Formation and antitumor activity of PNU-159682, a major metabolite of nemorubicin in human liver microsomes.

PURPOSE: Nemorubicin (3'-deamino-3'-[2'(S)-methoxy-4'-morpholinyl]doxorubicin; MMDX) is an investigational drug currently in phase II/III clinical testing in hepatocellular carcinoma. A bioactivation product of MMDX, 3'-deamino-3',4'-anhydro-[2'(S)-methoxy-3'(R)-oxy-4'-morpholinyl]doxorubicin (PNU-159682), has been recently identified in an incubate of the drug with NADPH-supplemented rat liver microsomes. The aims of this study were to obtain information about MMDX biotransformation to PNU-159682 in humans, and to explore the antitumor activity of PNU-159682. EXPERIMENTAL DESIGN: Human liver microsomes (HLM) and microsomes from genetically engineered cell lines expressing individual human cytochrome P450s (CYP) were used to study MMDX biotransformation. We also examined the cytotoxicity and antitumor activity of PNU-159682 using a panel of in vitro-cultured human tumor cell lines and tumor-bearing mice, respectively. RESULTS: HLMs converted MMDX to a major metabolite, whose retention time in liquid chromatography and ion fragmentation in tandem mass spectrometry were identical to those of synthetic PNU-159682. In a bank of HLMs from 10 donors, rates of PNU-159682 formation correlated significantly with three distinct CYP3A-mediated activities. Troleandomycin and ketoconazole, both inhibitors of CYP3A, markedly reduced PNU-159682 formation by HLMs; the reaction was also concentration-dependently inhibited by a monoclonal antibody to CYP3A4/5. Of the 10 cDNA-expressed CYPs examined, only CYP3A4 formed PNU-159682. In addition, PNU-159682 was remarkably more cytotoxic than MMDX and doxorubicin in vitro, and was effective in the two in vivo tumor models tested, i.e., disseminated murine L1210 leukemia and MX-1 human mammary carcinoma xenografts. CONCLUSIONS: CYP3A4, the major CYP in human liver, converts MMDX to a more cytotoxic metabolite, PNU-159682, which retains antitumor activity in vivo.     

The Effect of Ramadan and COVID-19 on the Relationship between Physical Activity and Burnout among Teachers

The objective of this study was to explore the effect of COVID-19 and Ramadan on physical activity (PA) and burnout in teachers and the relationship between them. A total of 57 secondary school teachers from public education centers participated in the present study. They were aged between 29 and 52 years. To determine the effect of Ramadan and COVID-19 on PA and burnout, participants completed the online questionnaires before COVID-19, one week before Ramadan and during the second week of Ramadan. The International Physical Activity Questionnaire-BREF and the Maslach Burnout Inventory-Human Services Survey were used to assess PA intensities and burnout, respectively. The data revealed that total PA (p < 0.001, p < 0.05, respectively) vigorous metabolic equivalent of task (MET) (p < 0.001, p < 0.05, respectively), moderate MET (p < 0.001, p < 0.01, respectively) were higher before COVID-19 and before Ramadan than during Ramadan. Regarding burnout subscales, emotional exhaustion (p < 0.001, p < 0.01, respectively) was higher before Ramadan than before COVID-19 and during Ramadan. A lower personal accomplishment was reported before Ramadan than before COVID-19 and during Ramadan (both p < 0.05). In addition, low to high correlations were observed between PA intensities and burnout subscales, except for the correlation between depersonalization and all PA intensities. In conclusion, Ramadan intermittent fasting along with PA was highly recommended for teachers and the general population to improve positive emotions and general health.     

Adriamycin-induced histamine release from heart tissue in vitro

 It has been proven that the anthracyclines induce an important, noncytotoxic histamine release from rat peritoneal mast cells. As mast cells derived from different tissues exhibit marked heterogeneity, the effect of Adriamycin in comparison with other antineoplastic agents was tested on fragments of the right heart auricle, which contain a great number of mast cells. In this experimental model, Adriamycin induced a dose-dependent histamine release that was significantly limited by the antiexocytotic drug sodium cromoglycate. The antineoplastic agents cisplatin and 5-fluorouracil, in contrast, did not provoke any comparable histamine release. In the formulation employed in clinical settings, paclitaxel was also capable of inducing a histamine release comparable with that of Adriamycin; the exocytotic activity, however, was also evident when the tissue fragments were treated with Cremophor EL alone, without the addition of paclitaxel, whereas treatment of samples with paclitaxel dissolved in ethanol did not induce any releasing action. These data thus suggest that the secretory activity should be ascribed to the solvent Cremophor EL and not to paclitaxel. The release of histamine induced by paclitaxel in Cremophor EL/ethanol was also limited by sodium cromoglycate. These results again indicate that histamine release from mast cells derived not only from the peritoneal cavity but also from the cardiac tissue could play a role in the cardiotoxicity of anthracyclines and of paclitaxel in the clinically employed formulation. Received: 18 August 1996 / Accepted: 22 December 1996     

Management of uterine giant myoma

BACKGROUND: Giant myomas of the uterus are uncommon, particularly in developed countries. CASE: This report illustrates a case of a woman with a bilobated giant myoma of the uterus weighed in total 27.7 kg. The patient had an abdominal distension first noted 18 months before and the personal history evidenced difficulties in walking and tiredness. Abdominal hysterectomy and bilateral salpingo-oophorectomy were carried out. CONCLUSIONS: The knowledge of the different clinical manifestation of these myomas may allow to face that with adequate perioperative care, in order to assure a carefully and successfully surgery, although sometimes a benign pathology may be not easy to suspect in a first time.