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C Hershko

Publications and source records attributed to C Hershko.

At least 73 records · Page 4Linked to original sources
PubMed1989

Biological models for studying iron chelating drugs.

Experimental models for studying the biological effects of iron chelators range from in vitro cell cultures to in vivo models in a variety of animals. Apart from screening for chelating efficacy, such models have been useful in providing information on the pharmacology of desferrioxamine and a number of other, orally effective iron chelators; in the identification of the biological source of iron mobilized by such chelators; in defining optimal methods of drug delivery; in providing evidence for the ability of iron chelators to prevent or reverse iron toxicity; and in exploring the potential usefulness of iron chelating therapy in conditions unrelated to iron overload, where iron may fulfil a central role in the pathogenesis of disease. Although cell cultures are inexpensive and permit the rapid screening of large numbers of new chelating compounds, they may overlook alternative sources of chelatable iron, pro-drugs, and orally effective compounds. In vivo models provide information on drug toxicity, allow comparison of oral versus parenteral efficacy, routes of excretion of chelated iron, monitoring of selective interaction with various iron pools, and promotion of the excretion of various trace metals. Although iron metabolism in large animals such as dogs and monkeys closely resembles that of humans, small animals such as mice and rats are usually preferred because of their low cost and ease of handling. Thorough knowledge of the pharmacology of iron chelators is a prerequisite for their successful therapeutic application. Interaction with a rapidly exchanging, intracellular, low molecular weight chelatable iron pool requires a steady supply of a drug capable of penetrating the relevant effector cells. The high effectiveness of continuous desferrioxamine infusion illustrates this point and underlines the need for developing new orally effective iron chelators which, by virtue of their slower absorption, would be more suitable for providing a continuous supply of circulating drug.

Animals↗
PubMed1989

Deficiency of the eighth component of complement. Evidence for linkage of C8 alpha-gamma pattern with C8 beta deficiency in sera of twelve patients.

The C8 alpha-gamma subunit of the eighth component of complement was analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and immunoblotting in sera from 68 normal individuals, 12 C8 beta-deficient patients (from seven unrelated families), and 10 of the parents of the latter. Three different forms of the C8 alpha-gamma subunit were observed: 34/68 normal individuals were found to have a C8 alpha-gamma triple band (termed C8 alpha-gamma 1, C8 alpha-gamma 2, C8 alpha-gamma 3 variants), 23/68 the C8 alpha-gamma 2 and C8 alpha-gamma 3 variants, and 11/68 the C8 alpha-gamma 1 and C8 alpha-gamma 3 variants. In contrast, all C8 beta-deficient patients had detectable C8 alpha-gamma 2 and C8 alpha-gamma 3 variants but lacked the C8 alpha-gamma 1 variant in addition to the C8 beta subunit. Three out of ten parents of the C8 beta-deficient patients were found to have the C8 alpha-gamma triple band, whereas 7/10, like their children, had the C8 alpha-gamma 2 and C8 alpha-gamma 3 variants only. We conclude that there is a linkage between the C8 alpha-gamma pattern and C8 beta deficiency. These data may support earlier findings that in humans the genes encoding for C8 alpha-gamma and C8 beta are closely linked on chromosome 1.

Adult↗
PubMed1989

Paraneoplastic hypercalcemia in endometrial carcinoma.

Humoral hypercalcemic syndrome associated with tumors of the female reproductive system is believed to be uncommon, and only 27 such cases have been identified prior to 1980. We describe 2 patients with humoral hypercalcemia in clear cell adenocarcinoma of the uterus, and review the literature on previously published cases. Both our patients fulfilled the criteria for humoral hypercalcemic syndrome, namely: hypercalcemia without bone metastases ranging from 12.8 to 14.1 mg/dl in the presence of normal serum parathyroid hormone levels, reduced tubular reabsorption of phosphate, and reduced serum albumin. We propose that humoral hypercalcemia is perhaps not a rare complication of uterine malignancy and, that increased awareness may result in early diagnosis of this important metabolic problem.

Adenocarcinoma↗
PubMed1989

Quality of life and survival following intensive medical care.

The relation between quality of life before admission and the outcome of admissions to the intensive care unit (ICU) was studied prospectively among 126 patients in a community hospital with a predominantly geriatric patient population. Fifty-four per cent of our patients were older than 65 years and 66 per cent suffered from chronic ill health. Their mean APACHE score was 18 +/- 8 (mean +/- SD). Quality of life was assessed by the Karnofsky index of physical performance; the linear analogue self assessment (LASA) score; sleep index; level of employment; sexual activity; housing status. Thirty-seven per cent of the patients died in ICU and another 10 per cent in hospital. The one year survival of the entire group was 37 per cent. Survival rates were significantly higher in patients with a Karnofsky index of 6 or more, LASA score of 55 or more, in employment, and with sleep index of 2 or more (p less than 0.05). The 12-month survival among patients with four favourable indicators was 59 per cent, with two or three favourable indicators 36 per cent (p less than 0.05), and in patients with no favourable indicators of quality of life or only one 17 per cent (p less than 0.001). Quality of life in patients who survived longer than six months after ICU care was high (Karnofsky index 7.9 +/- 2.0; LASA score 71 +/- 20 (mean +/- SD) and unimpaired when compared with their ratings before admission to the unit. These findings indicate that quality of life before admission is an important predictor of survival and that a high proportion of critically-ill subjects whose quality of life was relatively good before the episode requiring admission will be long-term survivors whose quality of life is comparable to that preceding critical care.

