Intensive chemotherapy with interferon for induction of true remission in chronic phase of chronic myelogenous leukemia.
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Adult↗
Biomedical subjects
Z Arlin
Publications and source records attributed to Z Arlin.
Two separate differentiation inducing proteins for human myeloid leukemia cells and their isolation from normal lymphocytes.
Conditioned medium from mitogen stimulated normal peripheral blood lymphocytes (PBL) has been demonstrated to contain a maturation inducer activity mediating the differentiation of human myeloid leukemia cells to monocytes and macrophages. The maturation inducer activity was isolated by salt precipitation, Sepharose CL-6B ion exchange and affinity chromatographies and electrophoresis. Two separate activities with M.W. ranges of 52-56 and 32-35 kDa capable of mediating the terminal differentiation of leukemic HL-60 promyelocytes to monocytes and macrophages were detected. The higher molecular weight species was determined to be a 54 kDa single polypeptide and was found to be distinct from IL-3 and IL-6 by ELISA and differentiation blocking assay. The inducing activity of the 32-35 kDa material was largely neutralized after treatment with anti-IL-3, but not with other antibodies. Employing the immunofluorescent antibody technique, the 54 kDa protein was detected on the surface membranes of PBL. The proportions and number of maturation inducer bearing lymphocytes in patients with acute myelogenous leukemia (0.4% and 35/mm3, respectively) were significantly lower than that of healthy donors (7.9% and 178/mm3) The role of these physiological factors in leukemia cell differentiation is discussed.
Cell Differentiation↗
Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL). Lederle Cooperative Group.
This phase III, randomized trial in previously untreated adults with ANLL compared mitoxantrone plus cytosine arabinoside with the CALGB "7 + 3" daunorubicin-based regimen. Two hundred evaluable patients (98 treated with the mitoxantrone-based regimen and 102 with the daunorubicin-based regimen) were included in the analysis of efficacy. The median age of the patients was 60 years. The induction regimen comprised cytosine arabinoside 100 mg/m2 by infusion daily for 7 days and mitoxantrone 12 mg/m2 or daunorubicin 45 mg/m2 daily for days 1-3. If needed, a second induction course was administered: cytosine arabinoside for 5 days and mitoxantrone or daunorubicin for 2 days. Postremission therapy consisted of two consolidation courses, identical to the second induction course. Sixty-three percent (62 of 98) of patients treated with mitoxantrone achieved complete remission (CR), compared to 53% (54 of 102) treated with daunorubicin. The median time to CR was 35 days in patients treated with mitoxantrone and 43 days for those treated with daunorubicin. Eighty-nine percent (55 of 62) of patients treated with mitoxantrone who entered complete remission achieved CR following one induction course, compared to 68% (37 of 54) of patients treated with daunorubicin who entered CR. The median duration of CR was 240 days in patients treated with mitoxantrone and 198 days in those treated with daunorubicin; the median length of survival was 328 days in patients who received mitoxantrone and 247 days in those who received daunorubicin. The toxicity profiles in patients treated with either of the two regimens were comparable in incidence and in severity. Patients treated with mitoxantrone required fewer median platelet units and were treated with fewer median days of intravenous antibiotics, compared to those who received daunorubicin. Mitoxantrone in combination with cytosine arabinoside is effective in previously untreated ANLL. complete remissions occur more frequently after a single induction course of the mitoxantrone-based regimen, compared to the standard Cancer and Acute Leukemia Group B regimen. This should be explored in further trials.
Adult↗
The effect of a prolonged in vitro exposure to 1-beta-D arabinofuranosylcytosine and deoxycytidine on the survival of normal (CFU-GM) and leukemic (L-CFU) human myeloid progenitor cells in suspension culture.
