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C Hershko

Publications and source records attributed to C Hershko.

At least 19 recordsLinked to original sources
PubMed1995

Results of long-term deferiprone (L1) therapy: a report by the International Study Group on Oral Iron Chelators.

This report updates the combined experience of four centres involved in the long-term treatment of transfusional iron overload in 84 patients with the oral iron chelator deferiprone (L1) over 167 patient-years. The source of L1 was variable, including two university research laboratories and three pharmaceutical firms. Compliance was rated as excellent in 48%, intermediate in 36%, and poor in 16% of patients. On a mean L1 dose of 73-81 mg/kg/d, urinary iron excretion was stable, at around 0.5 mg/kg/d, with no indication of a diminishing response with time. Serum ferritin showed a very steady decrease with time from an initial mean +/- 1 SD of 4207 +/- 3118 to 1779 +/- 1154 micrograms/l after 48 months (P < 0.001). 17 patients abandoned L1 therapy. Major complications of L1 requiring permanent discontinuation of treatment included agranulocytosis (three), severe nausea (four), arthritis (two) and persistent liver dysfunction (one). The remaining patients abandoned treatment because of low compliance (three) and conditions unrelated to L1 toxicity (four). Lesser complications permitting continued L1 treatment included transient mild neutropenia (four), zinc deficiency (12), transient increase in liver enzymes (37), moderate nausea (three) and arthropathy (17). There was no treatment-related mortality. Although the complications associated with L1 treatment are significant and require close monitoring, they do not preclude effective long-term therapy in the vast majority of patients. Further well-controlled prospective studies of L1 are required in order to enable proper judgement of its suitability for general long-term clinical use.

Adult↗
PubMed1995

The haematologist as watchdog of community health by full blood count.

Although full blood counts (FBC) are among the most commonly performed laboratory tests, the contribution of routine FBCs to the diagnosis of new problems is controversial. This study represents a unique linkage of a consultant haematology team, reviewing all abnormal blood counts, to an organization providing ambulatory health care to 350,000 patients. The objective was to establish the underlying clinical disorders responsible for all abnormal FBCs during a 2-month period, and to estimate the impact of the haematology team on the diagnostic work-up and management of newly identified problems. 572 (2.55%) of the 22,454 FBCs were abnormal. Of these, 357 showed microcytosis, caused by iron deficiency (58%), thalassaemia minor (35%), inflammation (6%) or chronic renal failure (1%). The most common causes of normocytic anaemia (25 patients) were disseminated malignancy and acute blood loss; of macrocytosis (27 patients), chronic liver disease and cancer; of erythrocytosis (16 patients), chronic hypoxia; of thrombocytopaenia (48 patients), chronic liver disease and ITP; of thrombocytosis (47 patients), iron deficiency and inflammation; of leukopaenia or pancytopaenia (20 patients), cirrhosis and disseminated malignancy; and of leukocytosis (26 patients), chronic leukaemias in the elderly and infection in children. Major new haematological abnormalities were encountered in 0.24% of all blood counts, representing about one new diagnosis per day. Routine blood counts do contribute to the health care of a population. Screening for haematological disease through a central clinical laboratory covering a large high-risk ambulatory population offers a cost-effective way of searching for serious clinical problems, alerting the primary physicians of their existence, and offering advice in continued evaluation and problem management.

Adolescent↗
PubMed1994

Ability of the orally effective iron chelators dimethyl- and diethyl-hydroxypyrid-4-one and of deferoxamine to restore sarcolemmal thiolic enzyme activity in iron-loaded heart cells.

In view of the profound functional and structural abnormalities shown in our previous studies in cultured, iron-loaded rat heart cells, we have examined the ability of the orally effective iron chelators dimethyl-3-hydroxypyrid-4-one (DMHP or L1) and diethyl-3-hydroxy-pyrid-4-one (DEHP or CP94) and of deferoxamine (DF) to reverse the damage caused by iron loading to heart cell organelles. At a concentration of 1.0 mmol/L, all three iron chelators were equally efficient in removing iron and restoring the activity of the thiolic sarcolemmal enzymes 5'-nucleotidase and Na,K,ATPase. However, at 0.1 mmol/L DMHP and DEHP were less effective than DF both in their iron-mobilizing effect and in promoting thiolic enzyme recovery. The superior efficiency of DF at low concentrations illustrates the advantage of the hexadentate chelating action of DF as compared with bidentate chelators such as DMHP and DEHP requiring a 3 to 1 molar ratio to iron for optimal effect. In contrast to its beneficial effect on sarcolemmal enzyme activity, iron chelation was unable to reverse the increase in beta-hexosaminidase activity caused by abnormal lysosomal fragility. Our study demonstrates for the first time that iron-induced peroxidative damage to the myocardial cell is associated with a marked loss of Na,K,ATPase activity, an enzyme with a major role in the maintenance of cellular resting potential. The timing of this damage and the restoration of Na,K,ATPase function by iron-chelating treatment suggest a cause-and-effect relationship between the observed injury to the sarcolemmal enzyme and the reversible electrophysiologic abnormalities observed in the same heart culture system in our previous studies.