Activities of Daily Living↗
PubMed1989

Iron chelation.

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Animals↗
PubMed1989

Iron loading modifies the fatty acid composition of cultured rat myocardial cells and liposomal vesicles: effect of ascorbate and alpha-tocopherol on myocardial lipid peroxidation.

Increased generation of free radicals and accelerated lipid peroxidation are important manifestations of iron toxicity. We have studied the effect of iron loading on lipid peroxidation in cultured rat myocardial cells by direct measurement of the fatty acid composition of cellular lipids. Iron loading produced by 24-hour incubation of cultured cells with 0.36 mmol/L ferric ammonium citrate resulted in a moderate reduction in polyunsaturated fatty acids (PUFAs) such as 22:5 and 22:6. A more drastic reduction in PUFAs and an apparent reciprocal increase in the proportion of saturated fatty acids were both obtained after 24 hours of incubation of liposomal vesicles prepared from whole cell lipid extracts with iron at between pH 4.5 and pH 5.5. Reduction of 22:5 and 22:6 was first noticed at 3 hours, and undetectable levels were reached by 12 and 24 hours of incubation. Ascorbate had a biphasic effect on liposomal PUFA levels: at low concentrations (0.057 mmol/L) it enhanced the iron-induced changes in liposomal fatty acid composition, but at higher concentrations (0.57 and 5.7 mmol/L), it inhibited these changes. Unlike ascorbate, alpha-tocopherol (0.023 to 2.3 mmol/L) inhibited the iron-induced reduction in PUFAs in a dose-dependent manner, with complete inhibition of the iron effect at 2.3 mmol/L. These observations underline the particular sensitivity of PUFAs to iron-induced lipid peroxidation. They also illustrate the ability of ascorbate and alpha-tocopherol to modify iron-induced lipid peroxidation. Further studies are required to explore the possible therapeutic implications of these observations in clinical iron overload.

Animals↗
PubMed1989

Effect of iron loading on transmembrane potential, contraction, and automaticity of rat ventricular muscle cells in culture.

The effect of iron loading on membrane potential and cellular contractility was examined in cultured heart cells obtained from newborn rat ventricles exposed to ferric ammonium citrate at iron concentrations of 20, 40, and 80 micrograms/ml for 24 hours. The main functional effect of iron loading was depression of the overshoot potential. Severe arrhythmias were encountered in two of eight studies with 40 micrograms/ml iron and in two of seven studies with 80 micrograms/ml iron, but they were not found in any of the 29 control studies (p less than 0.01). Iron loading also resulted in a significant enhancement of cellular LDH release, indicating a loss of cell membrane integrity. In vitro treatment of iron-loaded cells with deferoxamine, a selective iron-chelating compound, resulted in a striking reversal of the iron-induced depression in the plateau phase of action potential, the disappearance of arrhythmias, and a reduction in LDH leakage. These favorable effects of deferoxamine lend support to the contention that the observed abnormalities following iron-loading were specific expressions of iron toxicity. Although these observations are consistent with iron-induced peroxidative damage to membrane lipid components, further studies are required in order to elucidate the nature of such a putative membrane effect of excess iron.

Animals↗
PubMed1988

Diagnostic value of ferritin in malignant pleural and peritoneal effusions.

The diagnostic usefulness of ferritin measurements in pleural and peritoneal effusions has been evaluated in 57 patients. Mean (+/- standard error [SE]) ferritin levels were 291 +/- 50 ng/ml in 24 patients with noninflammatory transudates (Group I), 942 +/- 253 in 15 patients with nonmalignant exudates (Group II), and 1805 +/- 257 in 18 patients with malignant exudates (Group III). The mean (+/- SE) ratio of effusion/serum ferritin in Groups I, II, and III was 0.7 +/- 0.1, 2.7 +/- 0.7, and 5.7 +/- 1.2, respectively. The specificity and predictive value of a ferritin ratio in excess of 1.5 in distinguishing transudates from all exudates and in distinguishing transudates from malignant exudates were both very high (94%) to 96%). In the lower range of values considerable overlap existed between ferritin ratios obtained in patients with benign versus malignant inflammatory exudates. However, very high ferritin levels (greater than 3000 ng/ml) and ferritin ratios (greater than 20:1) were only encountered in malignant exudates. These results indicate that the measurement of ferritin levels and ferritin ratios may be a useful aid in the diagnosis of malignant pleural and peritoneal effusions.