We examined the effect of a 96-h exposure to 1-beta-D arabinofuranosylcytosine (Ara-C) and deoxycytidine (dCyd) in medium lacking an exogenous source of colony-stimulating activity (phytohemagglutinin-stimulated leukocyte-conditioned medium, PHA-LCM) on the survival of normal human committed myeloid progenitor cells (day-7 and day-14 granulocyte-macrophage colony-forming units [CFU-GM] as well as leukemic progenitors (leukemic colony-forming units, L-CFU) derived from myeloblasts obtained from 13 patients with acute nonlymphocytic leukemia (ANLL). Coadministration of Ara-C (20-50 microM) in conjunction with dCyd (50-100 microM) permitted the survival of an average of 9%-57% of day-7 CFU-GM and 32%-65% day-14 CFU-GM, depending upon the relative concentrations of dCyd and Ara-C. In contrast, exposure of leukemic myeloblasts to identical regimens resulted in considerably greater reductions in L-CFU survival, which in general exceeded 90% and in some cases was 100%. In addition, exposure of leukemic myeloblasts to Ara-C and dCyd for 96 h in culture medium lacking PHA-LCM eliminated the secondary plating efficiency (PE2) of leukemic colonies in 11 of 13 samples assayed and reduced values dramatically in the remaining 2. Substantial preservation of CFU-GM formation was also noted when normal bone marrow samples depleted of T cells and marrows obtained from two patients with ANLL in remission were assayed. These studies suggest that in contrast to certain normal committed myeloid progenitor cells, leukemic progenitors, particularly those with self-renewal capacity, are highly vulnerable to a prolonged exposure to Ara-C and dCyd in the absence of an exogenous source of colony-stimulating activity. They also raise the possibility that a combined regimen utilizing chemotherapeutic agents in conjunction with modifications of long-term culture techniques may represent a novel approach to the ex vivo purging of leukemic cells from bone marrow in conjunction with autologous bone marrow transplantation.
Cell Survival↗
Severe intrahepatic cholestasis in patients treated with recombinant interleukin-2 and lymphokine-activated killer cells.
Immunotherapy with recombinant interleukin-2 (rIL-2) and lymphokine-activated killer cells (LAK) has become a new form of therapy that has been shown to induce remissions in patients with renal cell carcinoma and melanoma. Despite encouraging results, this form of therapy has been associated with increasing toxicity, often requiring therapy in an intensive-care unit. In this report severe intrahepatic cholestasis occurred in two patients receiving rIL-2 and LAK cells. This form of cholestasis appeared to be directly related to rIL-2 administration at a doses of 2 x 10(6) U/m2 and 3 x 10(6) U/m2 t.i.d. A liver biopsy showed moderate hepatocellular bile stasis, with lobular and portal inflammation. All other studies for potential cause of this cholestasis were negative, including studies for metastatic disease. When therapy was discontinued, evidence for cholestasis and bile stasis resolved. We conclude that rIL-2 is a drug with a potential to induce severe hepatic injury that is reversible upon cessation of therapy with rIL-2. Further care should be exercised when rIL-2 is administered to patients with abnormal liver function.
Adult↗
Analysis of the individual and combined reactivities of monoclonal antibodies H25, H366, and MY9 with normal progenitor cells and blast cells from patients with acute myeloblastic leukemia.
Recently we reported that two monoclonal antibodies (MoAbs), H25 and H366, which react with human natural killer cells and monocytes, also react with normal in vitro colony-forming cells including granulocyte-monocyte colony-forming units (CFU-GM), erythroid burst-forming units (BFU-E), and erythroid colony-forming units and with leukemic blasts in preliminary testing of cells from patients with myeloid leukemias and T cell acute lymphocytic leukemia. In the present studies we examined the reactivities of MoAbs H25, H366, and MY9 (singly or combined) with the total leukemic cell population and the leukemic clonogenic cells (L-CFC) from 28 patients with acute myeloblastic leukemia. Using cytofluorography, we found the extent of expression of antigen H25 comparable to MY9 in the majority of patients, and both were more highly expressed than antigen H366. Incubation with H25 and H366 MoAbs simultaneously did not increase the number of positive cells over that seen when stained with H25 alone; however, the amount of antibody fluorescence intensity (FI) was increased. Leukemic cells simultaneously stained with MoAbs H25, H366, and MY9 displayed the highest number of positive cells and FI. Using magnetic beads coated with sheep anti-mouse IgG for depleting antibody-binding cells, greater than or equal to 90% of L-CFC were depleted by a combination of H25 and H366 MoAbs in 76% of AML cases tested as compared to 41% of the cases with MoAb MY9. Using a MoAb cocktail of H25, H366, and MY9, greater than or equal to 90% of L-CFC were depleted in 94% of cases tested, and greater than or equal to 99% of L-CFC were removed in 76% of the cases. Using the same depletion methods for normal bone marrow cells, a combination of anti-H25 and anti-H366 removed 90%, 98%, and 84% of CFU-GM, BFU-E, and multipotent colony-forming units (CFU-GEM), respectively, whereas the cocktail of H25, H366, and MY9 MoAbs removed 98%, 99.5%, and 97% of CFU-GM, BFU-E, and CFU-GEM, respectively. Incubation of H25 and H366-depleted bone marrow cells for 2 weeks in the presence of irradiated adherent cell layers from long-term marrow cultures generated CFU-GM and some BFU-E, as did H25, H366, and MY9-depleted marrow cells, although to a much lesser extent. Based on the overall data, combinations of H25, H366, and MY9 MoAbs and immunomagnetic beads conceivably might have therapeutic potential for ex vivo elimination of leukemic cells from AML remission marrows prior to autologous transplantation.
