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Biomedical subjects

J Lindenbaum

Publications and source records attributed to J Lindenbaum.

At least 55 records · Page 3Linked to original sources
PubMed1986

Variability of steady-state digoxin kinetics during administration of tablets or capsules.

An encapsulated solution of digoxin has been repeatedly shown to have greater bioavailability than tablet forms of the drug. It is predicted that such a preparation would show reduced within- and between-patient variability in absorption, as most studies in normal subjects have shown reduced intersubject variation with the capsule. We tested inter- and intrapatient variability during 4-week periods of dosing with digoxin capsules and tablets in 28 subjects with cardiac disease. In the overall group there were no significant differences between the formulations at steady state in between-patient variability in trough serum digoxin concentrations or 24-hour urinary digoxin excretion. Within-patient variability in urinary digoxin excretion was somewhat lower for the capsules. In a subgroup of six patients who excreted significant amounts of cardioinactive bacterial metabolites (digoxin reduction products [DRP]), the mean (+/- SD) percent urinary DRP excretion was less (p less than 0.05) during capsule (20.5% +/- 15.1%) than tablet (34.4% +/- 10.9%) dosing. Within-patient variability in urinary DRP excretion was much greater after tablets than capsules. Certain subgroups of patients should benefit from the enhanced bioavailability of digoxin capsule preparations.

Absorption↗
PubMed1986

Anemia in alcoholics.

In order to develop a diagnostic approach to the common problem of anemia associated with alcoholism, 121 chronic alcoholics admitted to a general medical service with a low hematocrit were evaluated. Multiple contributing causes of anemia were present in most patients. Megaloblastic marrow change was found in 33.9% of patients, sideroblastic change in 23.1%, absent iron stores in 13.2%, aggregated macrophage iron in 81.0%, and acute blood loss in 24.8%. The MCV was of little value in predicting the presence of megaloblastic change unless markedly elevated (greater than 110 fl). In 15 of 41 patients with megaloblastic marrow morphology (36.6%) the MCV was normal or low. Among 40 patients with MCV values between 100 and 110 fl, megaloblastic change was not present in the bone marrow smears of 24 (60.0%). Neutrophil hypersegmentation was 95% specific but only 78% sensitive for megaloblastic change; in contrast, the presence of macroovalocytosis was 90% sensitive but only 68% specific. Serum lactic dehydrogenase, plasma folate, and erythrocyte folate levels had such low sensitivities and specificities for megaloblastic change as to be of little predictive value. Hematologic responses to folic acid were often inadequate in patients with megaloblastic morphologic changes, apparently because of associated acute and chronic illness. Our findings are consistent with the hypothesis that 2 mechanisms account for the development of megaloblastic hematopoiesis in alcoholics: induction of folate deficiency and a direct toxic effect of alcohol on erythroid precursors independent of folate depletion, as reflected by the presence of normal plasma and erythrocyte folate levels in several patients with megaloblastic change. In no patient was sideroblastic change the sole apparent cause of anemia. Megaloblastic hematopoiesis and aggregated macrophage iron frequently accompanied sideroblastic change. Examination of the blood smear revealed siderocytes in one-third of patients with sideroblastic marrows and dimorphic erythrocyte morphology in the majority. Dimorphic blood smears, however, were neither sensitive nor specific for sideroblastic change. Serum iron concentrations were usually not elevated in the group with sideroblastic abnormalities. In predicting marrow iron stores, serum iron and iron-binding capacity concentrations were often non-diagnostic or misleading. Serum ferritin levels less than 100 ng/ml, however, showed 100% sensitivity and 95% specificity for absent marrow iron stores despite the frequent presence of abnormal liver function. On the basis of our findings, practical guidelines have been formulated for the evaluation and therapy of anemia in alcohol

Adult↗
PubMed1986

Assay of methylmalonic acid in the serum of patients with cobalamin deficiency using capillary gas chromatography-mass spectrometry.

To determine the incidence of elevated levels of serum methylmalonic acid in patients with cobalamin deficiency, we utilized a new capillary gas chromatographic-mass spectrometric technique to measure methylmalonic acid in the serum of 73 patients with clinically confirmed cobalamin deficiency. Values ranged from 55 to 22,300 ng/ml, and 69 of the 73 patients had values above the normal range of 19-76 ng/ml as determined for 50 normal blood donors. In the cobalamin-deficient patients, serum methylmalonic acid was significantly correlated with the serum folate level and the degree of neurologic involvement. Some patients with pernicious anemia who were intermittently treated with cyanocobalamin were found to have elevated serum levels of methylmalonic acid while free of hematologic and neurologic abnormalities. A cobalamin-deficient patient is described with a normal serum cobalamin and an elevated serum methylmalonic acid. We conclude that the ability to measure methylmalonic acid in human serum will be useful in studies designed to determine the incidence of cobalamin deficiency in various patient populations.

