLUSION: BP tends to increase over time in active elders, regardless of changes in body composition or level of physical activity. ABPM is an appropriate method for detecting these BP variations in active elders and to reveal cases of masked hypertension that might otherwise escape detection by OBPM.

Efficacy of specific bioelectrical impedance vector analysis (BIVA) for assessing body composition in the elderly.

OBJECTIVES: This study aimed to ascertain the efficacy of bioelectrical impedance vector analysis (BIVA) in assessing body composition in the elderly by comparing findings with the results of dual-energy X-ray absorptiometry (DXA), and to test an analytical variant of the method (specific BIVA). DESIGN: Cross-sectional study. PARTICIPANTS: The sample comprised 207 free-living elderly individuals (75 men and 132 women) aged 65 to 93 years. MEASUREMENTS: Anthropometric and bioelectrical measurements were taken according to standard criteria. BIVA was applied using the 'classic' procedure and correcting bioelectrical values for body geometry to obtain an estimate of the whole-body impedivity. DXA was used as a reference body composition assessment method. BIVA (classic and specific values) and DXA findings were compared using Student's t and Hotelling's T2 tests, and Pearson's correlation coefficient. RESULTS: In both sexes, BIVA distinguished between individuals with different amounts of fat and fat-free mass (lean mass including bone mineral content), according to DXA, but not between those with different proportions of fat mass (FM%). Specific bioelectrical values detected changes in body composition. CONCLUSION: BIVA should be used with caution for evaluating body composition in the elderly. Specific bioelectrical values proved effective, showing promise as a methodological variant of BIVA, suitable for identifying age-related changes in body fatness.

Hydrogen bond network relaxation in aqueous polyelectrolyte solutions: the effect of temperature.

Dielectric spectroscopy data over the range 100 MHz­40 GHz allow for a reliable analysis of two of the major relaxation phenomena for polyelectrolytes (PE) in water. Within this range, the dielectric relaxation of pure water is dominated by a near-Debye process at ν = 18.5 GHz corresponding to a relaxation time of τ = 8.4 ps at 25 °C. This mode is commonly attributed to the cooperative relaxation specific to liquids forming a hydrogen bond network (HBN) and arising from long range H-bond-mediated dipole­dipole interactions. The presence of charged polymers in water partially modifies the dielectric characteristics of the orientational water molecule relaxation due to a change of the dielectric constant of water surrounding the charges on the polyion chain. We report experimental results on the effect of the presence of a standard flexible polyelectrolyte (sodium polyacrylate) on the HBN relaxation in water for different temperatures, showing that the HBN relaxation time does not change by increasing the polyelectrolyte density in water, even if relatively high concentrations are reached (0.02 monomol l(−1) ≤ C ≤ 0.4 monomol l(−1)). We also find that the effect of PE addition on the HBN relaxation is not even a broadening of its distribution, rather a decrease of the spectral weight that goes beyond the pure volume fraction effect. This extra decrease is larger at low T and less evident at high T, supporting the idea that the correlation length of the water is less affected by the presence of charged flexible chains at high temperatures.

Changes in total body and limb composition and muscle strength after a 6-8 weeks sojourn at extreme altitude (5000-8000 m).

AIM: Weight loss at extreme altitudes affects quantitative changes in fat-free mass (FFM), muscle mass and fat mass. No studies to date have focused on regional body composition and physical performance using reference methods after stays at extreme altitudes. The aim of this study was to investigate the changes in total and regional body composition, and muscle strength induced by the extreme altitudes. METHODS: Eight men aged 38.8±5.8 who took part in two different Italian expeditions on Mt. Everest (group A) and on Gasherbrum II (group B). Before and after the expedition all participants underwent anthropometric measurements, total and regional body composition assessment by DEXA, and handgrip and knee extensor strength measurements by dynamometry. RESULTS: The variations in body composition mainly involved FFM, with a similar loss in group A (-2.4±1.9 kg; P<0.05) and group B (-2.4±1.2 kg; P<0.05). Most of the FFM loss involved the limbs (-2.1±1.4 kg; P<0.01), and especially the upper limbs (-1.6±1.1 kg; P<0.01). The isotonic knee extensor strength declined in 6 of the 8 study participants, with a mean drop of -4.4±6.1 kg. CONCLUSIONS: In conclusion, our study evidence that extreme altitudes induce weight loss due mainly to a loss of fat-free mass in the limb.

A retrospective pilot study on the development of cognitive, behavioral and functional disorders in a sample of patients with early dementia of Alzheimer type.

