Biochemical and biological activity of the anthracycline analog, 4-demethyl-6-0-methyl-doxorubicin

Summary The chromophore-modified derivative of doxorubicin, 4-demethyl-6-0-methyl-doxorubicin, has been tested for antitumor activity in a range of experimental murine tumor systems. In contrast to the inactive 6-0-methyl derivative of daunorubicin, 4-demethyl-6-0-methyl-doxorubicin provided antitumor effects comparable to that of the parent compound. In addition, detailed DNA-interaction studies showed that the doxorubicin derivative retains the ability to bind DNA by the intercalation mechanism. However, the binding affinity was appreciably reduced following structural modification in the anthraquinone chromophore. On the basis of the proposed models of intercalation, these results could be rationalized in terms of steric influence of the bulky methoxy group. The results of this study are in agreement with the correlation already observed between DNA binding and relative antitumor activity of anthracyclines.     

Lofepramine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness

Lofepramine is a tricyclic antidepressant that is structurally similar to imipramine and is extensively metabolised to desipramine. In the absence of other major pharmacological effects it appears that its antidepressant activity stems from the facilitation of noradrenergic neurotransmission by uptake inhibition, and possibly by the additional facilitation of serotoninergic neurotransmission. The overall therapeutic efficacy of lofepramine is comparable to that of imipramine, amitriptyline, clomipramine, maprotiline and mianserin in patients with depression of varying severity, and coexisting anxiety. Dry mouth is the most commonly reported side effect of usual therapeutic doses of lofepramine, but the incidence of this and other anticholinergic side effects is less among patients treated with lofepramine than with imipramine. Lofepramine has not been associated with adverse effects on cardiac function even in cases of attempted suicide by overdose. Thus, providing its apparent favourable side effect profile is confirmed in practice, lofepramine may be a valuable alternative for treatment of the depressed patient where a tricyclic is indicated.     

Carcinoma of the prostate with atypical immunohistological features. Clinical and histologic correlates

In seven patients with undifferentiated carcinoma of the prostate, the immunohistochemical stain for prostate-specific antigen was negative. The stain for prostatic acid phosphatase done on the same tissue samples was diffusely positive in three, focally positive in three, and negative in one. Only the three with diffusely positive immunostaining had elevated serum acid phosphatase levels, although five had evidence of metastatic disease. All seven neoplasms were histologically similar, being composed of large cells with large nuclei, a moderate amount of cytoplasm, and indistinct cell borders. All tumors grew as broad sheets within the prostatic stroma as well as in the prostatic urethra; in six cases. Thus, prostatic carcinoma with this histologic pattern frequently loses prostate-specific antigen immunoreactivity. Awareness of this occurrence should prevent a misdiagnosis of urothelial carcinoma in such cases. The prostatic origin of these neoplasms can usually be verified by prostatic acid phosphatase immunostaining, which proves to be more sensitive in this particular setting.     

Successful Liver and Kidney Transplantation From Cadaveric Donors With Left-Sided Bacterial Endocarditis

Bacterial infections are frequent in cadaveric organ donors and can be transmitted to the transplantation recipient, which could have devastating consequences for the recipients if adequate preventive measures are not adopted.
From the 355 consecutive brain dead cadaveric organ donors procured at our center in the last four years, 2000–2003, four of them (1.1%) had bacterial endocarditis as cause of death. The bacteria responsible for the endocarditis were Staphylococcus epidermidis, coagulase-negative Staphylococcus , Staphylococcus hominis and Streptococcus viridans , respectively. We performed five kidney and two liver transplantations on seven recipients. All donors and recipients received antibiotic treatment against the germ causing the respective endocarditis.
Infection by the bacteria responsible for the endocarditis in the respective donors was not transmitted to any of the recipients. Six of the seven recipients were alive with normal-functioning grafts after between 13 and 24 months' follow-up. Transplantectomy was performed on one kidney recipient due to thrombosis of the renal vein of the graft not related to the endocarditis.
Liver and kidney transplantation from donors dying from bacterial endocarditis can be performed without causing the transmission of infection to the recipient or the dysfunction of the graft.     