Adolescent↗
PubMed1985

Expression in Escherichia coli of a fusion protein product containing a region of the adenovirus DNA polymerase.

The bulk of an open reading frame extending from map coordinates 23.3 to 14.2 in region E2b of the adenoviral genome has been cloned and expressed from a chimeric plasmid in Escherichia coli. The cloning strategy used created a fusion protein of 124,000 daltons, which contained greater than 98% adenovirus-encoded sequences. Antiserum raised against this protein reacted with the authentic 140,000-dalton adenovirus DNA polymerase. Another serum raised against a synthetic hexapeptide whose sequence corresponded to the predicted carboxyl terminus of adenovirus-encoded DNA polymerase also reacted with the fusion protein and authentic adenovirus DNA polymerase. These results demonstrate that the cloned region of DNA encodes the adenovirus DNA polymerase.

Adenoviridae↗
PubMed1984

Race, poverty, and survival in multiple myeloma.

To identify possible interracial differences in the behavior of multiple myeloma, the records of 52 black myeloma patients at Harlem Hospital Center (HHC) and 46 black and 46 white patients at Columbia-Presbyterian Medical Center (CPMC) were reviewed. In addition to clinical variables such as tumor burden, azotemia, and hypoalbuminemia, the effect of poverty on prognosis was examined, using socioeconomic indices from the United States census block group data of each patient. The median survival of CPMC black and white patients was comparable (34 and 29 months, respectively) whereas that of the HHC group was 12 months (Breslow test, P less than 0.0001). Overcrowding and hypoalbuminemia were the most significant prognostic factors by multivariate regression analysis on all 144 patients (P = 0.001); for HHC patients, overcrowding was the single significant variable affecting survival (P = 0.004). By all socioeconomic indices, HHC patients were more impoverished than CPMC patients (P less than 0.001); they also presented with more advanced disease. Race is not a significant prognostic factor in myeloma, whereas the effect of socioeconomic status on survival appears to equal that of previously described clinical features.

Adult↗
PubMed1984

Protein-primed replication of plasmids containing the terminus of the adenovirus genome. I. Characterization of an in vitro DNA replication system dependent on adenoviral DNA sequences.

An in vitro system which replicates plasmid DNA containing the replication origin of adenovirus DNA has been established. Replication of plasmid pLA1 DNA, which contains the left-hand terminus (0-9.4 map units) of adenovirus serotype 5 DNA but which lacks the 55,000-dalton terminal protein, is initiated by a protein-primed mechanism in a manner similar to that found with adenovirus DNA. Initiation of DNA replication using plasmid pLA1 as a template requires (i) that the cloned adenovirus sequence be present at the terminus of a linearized (form III) DNA molecule ( Tamanoi , F., and Stillman , B. W. (1982) Proc. Natl. Acad. Sci. U. S. A., 79, 2221-2225; van Bergen, B. G. M., van der Ley , P. A., van Driel , W., van Mansfield , A. D. M., and van der Vliet , P. A. (1983) Nucleic Acid Res. 11, 1975-1979), and (ii) the presence of the 80,000-dalton precursor to the 55,000-dalton terminal protein and the adenovirus coded DNA-dependent DNA polymerase. In the presence of the four deoxy-nucleoside triphosphates, the preterminal protein, the adenovirus coded DNA binding protein, and an extract prepared from uninfected HeLa nuclei, the adenovirus DNA polymerase can elongate the preterminal-protein dCMP initiation complex formed on pLA1 DNA to full length (6.6 kilobase) DNA molecules. These results suggest that the 55,000-dalton terminal protein covalently linked to the 5' termini of adenovirus DNA is not essential for the replication of this DNA.

Adenoviridae↗
PubMed1983

Digoxin-inactivating bacteria: identification in human gut flora.

Digoxin, the most widely used cardiac glycoside, undergoes significant metabolic conversion in many patients to cardioinactive metabolites in which the lactone ring is reduced. This appears to occur within the gastrointestinal tract. An attempt was made to isolate and identify the organisms capable of reducing digoxin from stool cultures obtained from human volunteers. Of hundreds of isolates studied, only Eubacterium lentum, a common anaerobe of the human colonic flora, converted digoxin to reduced derivatives. Such organisms were also isolated in high concentrations from the stools of individuals who did not excrete these metabolites when given digoxin in vivo. When the growth of E. lentum was stimulated by arginine, inactivation of digoxin was inhibited. Neither the presence of these organisms alone nor their concentration within the gut flora appeared to determine whether digoxin would be inactivated by this pathway in vivo.