This pilot study retrospectively analyzes the evolution of cognitive-behavioral symptoms and functional autonomy in a sample of patients with early diagnosis of probable Alzheimer's disease (AD). One hundred patients with early mild cognitive impairment (MCI) were considered and submitted to a multidimensional evaluation: the 53% presented probable AD. These 53 subjects were evaluated for cognitive performance by using the mini mental examination (MMSE), behavioral functions by the neuropsychiatric inventory (NPI) and functional dependence by the activities of daily living (ADL) and the instrumental ADL (IADL) scales at basal time and after 6-12 months. Results were analyzed according to the duration of therapy with acetyl-cholinesterase inhibitors (ACHEI) and to the timing of the beginning with respect to the diagnosis. AD patients treated with ACHEI at the moment of the diagnosis, showed a statistically significant improvement in MMSE (2.7+/-1.5) after 6 months (p=0.012) which was maintained even after 12 months. Subjects beginning ACHEI at the visit of 6 months showed a statistically worsened MMSE, even after 6 months of therapy (-2.8+/-1.7, p=0.026). We conclude that the timing of administration of ACHEI therapy in mild AD is essential to obtain beneficial effects on cognitive decline.

Molecular staging of the sentinel lymph node in melanoma patients: correlation with clinical outcome.

BACKGROUND: This study was designed to determine the debated prognostic significance of reverse transcriptase-polymerase chain reaction (RT-PCR) positivity in melanoma patients' sentinel lymph node (SLN) negative by conventional histopathology (PATH). PATIENTS AND METHODS: Patients with primary stage I-II cutaneous melanoma underwent radioguided sentinel lymphadenectomy. Their SLNs were assessed for tyrosinase (Tyr) and melanoma antigens recognized by T-cells (MART-1) mRNA expression using RT-PCR, in parallel with hematoxylin and eosin staining and immunohistochemistry. Tyr and MART-1 expression in the SLNs were correlated with PATH assay results, standard prognostic factors, time to progression and overall survival. RESULTS: Twenty-three of the 124 patients (18.5%) had positive SLNs by both PATH and RT-PCR (PATH+/PCR+). Sixteen patients (13%) were negative by PATH and positive by RT-PCR (PATH-/PCR+). Eighty-five patients (68.5%) had SLNs that were negative by both PATH and RT-PCR (PATH-/PCR-). At a median follow-up of 30 months, recurrence rates among the three cohorts were statistically different (PATH+/PCR+, 60%; PATH-/PCR+, 31%; PATH-/PCR-, 9.4%). Seven of 23 (30%) and two of 16 (12.5%) patients died in the PATH+/PCR+ and PATH-/PCR+ SLN groups, respectively, whereas no patient died in the PATH-/PCR- SLN group. CONCLUSIONS: RT-PCR is more sensitive than PATH to detect SLN metastases and it is a reliable predictor of disease relapse in stage I-II melanoma patients.

Anti-inflammatory activity of cubebin, a lignan from the leaves of Zanthoxyllum naranjillo Griseb.

Cubebin, a dibenzylbutyrolactone lignan isolated from the crude hexane extract of the leaves of Zanthoxyllum naranjillo, showed a significant anti-inflammatory activity by using the paw edema induced by carrageenin in rats, but did not provide a significant reduction in the cell migration for the acute carrageenin-induced inflammatory reaction in the peritoneal cavity of rats. Neither was it effective in reducing the edema induced by dextran nor the edema induced by histamine. It partially reduced the edema induced by serotonin. Moreover, it significantly reduced the edema induced by prostaglandin PGE2 and the number of writhings induced by both acetic acid and PGI2 in mice. Therefore, it may be suggested that the mechanism of action of cubebin is similar to that observed for most of the non-steroidal drugs.

Anti-inflammatory activity of the crude extract from the fruits of Pterodon emarginatus Vog.

The vegetal species Pterodon emarginatus Vog. (Leguminosae/Papilonaceae), popularly known in Brazil as 'sucupira branca', is widely used by domestic medicine as an anti-inflammatory. From these observations, the hexanic crude extract (HCE) of the fruits was obtained and submitted for assessment of its anti-inflammatory activity. For this purpose, the following tests were used: (1) Determination of ED50 and LD50; (2) Paw edema induced by carrageenin, dextran, histamine and nystatin; (3) Peritonitis caused by carrageenin and (4) Granuloma test. The ED50 (oral) in the edema induced by carrageenin was 500 mg/kg, and LD50 (oral) was 4.02 g/kg. In the edema caused by nystatin, there was a significant inhibition by 45% (P < 0.05 student's t-test) at the 6th hour following the treatment. In the granuloma test performed in animals treated with HCE, there was an inhibition of the granulomatous tissue formation by 22%. The migration of neutrophils towards the peritoneal cavity was inhibited in HCE treated animals by 43% (P < 0.05). However, in the edema caused by dextran and histamine, there was no significant response in HCE treated animals.

Anti-inflammatory activity of flavone and some of its derivates from Virola michelli Heckel.

