Effects of amiodarone and desethylamiodarone on rabbit myocardial beta-adrenoceptors and serum thyroid hormones--absence of relationship to serum and myocardial drug concentrations

The antiadrenergic actions of amiodarone (Am) are well known but its effect and that of its metabolite, desethylamiodarone (DAm), on beta-receptor density (Bmax) and affinity (KD) are poorly defined. Thus, the acute and chronic effects of Am and DAm on myocardial beta-receptors in rabbits were determined relative to changes in thyroid hormones and serum and tissue drug concentrations. Bmax and KD were measured by radio-ligand binding, thyroid hormones by RIA, and drug levels by HPLC. Compared with controls, intravenous Am (20 mg/kg) reduced Bmax by 23% (p less than 0.05) and DAm (20 mg/kg) by 32% (p less than 0.05). After 3 weeks of chronic drug, the corresponding value for Am was 24% (p less than 0.05) versus 45% (p less than 0.05) for DAm. The effect of DAm was significantly greater (p less than 0.05) than that of Am, being comparable to that of Am (-44%) after 6 weeks. In the case of Am, doubling the dose (and myocardial level) led to no further decrease in Bmax. DAm also reduced Bmax more following chronic treatment than after acute administration (-45 versus -32%), a difference of borderline significance. Following 3 weeks of p.o. Am, T3 decreased 3% (NS) and reverse T3 (rT3) increased 90% (p less than 0.05); after 6 weeks, the corresponding values were 25% (p less than 0.05) and 181% (p less than 0.01). After 1 week of p.o. DAm, T3 did not change but rT3 increased by 34% (p less than 0.05); after 3 weeks the corresponding values were 21% (p less than 0.01) and 64% (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

The health and wellbeing of informal caregivers: a review and study program

Abstract: Informal caregivers are the families and other unpaid caregivers in the home who support people of all ages with severe and chronic mental or physical disabilities. Home care of this sort has been increasing over the past 30 years because of the reduced number of beds in hospitals and nursing homes and increased outpatient and community care. Moreover, with an aging population and increasing rates of disability, the demand for family caregiving will continue to rise. This has important implications for the development of health, community service and social policy. At the same time, however, very little is known about the impact such changes are having on the caregivers of various ages and in various circumstances. The Victorian Health Promotion Foundation is funding a research and intervention program in Melbourne to promote wellbeing and prevent ill-health in caregivers.     

Antibodies against factor VIII in patients with solid tumors: successful treatment of cancer may suppress inhibitor formation.

Between 1995 and 1998, we treated 5 patients with anti-factor VIII antibodies and spontaneous bleeding. All patients had underlying malignant conditions. Initial control of the bleeding episodes and reduction in inhibitor titer was achieved in all patients. Disappearance of factor VIII inhibitor occurred in 3 patients after either resection of the tumor or chemotherapy. Immunosuppression therapy failed to eradicate the antibody in 2 patients with metastatic disease. Antibodies against factor VIII appearing in certain patients may be directly associated with the underlying malignancy, rather than a coincidental finding. Attempts to reduce the titer or eradicate the inhibitor may fail if recognition of the underlying condition is not sought, or an appropriate treatment of cancer is not offered.     

Studies on the mechanism of 3-deazaguanine cytotoxicity in L1210-sensitive and -resistant cell lines