Adult↗
Treatment of patients with HIV thrombocytopenia and hemolytic uremic syndrome with protein A (Prosorba column) immunoadsorption.
Both antibodies and circulating immune complexes (CIC), which bind to platelets and induce the destruction and clearance of platelets by the reticuloendothelial system, are found in patients with human immunodeficiency virus (HIV) and immune thrombocytopenic purpura (ITP). IgG and CIC were removed from patients' plasma by extracorporeal immunoadsorption using protein A-silica columns (PROSORBA columns). Of the 36 HIV-positive ITP patients treated, 29 received more than one treatment and were evaluated for response. Sixteen patients showed more than a 50% increase in their platelet counts. Platelet-associated IgG (PAIgG) and/or platelet-directed IgG and CIC were elevated in all patients. After four to eight treatments, 16 of 29 patients showed a 170% to 430% increase in platelet counts. A decrease in CIC and PAIgG was noted in responding patients. The median duration of response to date was 8 to 12 months. This treatment was associated with immune modulation and the development of an anti-F (ab')2 antibody response. The antibody functions by complexing with both platelet-binding IgG and CIC, neutralizing their binding capacity for platelets and enhancing their clearance from the circulation. Nine patients with mitomycin-C-induced hemolytic uremic syndrome (HUS) were also treated with PROSORBA columns. Pretreatment platelet counts were markedly reduced while a definite increase in platelet counts was observed upon completion of therapy. There was a decrease of hemolysis and stabilization of renal function in three patients. PROSORBA column treatment has demonstrated marked activity against both HIV-ITP and HUS, and has successfully freed patients from the bleeding diathesis associated with these syndromes.
Acquired Immunodeficiency Syndrome↗
Fine mapping of chromosome 22 breakpoints within the breakpoint cluster region (bcr) implies a role for bcr exon 3 in determining disease duration in chronic myeloid leukemia.
The chromosomal translocation that fuses the phl gene with the c-abl proto-oncogene appears to be a pivotal step in the pathogenesis of some leukemias. In chronic myeloid leukemia (CML) the breakage within the phl gene is largely confined to a 5.8-kb segment referred to as the breakpoint cluster region (bcr). To determine whether the presence of specific bcr exons on the Philadelphia chromosome has any clinical significance, we have analyzed the bcr breakpoints in 134 patients with CML. As many as five probes were used in this analysis, including a synthetic oligonucleotide probe homologous to the bcr exon 3 (phl exon 14) region. The distribution of breakpoints indicates that, in fact, breakage is largely confined to a 3.1-kb segment lying between bcr exon 2 and exon 4 (phl exons 13-15). In 61 CML patients analyzed within 1 year of diagnosis, the distribution of breakpoints appeared to be random within the 3.1-kb region. However, a significant excess of 5' breakpoints was observed in the total population studied, consistent with previous data showing that patients with 3' breakpoints have shorter disease durations. Analysis using the bcr exon 3 sequence probe indicated it was probably the presence or absence of bcr exon 3 on the Philadelphia chromosome that accounts for some of the variability in disease duration seen in CML. The data suggest that the phl/abl protein product may influence the timing of the onset of blast crisis and imply a continuing role for this protein during the evolution of the disease.
Blotting, Southern↗
The karyotype of Philadelphia chromosome-negative, bcr rearrangement-positive chronic myeloid leukemia.