Arginine↗
PubMed1983

Relapses after interruption of cyanocobalamin therapy in patients with pernicious anemia.

One or more episodes of recurrent megaloblastic anemia occurred in 36 (10.8 percent) of 333 patients with pernicious anemia following interruption of therapy. Treatment had most commonly been discontinued by patients because they felt well, or by physicians due to error. Thirty-five episodes of recurrent cobalamin deficiency were analyzed in detail. In the 24 patients in whom the exact date of cessation of therapy was recorded, the mean interval before relapse was diagnosed was 64.5 months (range 21 to 123 months). Recurrence manifested as macrocytosis in the absence of anemia occurred earlier (mean, 49.2 months) than that associated with anemia (73.1 months). A weak correlation was apparent between the amount of previous cyanocobalamin treatment and time to relapse. One third of relapses were unrecognized and left untreated for more than two years, while usually slow hematologic progression occurred. Recurrences of cobalamin deficiency in individual patients exhibited mimetic features. Further study is necessary to establish the optimal dosage and frequency of maintenance therapy in pernicious anemia.

Adult↗
PubMed1983

Decreased digoxin cardioinactive-reduced metabolites after administration as an encapsulated liquid concentrate.

The generation by intestinal bacteria of large amounts of cardioinactive metabolites of digoxin with a reduced lactone ring (digoxin reduction products, or DRP) may be associated with increased dosage requirements. Since DRP excretion varies inversely with bioavailability, we compared the 6-day urinary excretion (CUE) of digoxin and DRP after 0.4-mg doses of an encapsulated liquid concentrate and a standard tablet in 22 normal subjects known to form substantial amounts of DRP. Mean (+/- SE) CUE of digoxin was greater with the capsules than the tablets (195.9 +/- 8.6 and 137.5 +/- 6.3 micrograms). CUE of DRP was less after the capsules (60.8 +/- 5.5 and 102.7 +/- 9.5 micrograms). Percent DRP was greater after the tablets in every subject (mean for tablets, 41.2 +/- 2.7%; capsules, 23.5 +/- 1.8%). Patterns of DRP excretion differed with the two preparations, probably reflecting differences in the routes whereby digoxin reached the colon. The use of highly bioavailable capsules in subjects with heavy DRP production should minimize metabolic inactivation during digoxin therapy.

Adult↗
PubMed1982

Folate nutrition in the elderly.

The consensus of this panel is that average dietary intake of folate in the free-living elderly population is probably adequate in most. Certainly more good data are needed; in addition, safe and reasonable dietary goals for folate intake are required. However, patients who have diseases requiring hospitalization or conditions for which institutionalization are required are obviously at greater risk. In addition, there is some evidence that the elderly poor in the US may be at greater risk of deficiency. Similarly, the evidence for folate deficiency based on blood assay data would seem to focus on the lower socioeconomic (largely Black and Hispanic) populations in addition to the hospitalized and institutionalized elderly. An additional factor in the genesis of folate deficiency among the aged is the factor of alcohol use which probably represents the single most important risk factor in folate deficiency among the elderly as well as among the nonelderly population. Although certain drugs such as anticonvulsants and sulfasalazine, may interfere with folate absorption or utilization, the number of elderly patients who are taking these drugs is relatively small and therefore this factor is not considered to be a major contributor to the problem of folate deficiency in the elderly. The question of folate malabsorption in the elderly has been examined. It is our conclusion that disease in the elderly population including gastric surgery and intestinal malabsorption, etc can certainly interfere with folate absorption but these problems are not widespread among the elderly population. There is only limited evidence that the physiological process of aging influences the intestinal absorption of folate.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1982

Biphasic pattern of bacterial infection in multiple myeloma.

Since the 1960s, gram-negative bacilli have become commoner pathogens than Streptococcus pneumoniae in multiple myeloma. To investigate this trend, we analyzed 75 bacterial infections in 57 patients with myeloma. Episodes of infection with Streptococcus pneumoniae and Haemophilus influenzae occurred at presentation, early in the disease, and in patients responding to chemotherapy. Gram-negative bacilli and Staphylococcus aureus caused 80% of infections seen after diagnosis and 92% of deaths from infection. Episodes of infection with gram-negative bacteria occurred in patients with active and advancing disease and in those responding to chemotherapy when neutropenia. Impaired antibody production may be the major immune defect leading to S. pneumoniae and H. influenzae infections whereas some additional factor or factors related to disease activity appear to predispose to gram-negative infection in myeloma.

Aged↗
PubMed1982

Inactivation of digoxin by Eubacterium lentum, an anaerobe of the human gut flora.