Summary 3-Deazaguanine (3-DG), a purine analogue, has unusual antitumor activity against experimental mammary tumor models and a number of other solid tumors. Others have shown that mutant CHO cells deficient in hypoxanthine guanine phosphoribosyl transferase (HGPRTase) or adenine phosphoribosyl transferase (APRTase) are resistant to 3-DG. We developed a L1210 cell line resistant to 3-DG, L1210/3-DG, by subculturing the parent L1210/0 cells in the presence of increasing concentrations of 3-DG. The IC₅₀ was 3.5 M and 620 M for L1210/0 and L1210/3-DG, respectively. Cytotoxicity studies proved the resistance to be stable. Examination of the baseline-specific activity of HGPRTase and APRTase showed that the former was 118-fold lower in L1210/3-DG than in L1210/0, and the latter demonstrated no difference. A 4-h treatment of the cell lines at IC₅₀ doses showed 48% and 23% reductions in IMP dehydrogenase in L1210/0 and L1210/3-DG, respectively. The rate of de novo purine biosynthesis was studied by using [¹⁴C]formic acid. Formate flux increased 2-fold in L1210/3DG in concert with the observed deficiency of HGPRTase in the cell line. 3-DG uptake was studied with [¹⁴C]-labelled compound. The total radioactivity was 9-fold higher in L1210/0 than in L1210/3-DG at 2 h. Subsequent chromatographic separation of radioactivity showed the 3-DG and 3-deazaguanosine pools of the drug to be equal in both lines. However, 3-DG nucleotide pools at 1 min and 2 h were 2.5-fold and 16-fold lower, respectively, in L1210/3-DG than in L1210/0. 3-DG incorporation studies with radiolabelled drug demonstrated that 3-deazaguanine is incorporated in the acid-insoluble fraction of the cell. These studies conclude that HGPRTase, and not APRTase, is required for the activation of drug. Inhibition of IMP dehydrogenase is partially responsible for antitumor activity of the drug. The incorporation of drug into nucleic acids may be a major mechanism for its antitumor activity. Further studies using a cloned cDNA probe for hypoxanthine guanine phosphoribosyltransferase (HGPRT) demonstrated no change in the DNA arrangements of the L1210/3-DG cell line, and Northern blot analysis showed approximately equal expression of mRNA in both cell lines.Abbreviations used APRTase adenine phosphoribosyltransferase - HGPRTase Hypoxanthine guanine phosphoribosyltransferase - IMPD Inosine mono-phosphate dehydrogenase - PRPP 5-Phosphorylribose-1-pyrophosphate - AOPCP , -Methyleneadenosine 5-diphosphate - NAD Nicotineamide dinucleotide - EDTA Ethylenediamine tetra acetic acid Presented at annual meeting of American Association of Cancer Research in May, 1986Supported in part by Warner-Lambert Company, Ann Arbor, Michigan     

Glutathione S-transferase isoenzymes in human lung tumors

In the present studies we have compared the levels of glutathione(GSH) and GSH-related enzymes in lung tumors and correspondingnormal tissues obtained from the same individuals. We have alsoimmunologically quantitated the relative amounts of glutathioneS-transferase (or GST-P) type antigen in tumors and adjacentnormal tissues from five patients. GST activities towards 1-chloro-2,4-dinitrobenzene (CDNB) and ethacrynic acid were found to beelevated in tumors from two out of five patients (patients #1and 4), whereas the activity towards these substrates was markedlysuppressed in the tumor tissue from one of the patients (#5).Immunotitration and Western blot studies using antibodies raisedagainst -type GST isoenzymes of human lung and placenta indicatedinduction of GST -type isoenzyme in tumors from patients #1and 4 and suppression of this isoenzyme in tumor from patient#5. The tumors from patients #2 and 3 did not show any increasein GST activity or GST -type antigen. Except for the tumor frompatient #5, the GSH content was higher in the tumors from otherpatients. GSH reductase activity was found to be elevated intumors of all the patients examined in this study. These resultsindicate that GSH and GSH related enzymes are differentiallyaltered in lung tumors and GSH levels and GST - or GST-P-typeisoenzyme(s) are not uniformly elevated in all tumors.     

Pancreatoblastoma (infantile pancreatic carcinoma)--a case report

Pancreatoblastoma or infantile pancreatic carcinoma is a rare pancreatic tumor with distinct acinar and squamoid cell differentiation that generally affects infants and young children. Ultrasound and CT scan may be useful but preoperative diagnosis is often quite difficult. The outcome is generally favourable. A such case of 10 years old boy with an abdominal mass is being presented.