Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0854467 (myelosuppression)
 5,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Quelamycin (triferric doxorubicin) is a derivative of Adriamycin with different pharmacologic properties. Our phase I clinical study of quelamycin includes 37 patients with a wide spectrum of solid tumors. The recommended dose in good-risk patients is 150 mg/m2, given as a 1-hour infusion every 3 weeks. The dose-limiting factor appears to be myelosuppression, especially leukopenia. Other toxic effects include gastrointestinal intolerance and alopecia. Chills and fever are commonly encountered and might be due to an excess of free iron in currently available preparations. Cardiotoxicity could not be properly assessed. An objective antitumor effect was seen in patients with lung, gastric, colon, and ovarian carcinomas as well as osteogenic sarcoma. Further preclinical and clinical studies with an improved pharmaceutic formulation of the drug are highly desirable.
 ...
PMID:Early clinical trial with quelamycin. 45 31

LF, an iron-binding glycoprotein, has myelosuppressive effects in vitro and in vivo. The present study evaluated the mode of LF action in vitro and the effects of various recombinant CSFs and ILs on this action. Normal human low-density BMC, at 2 x 10(6)/ml, were exposed to purified and endotoxin-depleted iron-saturated LF for 2 h, washed three times, and plated for CFU-GM and BFU-E in the presence of rhuCSFs (e.g., GM-CSF, Epo, IL-3) and in the absence and presence of rhuIL-6, rhuIL-1 alpha, or rhuIL-1 beta. LF caused a 40-65% plateau curve of inhibition for CFU-GM and BFU-E that was not apparent when adherent mononuclear cells (monocytes) were removed from the target population of cells. This myelosuppression was ablated by rhuIL-6, but not by rhuIL-1 alpha or rhuIL-beta. These results suggests a role for IL-6 in the accessory cell-mediated suppressive effect of LF on CFU-GM and BFU-E and open up the possibility that IL-6 may have stimulatory/enhancing or cofactor activities necessary for optimal proliferation of hematopoietic progenitor cells.
 ...
PMID:Interleukin-6 ablates the accessory cell-mediated suppressive effects of lactoferrin on human hematopoietic progenitor cell proliferation in vitro. 206 24

A clinical phase (spent phase) in the course of polycythaemia vera (PV) cases is described as enlargement of the spleen in spite of treatment, frequent cytopenia of one or several lines, persistent red cell hypervolaemia with considerable increase of plasma volume, persistence of myeloid hyperplasia with no collagen myelofibrosis or osteomyelosclerosis, absence of hepatosplenic erythroblastic metaplasia, as shown by radio-iron kinetics and/or 111In-transferrin scintigraphy. The frequency of this phase was 5% in a study where it was not systematically sought, but it could in fact be greater. Its occurrence is not related to the clinical and biological parameters of PV. On the other hand, it is significantly more frequent and earlier in patients treated by phlebotomies than in those treated by myelosuppression (32P). In four of the 12 cases, this phase was rapidly followed by an acute leukaemia. In eight cases there was a 1-5 year interval before a myelofibrosis with splenic myeloid metaplasia. This evolution could at this stage be delayed by chemotherapy. The efficacy of splenectomy should be studied.
 ...
PMID:The 'spent' phase of polycythaemia vera: hypersplenism in the absence of myelofibrosis. 658 68

ICRF-187, the enantiomer of ICRF-159 formulated for iv use, was administered to 23 patients in a phase I clinical trial. The dose ranged from 500 to 1500 mg/m2 every day for 3 days and was repeated every 28 days. The toxic effects included moderate to severe leukopenia and thrombocytopenia, which recovered by the 21st day of a treatment cycle. Myelosuppression was more severe in patients with prior nitrosourea treatment. Nonmyelosuppressive toxic effects included nausea and vomiting, transient elevations in liver function tests, alopecia, and increased urinary clearances of iron and zinc. The starting dose for phase II trials should be 1250 mg/m2 daily for 3 days repeated at 21-day intervals.
 ...
PMID:Phase I study of ICRF-187 using a daily for 3 days schedule. 678 38

Anemia is a common side effect of cisplatin, especially after repeated infusions. The primary mechanisms is a myelosuppression caused by cisplatin's interference with iron metabolism, resulting in a lower count of red cell precursors. Some authors report a hemolytic anemia similar to penicillin-induced anemia, in which hemolysis is caused by an antiglobulin antibody directed against red cell membrane-bound cisplatin. The authors report two cases of cisplatin-induced anemia and suggest that the immune-complex hypothesis is responsible for hemolysis. The first case of carboplatin-induced hemolysis is also reported. Mechanisms of hemolysis and clinical practice are discussed.
 ...
PMID:Platin salts-induced hemolytic anemia: cisplatin- and the first case of carboplatin-induced hemolysis. 779 80