5'-Nucleotidase↗
PubMed1994

Plasma cell dyscrasia with marrow fibrosis. A reversible syndrome mimicking agnogenic myeloid metaplasia.

BACKGROUND: The interrelation between plasma cell dyscrasia and myelofibrosis or agnogenic myeloid metaplasia (AMM) is unclear. The existence of two distinct syndromes has been proposed: (1) plasma cell dyscrasia associated with simple marrow fibrosis caused by the secretion of lymphokines and (2) myeloma coexisting with AMM representing two distinct clonal diseases. METHODS: The authors report the case of a 68 year-old man seen initially with severe anemia, massive splenomegaly, a leuko-erythroblastic blood morphology, and myelofibrosis coexisting with massive bone marrow infiltration with IgA lambda-producing plasmacytoid cells. RESULTS: Cyclic therapy with vincristine, carmustine, cyclophosphamide, melphalan, and prednisone resulted in clinical remission of the myeloma lasting for 2 years and complete resolution of all the clinical features resembling AMM. CONCLUSIONS: The authors' observations and the report of two other patients in whom remission of AMM has been observed after myeloma treatment underline the broad spectrum of secondary abnormalities ranging from moderate bone marrow fibrosis to the full clinical expression of a syndrome closely mimicking AMM. These secondary abnormalities are potentially reversible even in the presence of advanced bone marrow fibrosis and massive splenomegaly.

Aged↗
PubMed1994

Control of disease by selective iron depletion: a novel therapeutic strategy utilizing iron chelators.

Recognition of the central role of iron in the generation of toxic, oxygen-derived species through the Haber-Weiss reaction, the ability of desferrioxamine (DFX) to prevent the damage associated with free radical generation in reperfusion injury, and its inhibitory effect on cell proliferation by inactivation of the iron dependent enzyme ribonucleotide reductase, resulted in an increasing number of studies exploring the novel therapeutic applications of iron chelating drugs: (a) Animal models of reperfusion injury have shown that DFX is able to decrease post-anoxic damage to the brain and heart as manifested in decreased infarct size and improved functional recovery. Iron chelators may be particularly useful in improving the preservation of organs intended for transplantation such as the heart, lung or kidney. (b) Anthracycline cardiotoxicity is aggravated by iron and inhibited by iron chelators. Because the mechanism of its antineoplastic effect differs from its cardiotoxic effect, it is possible to inhibit anthracycline cardiotoxicity without interfering with therapeutic efficacy. In vivo and in vitro animal studies have yielded encouraging results but much additional experimental work is still required before iron chelating therapy may be advocated for use in patients on anthracycline therapy. (c) Cell proliferation can be inhibited by iron chelators through the reversible inhibition of ribonucleotide reductase, a rate-limiting enzyme in DNA synthesis. This may be exploited for the treatment of malignant disease, and preliminary studies have already shown that DFX in combination with multidrug chemotherapy is effective in controlling neuroblastoma and other tumours. However, the contribution of DF to the overall clinical effect is unclear. Prospective controlled clinical studies are required in order to establish whether the antiproliferative, or cell synchronizing properties of DFX may be of practical usefulness in the control of malignant disease. (d) Control of protozoal infection: Experimental in vivo and in vitro models have shown that malarial infection may be inhibited by iron chelating therapy. This useful effect of DFX and other iron chelators is most probably related to ribonucleotide reductase inhibition. Clinical studies of asymptomatic P. falciparum malaria and of cerebral malaria have shown both an accelerated rate of parasite clearance and earlier recovery from coma. These observations lend new meaning to the term 'nutritional immunity' and open new channels for exploring the possibility of controlling infection by means of selective intracellular iron deprivation. Experimental models for studying the effect of iron chelators on other intracellular pathogens such as Toxoplasma gondii, Chlamydia psittaci, or Mycobacterium tuberculosis should be established.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

The changing clinical spectrum of liver abscess: the Jerusalem experience.