Digoxin is converted to cardioinactive reduced metabolites (DRP) in vivo and in vitro by the human gut flora. Digoxin inactivation is mediated by Eubacterium lentum, a normal inhabitant of the gastrointestinal flora. E. lentum appears to be the sole organism performing this reaction. Fecal bacteria that convert digoxin to DRP in vitro have been found to be present in some subjects who fail to make DRP in vivo. DRP-forming E. lentum have been isolated from the stools of two such subjects. When increasing amounts of arginine are supplied as a growth substrate to E. lentum, bacterial growth and DRP production vary inversely. Further study will be required to identify the factors which determine why digoxin is inactivated in vivo by the gut flora of certain patients and not by others.

Adult↗
PubMed1981

Inactivation of digoxin by the gut flora: reversal by antibiotic therapy.

In approximately 10 per cent of patients given digoxin, substantial conversion of the drug to cardioinactive, reduced metabolites (digoxin reduction products, or DRPs) occurs. The site and clinical importance of this conversion is unknown. In four normal volunteers taking digoxin daily for four weeks, urinary excretion of DRPs was greatest after a poorly absorbed tablet was ingested, and least after intravenous administration, Stool cultures from subjects known to make DRPs in vivo ("excretors") converted digoxin to DRPs; cultures from nonexcretors did not. Three excretors were given tablets for 22 to 29 days. A five-day course of erythromycin or tetracycline, administered after a base-line period of 10 to 17 days, markedly reduced or eliminated DRP excretion in urine and stool. Serum digoxin concentrations rose as much as twofold after antibiotics were given. We conclude that in some persons digoxin is inactivated by gastrointestinal bacteria. Changes in the enteric flora may markedly alter the state of digitalization.

Anti-Bacterial Agents↗
PubMed1981

Urinary excretion of reduced metabolites of digoxin.

The urinary excretion of the relatively cardioinactive reduced metabolites of digoxin, dihydrodigoxin and related compounds was measured by radioimmunoassay in 131 normal subjects during studies of the bioavailability of digoxin preparations. Digoxin reduction products (DRP) constitute more than 5 percent of the excretion of digoxin and its metabolites in one-third of the volunteers after the administration of single or multiple doses of digoxin. There was little or no output of DRP during the first 8 hours after a single dose, with maximal excretion usually occurring on the second day. Most subjects who excreted more than 5 percent DRP on one occasion did so with each subsequent exposure to digoxin. Six volunteers, however, in whom substantial amounts of DRP had previously been found, failed to excrete detectable quantities after subsequent doses. In two, this change occurred shortly after they took erythromycin. Urinary DRP were less after the intravenous administration compared to the oral administration of digoxin. After oral doses, DRP excretion tended to vary inversely with the bioavailability of the preparation. The findings are consistent with the hypothesis that DRP are formed as the result of the activity of a variable component of the intestinal flora. Prospective studies will be necessary to prove this hypothesis.

Adult↗
PubMed1981

Lack of difference in digoxin urinary excretion with two intravenous infusion rates.

Ten normal subjects were given 0.4 mg digoxin intravenously by bolus injection over 3 to 5 min and by constant-rate infusion for 1 hr. Urinary excretion of digoxin over the next 6 days, as measured by radioimmunoassay, was similar after both the rates of intravenous injection. In one subject, who excreted substantial amounts of digoxin reduction products, no difference was apparent in the amount of reduced metabolites excreted. These results are not in agreement with previous reports of an effect of intravenous infusion rate on urinary digoxin excretion.

Adult↗
PubMed1980

Bioavailability of digoxin tablets in patients with gastrointestinal dysfunction.

In 47 patients with disorders of the gastrointestinal tract, the bioavailability of digoxin tablets was assessed by measuring the area under the serum concentration-time curve (AUC) after the oral administration of single 0.5 mg doses. In 13 or 14 patients who had undergone a previous ileal resection, in 10 of 10 patients with sprue and in 14 of 14 patients with a variety of disorders of the gastrointestinal tract, digoxin absorption was normal despite marked steatorrhea in many. A patient with extensive jejunal and ileal resection, and inflammation of the remaining small bowel,was the sole exception. Impaired digoxin bioavailability was found in five of nine patients who had undergone jejunoileal bypass procedures (bypass patients. A strong correlation was noted between the length of jejunum remaining in continuity and the AUC (r = 0.86, p less than 0.01). Two of three bypass patients also showed decreased absorption of more rapidly dissolving tablets or an elixir. Digoxin bioavailability correlated significantly with and 2 hour serum xylose levels but not with urinary xylose excretion, fecal fat or the Schilling test result. The findings are consistent with the role of the upper small bowel as the predominant site of digoxin absorption as well as the reserve function of the ileum in the event of jejunal dysfunction or bypass.

Adult↗