To estimate the incidence and causes of secondary thrombocytosis in children, a 12 month study of all patients attending a children's hospital and discovered to have a platelet count over two times the upper normal limit (> 800 x 10(9)/l) was undertaken. Data so obtained were analysed both separately and together with those from two previous studies to gain as broad a perspective as possible. Of 7916 children who had platelet counts during the study period, 36 (0.5%) produced a value > 800 x 10(9)/l; there were 19 boys and 17 girls. There was a preponderance of young infants (median age 13 months). Twenty seven of the 36 had some sort of associated infection, bacterial in 18 and viral in nine. The other nine were either recovering from anti-neoplastic chemotherapy (n = 6), were post-operative (n = 2), or simply iron deficient (n = 1). Combining these patients with those described in previous studies allowed a review of 139 unselected children with very high platelet counts. Fifty three (38%) had infections, 29 (20%) had traumatic or surgical tissue damage, 16 (11%) had malignant disease undergoing chemotherapy or surgery, and 13 (9%) had connective tissue or autoimmune disorders. Secondary thrombocytosis is not rare and is most frequently seen in very young infants after infection. It can arise in a wide variety of other circumstances including rebound from myelosuppression, iron lack, or as part of an acute phase response. It is clinically unimportant in terms of morbidity and requires no treatment other than that for the primary condition.
 ...
PMID:Secondary thrombocytosis. 802 12

Anthracycline-induced cardiotoxicity is believed to be related to the generation of reactive oxygen species by at least two mechanisms: enzymatic reduction of the quinone with subsequent redox cycling and/or formation of an iron-anthracycline complex capable of intramolecular reduction and redox cycling. Both pathways may lead to the production of superoxide anions and highly reactive metabolites, such as hydroxyl radicals and hydrogen peroxide. As a result, membrane lipid peroxidation may ensue, producing damage in tissues like the heart, which have low antioxidant defenses (superoxide dismutase glutathione and especially, glutathione-peroxidase). Pharmacologic methods of interrupting this cycle have involved numerous antioxidants, such as the sulfhydryls N-acetylcysteine and cysteamine, and the lipophilic vitamin alpha tocopherol. Unfortunately, none of these compounds has been proven to be cardioprotective in patients receiving doxorubicin. In contrast, the water-soluble d-isomer of the iron chelator razoxane, dexrazoxane or ICRF-187, has been shown to reduce doxorubicin-induced cardiomyopathy. This has afforded greater cumulative doses of doxorubicin to be safely administered. The cytoprotective effect is apparently limited to the heart since there is no effect on antitumor efficacy and, unfortunately, no reduction in gastrointestinal toxicity, and with a slight increase in myelosuppression. More recent preclinical studies have also demonstrated cardioprotective activity for the aminothiol amifostine (WR-2721). In vitro, this agent has been shown to scavenge superoxide anions and hydroxyl radicals, the latter effect mediated by the active (dephosphorylated) metabolite, WR-1065. In tumor-bearing mice, amifostine reduces the lethality of high doses of doxorubicin without affecting antitumor activity. Finally, in vitro studies in neonatal rat heart cells have shown direct evidence of anthracycline cardioprotection for both amifostine and WR-1065. Cytoprotective drug levels of either agent were limited to 2.0 microg/mL, which is one tenth of the achievable peak plasma levels in humans. At this concentration, a 15-minute sulfhydryl pretreatment significantly prevented doxorubicin-induced depressions of myocyte adenosine triphosphate levels. Overall, these studies suggest that amifostine may have cytoprotective activity against doxorubicin-induced cardiac damage. Animal studies in a chronically dosed doxorubicin model are indicated; if positive, clinical trials testing this hypothesis will be warranted.
 ...
PMID:Cytoprotective agents for anthracyclines. 878 63