Limited role of aortic size in the genesis of acute type A aortic dissection

Objective: Increased dimension of the aortic root and proximal aorta is considered a significant risk factor for catastrophic events that involve the ascending aorta. The objective of this study was to determine the possible correlation between pre-dissection aortic diameter and the occurrence of Stanford type A aortic dissection. Methods: Samples of dissected ascending aortas were obtained from 220 patients at the time of their operation. Two groups were identified: patients with connective tissue disorders (Group 1, n = 94) and those without (Group 2, n = 126). Measurements of the true (intimal) lumen were conducted and extrapolated as reliable approximation of pre-dissection aortic diameter. The possible association of intimal diameter with anthropometric and demographic data was analyzed. Results: Median aortic diameter was, respectively, 41.8 and 41.3 mm for patients with and without connective tissue disorders (41.4 mm for the entire cohort). Data analysis indicated that 57% of patients had aortic diameter above 40 mm, while patients with frank aneurysm accounted only for 10%; this proportion was higher in Group 1 compared to Group 2 (17.2% vs 4.7%). Poor or no correlation was demonstrated between aortic size and any of the anthropometric or demographic variables essayed. Significant subgroup differences were found among patients with a history of cigarette smoking, hypertension, diabetes, chronic renal insufficiency, and bicuspid aortic valve. Conclusion: Although aortic diameter remains a strong indication for preventive surgery in patients with inherited connective tissue disorders, acute aortic dissection occurs rarely in the setting of true ascending aortic aneurysms, and despite normal or near-normal aortic size in more than one-third of subjects. Dissection superimposing on small aortic diameters can be regarded as an expression of substantial functional tissue susceptibility to aortic catastrophic events.     

Changes in pulmonary function test and cardio-pulmonary exercise capacity in COPD patients after lobar pulmonary resection.

OBJECTIVE: Pulmonary Function Tests (PFT) and Cardio-Pulmonary Exercise Testing (C-PET) are useful to evaluate operability in functionally compromised patients. Although modifications of PFT and C-PET after lung surgery have been widely explored, little information exists as to modifications of exercise capacity in COPD patients undergoing lung resection. We prospectively analyzed the changes in PFT and C-PET in patients with COPD after a pulmonary lobar resection. METHODS: From January 2003 to March 2004 all patients scheduled for lung resection were considered for participation in the study protocol. Those patients with a preoperative diagnosis of COPD on PFT were explored through a C-PET. Only patients who had undergone a lobar pulmonary resection were subsequently considered; these patients had a new complete cardio-respiratory evaluation 3 months after surgery. The pre- and postoperative values compared were those of FEV1, TLC, DLCO, VO2max, and VE/VCO2. Data are expressed as mean +/- standard deviation (SD). Statistic evaluation was made using the Wilcoxon test. RESULTS: During this period 11 patients completed the study protocol. Ten patients underwent surgery for NSCLC and one for a pulmonary aspergilloma. Nine lobectomies and two bilobectomies were performed. In the study population, the preoperative mean value of FEV1 resulted as being 53% (SD+/-20) of the predicted mean value, that of TLC 120% (SD+/-35) and that of DLCO 65% (SD+/-27). The preoperative mean value of VO2max resulted as being 17.8 ml/Kg/min (SD+/-3.25) and mean VE/VCO2 resulted as being 35.7 (SD+/-4). Three months after surgery the measured mean value of FEV1 was 53% (SD+/-18), that of TLC was 99% (SD+/-24) and that of DLCO 52% (SD+/-18). The mean value of VO2max resulted as being 14.1 ml/Kg/min (SD+/-3.04) and that of VE/VCO2 was 42.5 (SD+/-12.8). Statistical analysis of PFT values showed that FEV1 and DLCO were not significantly modified (P > 0.05); in contrast, TLC had significantly decreased (P = 0.008). VO2max had significantly decreased (P = 0.004) and VE/VCO2 had significantly increased (P = 0.018). CONCLUSIONS: Three months after a lobar pulmonary resection, patients with COPD were found to have a significant decrease in exercise tolerance. PFT alone can underestimate the postoperative loss of exercise capacity through exercise.