Philadelphia (Ph) chromosome negative chronic myeloid leukemia (CML) can be distinguished from clinically similar disorders on the basis of the presence of rearrangement of the breakpoint cluster region (bcr) of chromosome 22. We have identified six patients with Ph-negative CML, each with bcr rearrangement. Apparently normal karyotypes were observed in two cases, and a third contained a rearrangement that did not appear to involve chromosomes 9 or 22. The other three cases had translocations involving chromosome band 9q34 but no case contained the common derivative chromosome 9pter----9q34::22q11----22qter. One case appeared to contain either a deletion of an unrearranged bcr locus in approximately 50% of cells or duplication of rearranged bcr, both 5' and 3' of the chromosome 22 breakpoint. Considerable complexity exists in the types of genetic changes that can juxtapose bcr and the c-abl oncogene in CML. Based on the molecular and cytogenetic analyses of these and other cases described in the literature, we conclude that most cases of true Ph-negative CML arise from submicroscopic genetic exchanges rather than masking of simple t(9;22)(q34;q11) translocations by secondary rearrangements.
Adult↗
Molecular heterogeneity of adult Philadelphia chromosome-positive acute lymphoblastic leukemia.
The (9;22) translocation which produces the Philadelphia (Ph1) chromosome activates the abl oncogene from chromosome 9 by recombination with the bcr gene from chromosome 22. This fusion gene is transcribed into a new 8.5-kilobase chimeric mRNA which is translated into a novel Mr 210,000 fusion protein which has a protein tyrosine kinase activity that is greatly increased in comparison to the activity of the normal abl protein. Studies from this laboratory and others have shown that virtually all patients with chronic myelogenous leukemia have this new bcr/abl fusion gene. In contrast to these findings in chronic myelogenous leukemia, a small number of patients with Ph1(+) acute lymphoblastic leukemia (ALL) have been studied and were found to lack the bcr/abl fusion gene [bcr(-)], but to have a new activation of abl, by recombination with an as yet undetermined region on chromosome 22. In this study, nine adults with Ph1(+)-ALL have been examined for evidence of a bcr/abl fusion gene. Of the nine patients, five have a bcr/abl recombination, whereas the remaining four patients do not. In contrast, the children studied to date have all been bcr(-). These data suggest that adults with Ph1(+)-ALL are a more heterogeneous group on a molecular level than are children, and that further studies will be required to determine the spectrum of molecular defects in patients with Ph1(+)-ALL, and the relationship of these various molecular defects to the clinical disease state of the individuals.
Adult↗
Phase II trial of fludarabine phosphate (F-Ara-AMP) in patients with advanced breast cancer.
Eighteen patients with advanced breast cancer were entered into a phase II study of fludarabine phosphate. Fludarabine phosphate was given by continuous infusion for 5 days, at a starting dose of 20 mg/m2 per day for patients previously treated with two or more regimens and 25 mg/m2 per day for minimally treated patients with less than two prior regimens; therapy was repeated every 3-4 weeks. Of the 18 patients, 11 had undergone more than two prior regimens and 7 patients had undergone one prior regimen. One patient achieved a partial response (PR) for 22 months. Myelosuppression was the most common toxicity observed. Four patients developed mild nausea and vomiting and two developed a nonspecific dermatitis that resolved spontaneously. No renal, hepato-, or neurotoxicity was observed. Our study demonstrates that in heavily pretreated patients, fludarabine phosphate given on this schedule has minimal efficacy in treating advanced breast cancer. This drug might possibly have shown more activity in a previously nontreated patient population. However, patients with advanced breast cancer, who have not undergone previous treatment are not often encountered.
Adult↗
A cause-specific hazard rate analysis of prognostic factors among 199 adults with acute lymphoblastic leukemia: the Memorial Hospital experience since 1969.