The effectiveness of thrombopoietin (TPO) in alleviating thrombocytopenia was evaluated in a placebo-controlled study involving rhesus monkeys exposed to 5 Gy total-body irradiation (TBI) (300-kV x-rays) to result in 3 weeks of pancytopenia. Supraoptimal treatment with human recombinant TPO (10 microg/kg/d subcutaneously, days 1 to 21 after TBI) was highly effective in preventing thrombocytopenia, with nadirs for thrombocytes, on average, far higher than 100 x 10(9)/L, a greatly accelerated recovery to normal values, and no need for thrombocyte transfusions. TPO appeared to act selectively in that neutrophil regeneration was not influenced but red blood cell lineage recovery was prominently stimulated, with reticulocyte regeneration being initiated 10 days earlier than in placebo-treated animals. The reticulocytosis was followed by a normoblastosis that occurred earlier and was more pronounced than in placebo-treated monkeys. The effect of TPO on the red blood cell lineage was also reflected in a less profound nadir for hemoglobin (Hb) and hematocrit values than in placebo controls. However, this effect was not followed by a rapid recovery to normal values, due to development of a microcytic hypochromic anemia. Iron depletion was demonstrated by measurements of total serum iron and total iron-binding capacity (TIBC) and could be prevented by prophylactic intramuscular (IM) iron before TBI or corrected by IM iron after TPO treatment. Rechallenging with TPO in week 8 after TBI demonstrated a homogenous thrombocyte response similar in magnitude to the initial response, but a greatly diminished reticulocyte response. This demonstrated that the erythropoietic response to TPO administration depends on the hemopoietic state of the animal and may reflect multiple TPO target cells. It is postulated that the extremely rapid erythropoiesis due to TPO treatment in the initial regeneration phase following myelosuppression results in iron depletion by a mechanism similar to that seen following erythropoietin treatment in patients with end-stage renal failure. It is concluded that protracted TPO therapy to counteract thrombocytopenic states may result in iron depletion and that the iron status should be monitored before, during, and after TPO treatment.
 ...
PMID:Prevention of thrombocytopenia by thrombopoietin in myelosuppressed rhesus monkeys accompanied by prominent erythropoietic stimulation and iron depletion. 920 38

Anemia occurs frequently among patients seropositive for human immunodeficiency virus (HIV), but its multifactorial origin complicates its differential diagnosis and adequate treatment. In addition, the etiology of anemia in HIV infection often remains unclear. In recent years several attempts have been undertaken to elucidate the mechanisms leading to HIV-associated anemia. Direct infection of erythroid progenitors has been discussed, but could not be proven. Furthermore, soluble factors like HIV proteins and cytokines have been suggested to inhibit growth of hematopietic cells in the bone marrow of HIV-infected patients. However, so far no statements can be made whether these factors are directly involved in myelosuppression or mediate their effect by inhibiting growth-factor synthesis. Opportunistic complications represent the underlying cause for anemia in a large number of HIV-infected patients. Next to this rather obvious reason for anemia, iatrogenic anemia induced by myelosuppressive drugs is also very common. It is of note, however, that modern dosages of < 600 mg zidovudine (ZDV) daily rarely cause anemia. Instead, other drugs that can induce anemia itself or by enhancing ZDV plasma concentrations must be considered important contributing factors. Deficiency of vitamin B12, folate and iron are frequently reported in HIV patients. However, specific investigations revealed appropriate storage amounts of these micronutrients. Supplementation may be beneficial in some patients, but often fails to reverse anemia in this population. In anemic HIV patients reticulocytopenia is a consistent finding. Additionally, inadequately low endogenous erythropoietin concentrations have been repeatedly reported. Thus, it is speculated that a blunted erythropoietin feedback mechanism contributes substantially to the pathogenesis of anemia in HIV patients.
 ...
PMID:Pathogenesis and pathophysiology of anemia in HIV infection. 943 73

Dose-limiting toxicity secondary to antineoplastic chemotherapy is due to the inability of cytotoxic drugs to differentiate between normal and malignant cells. The consequences of this may include impairment of patient quality of life, because of toxicity, and reduced tumour control because of the inability to deliver adequate dose-intensive therapy against the cancer. Specific examples of toxicity against normal tissues include cisplatin-related neurotoxicity and nephrotoxicity, myelotoxicity secondary to treatment with alkylating agents and carboplatin, oxazaphosphorine-induced haemorrhagic cystitis, and cumulative dose-related cardiac toxicity secondary to anthracycline treatment. Chemoprotectants have been developed as a means of ameliorating the toxicity associated with cytotoxic agents by providing site-specific protection for normal tissues, without compromising antitumour efficacy. Clinical trials with toxicity protectors must include sufficient dose-limiting events for study, and assessment of both toxicity (allowing for measurement of efficacy of protection) and antitumour effect. Several chemoprotective compounds have now been extensively investigated, including dexrazoxane, amifostine, glutathione, mesna and ORG 2766. Dexrazoxane appears to complex with metal co-factors including iron, to reduce the incidence of anthracycline-induced cardiotoxicity, allowing the delivery of higher cumulative doses of anthracyclines without the expected consequence of cardiomyopathy. Numerous studies have demonstrated that sulfur-containing nucleophiles, including amifostine, glutathione, and mesna can specifically bind cisplatin- or alkylating agent-generated free radicals or alkylating agent metabolites to reduce the incidence of cisplatin-associated neurotoxicity and nephrotoxicity, or alkylating agent-associated myelosuppression and urothelial toxicity. These studies, in the majority of instances, have not revealed any evidence of reduction in antitumour efficacy. Further randomised trials are required to identify the optimal role of chemoprotectants when used alone or in combination with other toxicity modifiers including haemopoietic growth factors.
 ...
PMID:Chemoprotectants: a review of their clinical pharmacology and therapeutic efficacy. 1019 84


1 2 3 4 Next >>