A retrospective study was conducted of all 31 patients with liver abscess admitted to Shaare Zedek Medical Center between 1979, the year computed tomographic scan and ultrasound were introduced, and 1992. Fever and abdominal pain were the most common symptoms. Duration of symptoms was short: 81% of patients had symptoms for < or = 5 days and none had symptoms for more than 3 weeks. Amoebic abscess was found in one patient only, the remainder were pyogenic. Biliary tract pathology remains the most common cause of liver abscess (39%). The diagnosis was made by ultrasound in 22/31 (71%) and by computed tomographic scan in 9/31 (29%) of patients. Treatment consisted of intravenous antibiotics and percutaneous drainage under ultrasound guidance in 24/31 patients (77%). Four patients died (13%), three of whom had underlying malignancies. Clinical features were compared with those from a similar series of 36 cases with liver abscess reported from Jerusalem predating ultrasound and computed tomographic scan (1967-1977). Several major changes have occurred. First, the relative incidence of amoebic abscess has dramatically decreased. Second, ultrasound and computed tomographic scan have facilitated earlier diagnosis and percutaneous drainage, contributing to improved survival and lower morbidity.

Adolescent↗
PubMed1993

The role of iron and iron chelators in anthracycline cardiotoxicity.

The redox cycling of anthracyclines promotes the formation of free radicals which are believed to play a central role in their cardiotoxicity. A number of observations indicate that the mechanism of the antineoplastic effect of anthracyclines is independent of their cardiotoxic effect and that it may be possible to prevent toxicity without interfering with therapeutic effect. Iron plays an important role in anthracycline toxicity by promoting the conversion of superoxide into highly toxic hydroxyl radicals through the Haber-Weiss reaction. Conversely, iron deprivation by its high-affinity binding to iron chelating compounds may inhibit anthracycline toxicity by interfering with free radical formation. ICRF-187, a bispiperazonedione which is hydrolyzed intracellularly into a bidentate chelator resembling EDTA, is able to decrease adriamycin-induced free hydroxyl radical formation and to prevent the development of clinical cardiac toxicity in patients receiving long-term anthracycline therapy. Our studies in rat heart cell cultures have shown that iron overload aggravates anthracycline toxicity and that this interaction can be prevented by prior iron chelating treatment. Since iron overload caused by multiple blood transfusions and bone marrow failure is a common condition in patients requiring anthracycline therapy, these observations may have significant clinical implications to the prevention of anthracycline cardiotoxicity.

Animals↗
PubMed1993

Anthracycline toxicity is potentiated by iron and inhibited by deferoxamine: studies in rat heart cells in culture.

The interrelation between iron, iron chelation, and anthracycline toxicity was investigated in a heart cell culture system. Two indicators of cellular damage have been used, lactate dehydrogenase (LDH) release and cell contractility. Both of these indicators have shown a marked increase in doxorubicin toxicity by prior iron loading. This was not a simple additive effect, because at the concentrations used, iron had only a minimal effect on LDH release and no effect at all on contractility, whereas doxorubicin had only a minor effect on contractility. Deferoxamine (DF) treatment of iron-loaded heart cells resulted in a marked decrease in anthracycline toxicity as judged both by LDH leakage and cell contractility. However, DF treatment of normal heart cells had no measurable protective effect against doxorubicin toxicity, whether DF was administered before or simultaneously with doxorubicin. Doxorubicin treatment did not alter cellular malondialdehyde (MDA) concentrations in either normal or iron-loaded cells. Conversely, the protective effect of DF in iron-loaded cells and its failure to prevent anthracycline toxicity in normal cells were both associated with a significant decrease in MDA measurements. Our data indicate that iron overload aggravates anthracycline toxicity and that this interaction may be prevented by effective iron chelating therapy. Because patients requiring anthracycline therapy often have increased tissue iron stores caused by multiple blood transfusions and bone marrow suppression, our observations may have important implications for the prevention of anthracycline toxicity.

Animals↗
PubMed1993

Iron loading of cultured cardiac myocytes modifies sarcolemmal structure and increases lysosomal fragility.