Adult↗
PubMed1988

Deferoxamine inhibition of malaria is independent of host iron status.

The mechanism whereby deferoxamine (DF) inhibits the growth of malaria parasites was studied in rats infected with Plasmodium berghei. Peak parasitemia was 32.6% (day 14) in untreated controls and 0.15% (day 7) in rats receiving 0.33 mg/g in 8 hourly DF injections, subcutaneously. DF inhibition of parasite growth was achieved without any reduction in transferrin saturation or hemoglobin synthesis and with only a partial (56%) depletion of hepatic iron stores. Dietary iron depletion resulted in anemia (hematocrit 25 vs. 46%), microcytosis (MCV 54 vs. 60 fl), and reduced transferrin saturation (17 vs. 96%) without any effect on infection (peak parasitemia 30 vs. 36%). Similarly, parenteral iron loading with ferric citrate over 10 d (75 mg iron/kg) failed to aggravate infection. In a search for evidence of direct interaction between DF and parasitized erythrocytes, gel filtration and ultrafiltration was performed on hemolysates obtained from in vivo 59Fe-labeled parasitized erythrocytes. This showed that 1.1-1.9% of the intracellular radioiron was located in a chelatable, labile iron pool. Incubation of intact cells with 0-500 microM DF resulted in a proportional increase in intracellular iron chelation, and the chelation of all available labile intracellular iron was completed within 6 h. These observations indicate that the severity of P. berghei infection in rats and its in vivo suppression by DF are independent of host iron status and suggest that DF inhibition of malaria involves intracellular chelation of a labile iron pool in parasitized erythrocytes.

Animals↗
PubMed1988

Reduced incidence of hyperkalemia and azotemia in patients receiving sulindac compared with indomethacin.

The incidence and severity of hyperkalemia and azotemia was investigated in a prospective randomized study involving 74 patients receiving either sulindac 200 mg p.o. b.i.d. or indomethacin 25 mg p.o. t.i.d. and 100 mg p.r. The mean +/- SE posttreatment increment in serum potassium was 0.8 +/- 0.1 mmol/l in patients treated by indomethacin compared to 0.5 +/- 0.1 in those receiving sulindac (p less than 0.025). The mean +/- SE posttreatment increment in blood urea nitrogen (BUN) was 3.1 +/- 0.4 mmol/l in patients on indomethacin compared to only 0.9 +/- 0.3 in patients on sulindac (p less than 0.001). In 5 patients who developed hyperkalemia while on indomethacin, changing to sulindac resulted in a sharp reduction of serum potassium in 3, and normalization of BUN in all patients. These data support the claim of a reduced risk of impaired renal function associated with the use of sulindac.

Aged↗
PubMed1988

Evolution of malignant lymphoma in agnogenic myeloid metaplasia.

Two young arab patients are described in whom malignant lymphoma developed within less than 1 year of the diagnosis of agnogenic myeloid metaplasia. Both patients showed a satisfactory response to combined chemotherapy. One of them died of hepatitis B at 10 months and the other is alive and in clinical remission 25 months after initial diagnosis. These observations demonstrate the close relation between myeloproliferative and lymphoproliferative syndromes and illustrate the diversity of malignant lymphoproliferative disorders into which agnogenic myeloid metaplasia may evolve in the course of disease. Our experience also demonstrates the ease with which some patients with an 'end stage' myeloproliferative disorder may respond to standard chemotherapy designed for the treatment of malignant lymphoma.

Adult↗
PubMed1988

Iron-chelating therapy.

Because of the catalytic action of iron in one-electron redox reactions, it has a key role in the formation of harmful oxygen derivatives and production of peroxidative damage to vital cellular structures. The clinical manifestations of iron overload may be prevented and even reversed by the effective administration of the iron-chelating drug deferoxamine (DF). Recent experimental evidence suggests that DF may also be useful in modifying disease conditions unrelated to iron overload by preventing the formation of free radicals, the powerful final effectors of tissue damage resulting from the respiratory burst of granulocytes and macrophages participating in the inflammatory response. Although much experimental work is still needed, this novel approach in iron-chelating therapy may have far-reaching implications in the management of autoimmune disease, adult respiratory distress syndrome, and organ transplantation. The poor intestinal absorption of DF, its almost prohibitive price, and short duration of action underline the need for new, orally effective iron chelators. A number of very promising orally effective drugs have been identified in recent years, such as the polyanionic amines, aryl hydrazones, and hydroxypyridones. Further development for clinical use of this new generation of iron-chelating drugs is a major challenge for future research.

Animals↗