The phytochemical study using Virola michelli Heckel (Myristicaceae) leaves allowed the isolation of a flavone named titonine (7,4'-dimethoxy-3'-hydroxyflavone). Titonine was further submitted to methylation and acetylation reactions yielding a 7,3',4'-trimethoxyflavone and a 7,3'-dimethoxy-4'-acetylflavone, respectively. These compounds were evaluated for both anti-inflammatory and analgesic activity. The anti-inflammatory activity was evaluated in rats using the paw edema test with carrageenin, while the analgesic activity was determined in mouse using the writhing test method. The different animal groups were treated with three compounds (10 mg/kg -i.p.) thirty min prior to stimuli application. The inhibition levels obtained for each compound were 22, 41 and 68%, respectively. Using the writhing test, oral doses of 5, 10 and 15 mg/kg of natural flavone reduced the acetic acid-induced contortions in a dose-dependent manner.

Investigation of anti-inflammatory and antinociceptive activities of trans-dehydrocrotonin, a 19-nor-clerodane diterpene from Croton cajucara. Part 1.

The anti-inflammatory and antinociceptive effects of trans-dehydrocrotonin, isolated from the bark of Croton cajucara (Euphorbiaceae), were investigated using several animal models. The trans-dehydrocrotonin produced a significant inhibition of carrageenin-induced paw edema and cotton pellet granuloma in rats. It also inhibited the writhings in mice induced by acetic acid, but did not show a significant effect in the hot-plate test in mice. The LD50 of t-DCTN was 555.0 mg/kg (p.o.) for mice.

Preliminary studies of analgesic and anti-inflammatory properties of Caesalpinia ferrea crude extract.

The crude aqueous extract of the fruits of Caesalpinia ferrea Mart. (Leguminosae) has been investigated for possible anti-inflammatory and analgesic properties. The carrageenan induced rat hind paw edema was significantly inhibited (P < 0.05) by oral administration of 300 mg/kg of this extract. A centrally mediated analgesic effect was not observed, however, there was a dose dependent reduction in the number of total writhes induced by acetic acid.

Quimioprofilaxia da doença de Chagas: bloqueio da transmissão transfusional por produtos naturais / Chemyprophylaxis of Chagas disease: blockage of blood transfusion transmission by natural products

Em busca da solução para o serio problema da transmissão transfusional da doença de Chagas em nosso meio, realizamos a avaliação de produtos naturais corn atividade tripanosomicida. Os testes "in vitro" foram realizados incubando-se a 4°C, sangue de camundongos contendo ± 10(6)/ ml formas tripomastigotas de Trypanosoma cruzi corn os extratos vegetais. Após diferentes períodos de incubação, frações sangüíneas foram examinadas em microscopia de fase. Os extratos que apresentaram atividade tripanosomicida ate 48 horas de incubação, foram examinados em microscopia eletrônica corn intuito de verificarmos sua toxicidade contra os elementos normais do sangue. Foram testados 242 extratos obtidos de 81 vegetais a 56 demonstraram atividade.

Considering the serius problem of blood transfusion transmission of Chagas disease in our environment, we realized the evalution of natural products against Chagas diseases. The tests were realized "in vitro" by in incubation at 4ºC mouse blood having ± 10(6)/ml of Trypanosoma cruzi, sample "y" and "Colombina" with the plant extracts. After different times of incubation, blood fractions were examined by phase microscopy. The drugs that showed activity until 48 hours of incubation, were examined by electron microscopy to virify the toxicity to blood elements. The tests were realized with 242 extracts from 81 plants and 56 extracts showed activity against T. cruzi.

Genotoxicity of the natural cercaricides "sucupira" oil and eremanthine in mammalian cells in vitro and in vivo.

"Sucupira" oil and the lactone eremanthine, extracted from Pterodon pubescens and Eremanthus elaeagnus, respectively, are known for their cercaricidal action in experimental animals. Because of their biological effect, they have the potential to be used for the prophylaxis of schistosomiasis caused by Schistosoma mansoni. To test the clastogenicity of these agents, "sucupira" oil, either pure or diluted in corn oil, was tested in vivo on Wistar rat bone marrow cells following dermal application. Metaphase analysis showed that the compound did not induce a significant increase in the frequencies of chromosomal aberrations. When eremanthine was tested on BALB/c mice following gavage at doses of 100, 200, and 300 mg/kg bw, it did not induce structural or numerical chromosomal aberrations. In the in vitro treatment of human lymphocyte cultures, eremanthine also did not cause any increase in chromosomal aberrations or sister chromatid exchanges at the following concentrations in culture medium: 1.25, 2.50, and 5.00 micrograms/ml. From these results, under our experimental conditions, neither "sucupira" oil nor eremanthine showed clastogenic effects on mammalian cells in vivo or in vitro.