The mechanism of damage to myocardial subcellular organelles was studied in iron-loaded rat myocardial cells in culture in an attempt to identify the primary target of iron's toxic effects. Lysosomes and sarcolemmal membranes were purified by fractionation of the postnuclear supernatant on a 6.7% colloidal polyvinylpyrrolidone-coated silica gradient. After 24-hour incubation with ferric ammonium citrate at a concentration of 20 micrograms/ml (0.36 mmol/L) iron, a selective depletion of polyunsaturated fatty acids was found in whole-cell homogenates, as well as in the postnuclear supernatant and sediment. Iron loading resulted in a sharp increase in the total activity of the lysosomal enzyme beta-hexosaminidase in unfractionated whole-cell homogenates, increased free enzyme activity, and loss of latent activity indicating increased lysosomal fragility. Conversely, iron loading resulted in a marked decrease in the activity of the sarcolemmal enzyme 5'-nucleotidase and a significant loss of total protein sulfhydryl group content. These studies in cultured heart cells are in agreement with previous observations indicating increased lysosomal fragility in iron-loaded hepatic and splenic tissues, attributed to increased membrane lipid peroxidation. In addition, the marked decrease in sarcolemmal 5'-nucleotidase activity and in total protein sulfhydryl group content imply that iron-induced peroxidative damage to membrane proteins may be a more important mechanism in the pathogenesis of altered myocardial function in the iron-loaded heart than formerly was recognized.

5'-Nucleotidase↗
PubMed1993

Effect of age and duration of disease on the clinical manifestations of brucellosis. A study of 73 consecutive patients in Israel.

We describe our experience with 73 patients diagnosed with brucellosis during the years 1979-91 at two Jerusalem hospitals: Hadassah Mount Scopus (37 patients from 1979-1984) and Shaare Zedek (36 patients from 1979-1991). The patients included 32 children less than 14 years old and 41 adults; 70 of the patients were non-Jews. In all cases the pathogen was Brucella melitensis. The high proportion of children and the equal sex distribution was quite different from the age and sex distribution of brucellosis in Western countries where it is more common in adult males, and similar to that reported from other near-Eastern countries where household dairy products, and not occupational exposure, are the most common source of infection. The short duration of disease (< 2 weeks) prior to diagnosis in 70% of the patients is attributed to the ready availability of appropriate medical care, and a very high index of suspicion for brucellosis in the Jerusalem non-Jewish population. Abdominal symptoms were more common in adults, whereas enlarged lymph nodes and liver, skin rash and pharyngitis were more frequently observed in children. Some of these differences may be attributed to the very short duration of disease in most children at the time of presentation. Combination therapy with tetracycline-streptomycin or tetracycline-rifampin yielded superior results as compared with single-drug treatment in terms of early defervescence and relapse rates. The present experience underlines the importance of endemic brucellosis which still represents a significant public health problem in children and adults in Mediterranean countries.

Adolescent↗
PubMed1992

Origin and fate of iron mobilized by the 3-hydroxypyridin-4-one oral chelators: studies in hypertransfused rats by selective radioiron probes of reticuloendothelial and hepatocellular iron stores.

The mechanism of in vivo iron chelation by 3-hydroxypyridin-4-ones (CP compounds) was studied in hypertransfused rats in which the major storage iron pools in hepatocytes and in the reticuloendothelial (RE) system have been labeled by selective radioiron probes. Both dimethyl-3-hydroxypyridin-4-one (CP 20 or L1) and diethyl-3-hydroxypyridine-4-one (CP 94) have an identical and very high (log beta 3 36) binding constant and selective affinity to iron(III), but the lipid solubility of CP 94 is considerably higher than that of CP 20. Both chelators induced an increase in the fecal excretion of hepatocellular iron with no effect on urinary excretion. In contrast, about one third to one half of the iron mobilized from RE cells was excreted in the urine. The chelating efficiency of CP 20 was comparable with that of deferoxamine (DF), whereas CP 94 was up to eight times more effective than DF. Unlike DF, which had no effect by the oral route, the oral and parenteral effectiveness of both CP compounds was identical. These findings indicate that: (1) lipid solubility is an important determinant of in vivo chelating efficiency; (2) urinary iron excretion induced by the CP compounds is derived from RE cells; (3) part of the iron mobilized from RE cells and all of the iron derived from hepatocytes is excreted through the bile; and (4) contrary to previous observations in cell cultures, there is no in vivo evidence for a diminishing chelating efficiency at the lowest doses used.

Animals↗