Results of a multivariable analysis of prognostic factors are reported for 199 previously untreated adults with acute lymphoblastic leukemia (ALL). These patients have long-term follow-up, and the probability of cure is estimated at approximately 35%. The cause-specific hazard rate analysis found lower rates of achieving complete remission (CR) in patients with WBC greater than 10,000/microL, AUL (undifferentiated) morphology, and older age. Since these patients required additional time to respond, fewer of them actually achieved CR. Characteristics directly associated with a higher rate of death during induction therapy due to severe bone marrow suppression were low serum albumin concentration (less than or equal to 3.5 g/dL), age greater than 50 years, acute undifferentiated leukemia (AUL) morphology, low Karnofsky performance status, and weight loss greater than 5%. Factors associated with a higher rate of relapse were WBC greater than 20,000/microL, non-T cell ALL, age greater than 60 years, Ph' + ALL, and time to achieve CR greater than 5 weeks. These criteria were used to identify patients at high risk of relapse. In addition, the predictive value of high WBC was found to disappear by 18 months of continuous CR. Finally, the rate of death following first relapse was higher in patients with a short first remission duration, high percentage weight loss at initial diagnosis, and older age. In summary, factors associated with a higher rate of death during attempted induction (ie, low albumin, high percent weight loss, and poor performance status) had no association with the patient's ability to remain relapse-free. Conversely, factors correlating with more extensive or resistant disease (ie, high WBC, null or B cell ALL, or Ph' + ALL) showed no association with the ability to tolerate therapy. Thus, a less toxic but more effective induction regimen is needed for patients with a poor clinical status, whereas a more intensive form of therapy appears warranted for patients presenting with more extensive or resistant disease.
Adult↗
The location of breakpoints within the breakpoint cluster region (bcr) of chromosome 22 in chronic myeloid leukemia.
Rearrangement of the breakpoint cluster region (bcr) was demonstrated by Southern blot analysis in the DNA in each of 68 patients with Ph chromosome-positive CML and in 3 of 7 patients with apparent Ph chromosome-negative CML. In contrast, no bcr rearrangement could be found in DNA from 17 normal individuals and 28 patients with various hematologic disorders other than CML or ALL. An analysis of the location of the breakpoints within the bcr indicated that 3' breakpoints were significantly more common in patients in blast crisis or accelerated phase disease compared to those with chronic phase disease. Patients with chronic phase disease and 3' breakpoints had shorter average disease duration than that for chronic phase patients with 5' breakpoints, although the difference between these two groups of patients was not statistically significant. For patients who had progressed to accelerated disease or blast crisis, a statistically significant difference in chronic phase disease duration could be demonstrated between 11 patients with 3' breakpoints (average chronic phase 30.2 months) and 15 patients with 5' breakpoints (average chronic phase 50.6 months). For 8 patients studied in both chronic phase and accelerated or blast crisis, the location of the breakpoint did not change. We suggest that the bcr-abl fusion protein associated with a 3' breakpoint could result in more rapid progression to acute disease, and this may account for differences in the relative frequency of 3' and 5' breakpoints at different disease stages. Although more studies are required, identifying CML patients with a higher propensity for early blast transformation may eventually prove to be of some clinical value.
Blast Crisis↗
Fibroblast growth inhibitor.
A new cytokine has been recognized in the conditioned media (CM) of freshly isolated acute myelocytic leukemia cells, cultured with 12-0-tetradecanayl phorbol acetate (TPA) 10(-8)M. The fraction with 70,000 MW was separated from CM by ammonium sulfate precipitation, ion-exchange cation and anion chromatography, and Sephadex G-200 gel filtration. It was a fibroblast growth inhibitor (FGI). This substance stopped fetal and skin (MALME 3 line) fibroblast propagation. The cytostatic effect was reversible on removal of FGI. At the same time, FGI did not inhibit macrophage proliferation. The fraction stimulated formation of monocytic and granulocytic colonies altered the phenotype of human U-2 osteosarcoma cells grown from epithelial-like to fibroblast-like cells, and stimulated differentiation of leukemic cells along the macrophage path. Some cells of promyelocytic leukemia line HL-60, grown in the presence of FGI, were stimulated to differentiate and some underwent lysis. The response to FGI of cells from different patients varied.
Bone Marrow↗
Effect of recombinant GM-CSF on the metabolism of cytosine arabinoside in normal and leukemic human bone marrow cells.
Human recombinant GM-CSF (rGM-CSF) is under investigation as a growth-protective agent for normal hematopoietic elements in phase I trials of myelosuppressive chemotherapy and in bone marrow transplantation. We determined the effect of rGM-CSF on the metabolism of high dose Ara-C in bone marrow mononuclear cells (BMMCs) from healthy volunteers and patients with ANLL. Cells were incubated with rGM-CSF alone, Ara-C alone, or a combination of the two drugs. Treatment with rGM-CSF alone yielded approximately a twofold increment in intracellular dCTP pools in normal BMMCs but not in leukemic blasts. Exposure to rGM-CSF in conjunction with Ara-C corrected Ara-C-mediated declines in dCTP levels and decreased cytosine arabinoside triphosphate (Ara-CTP) accumulation in normal BMMCs but not in their leukemic counterparts. Furthermore, when exposure to Ara-C was preceded by treatment with rGM-CSF for 18 hr, an even greater reduction in the Ara-CTP/dCTP pool ratio was observed in normal versus leukemic elements; however, this did not significantly change Ara-C DNA incorporation in the two cell types. The differential effect of rGM-CSF on the phosphorylation of Ara-C in normal BMMCs versus leukemic blasts has potential implications for the use of a regimen consisting of rGM-CSF and high dose Ara-C in the treatment of ANLL with chemotherapy or autologous bone marrow transplantation.
Bone Marrow↗
Selenium status and the polyp-cancer sequence: a colonoscopically controlled study.
Diminished blood selenium levels have been associated with increased risk of gastrointestinal cancers in man, while dietary selenium supplementation reduces the incidence of experimental colon cancer in rats. However, no previously published data are available concerning selenium and the evolution of colon cancer from benign neoplastic colonic polyps through localized and metastatic cancer. To assess any influence of selenium on this polyp to cancer sequence, we measured plasma and erythrocyte selenium levels in colonoscopically and histologically evaluated patients with adenomatous polyps (group I), locally resectable colon cancer (group II), metastatic colon cancer (group III), and selected colonoscopy negative controls (group IV). We found no difference in selenium levels between groups IV versus groups I or II. Likewise, within group I, no difference in selenium was present for different polyp histologies or numbers of polyps. However, selenium levels did drop progressively (p = 0.028, ANOVA) from polyp (group I) to local cancer (group II, p = NS vs group I) to metastatic cancer (group III, p less than 0.05 vs group I or group II). Parallel changes were seen in both plasma and erythrocyte levels, suggesting that these selenium abnormalities are of long duration, reflecting tissue stores, and therefore capable of influencing cancer risk. We conclude that selenium stores may not be an important factor in the de novo formation of benign neoplastic colonic polyps. Although these data suggest that selenium does not affect the polyp-cancer sequence, it is possible that a subset of patients with polyps and the lowest selenium levels are at higher risk for malignant transformation. However, these human data do not support a significant role for selenium in colon carcinogenesis.
Aged↗
Malignant lymphomas in a population at risk for acquired immune deficiency syndrome.
Certain neoplasia are closely associated with acquired immune deficiency syndrome (AIDS). To evaluate this relationship the authors reviewed the occurrence of lymphomas in populations at high risk for AIDS; the study population included prisoners from New York State and nonprisoner intravenous drug abusers (IVDA). Non-Hodgkin's lymphoma was diagnosed in 16 prisoners, all of whom were IVDA, and four nonprisoner IVDA. The observed number of prisoners with non-Hodgkin's lymphoma (11) diagnosed between January 1, 1981 and December 12, 1984, significantly greater than the expected number (2.28) based on age adjusted incidence rates for the US population (P less than 0.001). The calculated average incidence rate for non-Hodgkin's lymphoma among New York State prisoners aged 20 to 49 years was 21.5/10(5) to 67.2/10(5), which was nearly sixfold to 18-fold higher than the general population. For prisoner IVDA, specifically, this incidence may be as high as 164/10(5), which represents a 40-fold increase in the relative risk compared with the general population. It is concluded that, non-Hodgkin's lymphoma is frequently a manifestation of AIDS among IVDA, and is the most common malignancy seen in IVDA with AIDS.
Acquired Immunodeficiency Syndrome↗
Amsacrine treatment of patients with supraventricular arrhythmias and acute leukemia.
Three patients with a history of supraventricular arrhythmia presented with relapse of acute leukemia. Two of the three patients were in sinus rhythm, receiving digoxin and/or verapamil daily. The third patient was in atrial fibrillation, but her heart rate was controlled with daily digoxin. All three patients received amsacrine without the occurrence of cardiac events. Although amsacrine may cause ventricular arrhythmias in the setting of hypokalemia, correction of the electrolyte abnormality permits its use in patients with a history of supraventricular arrhythmias.
Acute Disease↗