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Biomedical subjects

V P Butler

Publications and source records attributed to V P Butler.

At least 37 records · Page 2Linked to original sources
PubMed1985

Studies on human low serum IgD phenotype and Gm markers.

The human "low serum IgD phenotype" was studied by simultaneous Gm typing and IgD immunoassay of several populations. An association between Gm (f+b+) haplotype and low human IgD was confirmed and extended to the "low serum IgD phenotype"--as defined from population distribution and genetic studies by Dunnette et al. 1978. Further, it was shown that Black American sera determined by Gm haplotype, had a similar percentage of "low serum IgD phenotype" samples (16%) although they lacked the "associated" Gm(f+b+) haplotype of White American samples. Sardinian sera showed a low incidence of the "low serum IgD phenotype" which was not correlated with Gm haplotype distribution. Familial aggregation of the "low serum IgD phenotype" was observed. No association was found between "low serum IgD phenotype" and serum IgE values. Age related abiotrophy of IgD could not be attributed to selective survival of "low serum IgD phenotype" persons.

Adult↗
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

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↗
PubMed1983

Immunoelectron microscopic localization of platelet factor 4 and fibrinogen in the granules of human platelets.

To determine the storage site of platelet fibrinogen and of platelet factor 4 (PF4) in human platelets by immunoelectron microscopic techniques, washed human platelets were briefly exposed to Karnovsky's fixative and embedded in water-soluble Durcupan. Thin sections of platelets were exposed to Fab fragments of rabbit anti-human fibrinogen or of goat anti-human PF4, followed by a peroxidase conjugate of Fab fragments of antibodies to rabbit immunoglobulin (Ig) G or to goat IgG. The technique enabled preservation of the antigenic determinants of the platelet proteins, accessibility of Fab fragments to the platelet proteins, and maintenance of the ultrastructural integrity of the platelets. Using this approach, it was directly demonstrated that platelet fibrinogen and PF4 are stored in the alpha-granules of human platelets.

Animals↗
PubMed1982

Treatment of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments: experience in 26 cases.

Purified Fab fragments of digoxin-specific antibodies obtained from sheep were used to treat 26 patients with advanced, life-threatening digoxin (23 cases) or digitoxin (3 cases) toxicity. These patients had advanced cardiac arrhythmias, and in some cases hyperkalemia, which were resistant to conventional treatment. All patients had an initial favorable response to doses of Fab fragments calculated (in most cases) to be equivalent, on a molar basis, to the amount of cardiac glycoside in the patient's body. In four patients treated after prolonged hypotension and low cardiac output, death ensued from cerebral or myocardial hypoperfusion. In one case the available Fab fragment supply was inadequate to reverse a massive suicidal ingestion of digoxin, and the patient died after recurrent ventricular arrhythmias. In the remaining 21 patients, cardiac rhythm disturbances and hyperkalemia were rapidly reversed, and full recovery ensued. There were no adverse reactions to the treatment. We conclude that the use of purified digoxin-specific Fab fragments is a safe and effective means to reverse advanced, life-threatening digitalis intoxication.

Adolescent↗
PubMed1982

Immunochemical studies of antisera to human fibrinopeptide-B.

The immunochemical specificity of rabbit antisera to human fibrinopeptide-B (FPB) has been studied by comparing the relative abilities of FPB and of various proteins and peptides containing the NH2-terminal segment of the B beta-chain of human fibrinogen to inhibit the binding of a radioiodinated FPB derivative by each of seven anti-FPB sera. Anti-FBP sera varied in the extent to which they cross-reacted with fibrinogen, the NH2-terminal disulfide knot of fibrinogen (N-DSK), B beta 1(Pyr)-118(Met), B beta 1(Pyr)-42(Arg), and desarginyl-FPB. Anti-FPB sera have been identified that discriminate effectively between FPB and larger FBP-containing peptides; such antisera can be used to measure FPB in the absence of the larger peptides or to demonstrate the presence of larger peptides such as B beta 1(Pyr)-42(Arg) in extracts of clinical plasma samples by means of an increase in FPB immunoreactivity following thrombin treatment. One anti-FPB serum has been identified that is capable of detecting desarginyl-FPB, and this antiserum has been used in the development of a radioimmunoassay for desarginyl-FPB. Thus, by precisely defining the specificity of anti-FPB sera, it has been possible to identify antisera that are useful, not only in the measurement of FPB, but also in the detection of other important related molecules, such as B beta 1(Pyr)-42(Arg) and desarginyl-FPB. The immunochemical detection of these FPB-related peptides should provide useful information concerning the action of proteolytic enzymes, such as plasmin on the NH2-terminal segment of the B beta-chain of fibrinogen, and of carboxypeptidase-B on free FPB, in human plasma.

Cross Reactions↗
PubMed1982

The development and application of a radioimmunoassay for dihydrodigoxin, a digoxin metabolite.

The cardioinactive digoxin metabolite, dihydrodigoxin, has been conjugated to bovine serum albumin and to bovine pancreatic ribonuclease by the periodate oxidation method. Rabbits immunized with the dihydrodigoxin-bovine serum albumin conjugate formed antibodies which bound a radioiodinated dihydrodigoxin-ribonuclease conjugate. This binding was inhibited by dihydrodigoxin. After affinity chromatography on a digoxin-ribonuclease-Sephacryl immunoadsorbent to remove antibodies which cross-reacted with digoxin, dihydrodigoxin was 300 times more effective than digoxin in inhibiting the binding of tracer by antibody. Digoxin-absorbed antidihydrodigoxin antibodies were coupled to Sephacryl and were used to develop a solid-phase radioimmunoassay capable of detecting 250 to 500 pg of dihydrodigoxin in 1 ml of human serum or urine. This radioimmunoassay has been used to define the pharmacokinetics of the metabolite in four normal human volunteers who ingested 125 to 500 micrograms of dihydrodigoxin by mouth. Dihydrodigoxin was quickly absorbed, with maximal serum concentrations achieved within 45 to 105 min, followed by a rapid fall in serum immunoreactivity over 2 to 4 hr and then by a slower, more gradual decline. The terminal half-life (beta) in serum varied from 4.24 to 11.9 hr (mean +/- S.E. = 8.1 +/- 1.3 hr). Most of the administered dose was excreted in the urine, with cumulative urinary recovery varying inversely with the dose. Urinary half-lives averaged 13.8 +/- 2.1 hr, and renal clearance rates were similar to those of creatinine. Dihydrodigoxin is rapidly absorbed and excreted in man and appears to be eliminated from the body at a faster rate than digoxin.

Adult↗
PubMed1982

Fab fragments of digoxin-specific antibodies used to reverse ventricular fibrillation induced by digoxin ingestion in a child.

Digitalis poisoning is a rare problem in children, but it may be life threatening. A case of massive overdose of digoxin in a 2 1/2-year-old boy that produced prolonged ventricular fibrillation refractory to conventional therapy is reported. After two hours the boy was given digoxin-specific Fab fragments of antibody in sufficient quantity to bind his estimated dose of 10 mg. By completion of the treatment minutes later, normal rhythm and circulation were restored. The serum free digoxin level before antibody administration was greater than 100 ng/ml, and it rapidly fell to undetectable levels after antibody was given. Digoxin bound to the antibody had a clearance half-life of approximately 48 hours. The child had no apparent neurologic damage and his intellectual function was normal on discharge. He had a transient hematuria and a residual incomplete right bundle branch block. Administration of purified Fab fragments of digoxin-specific antibodies can be life saving in children with digitalis poisoning, and prolonged cardiopulmonary resuscitation in children is justified when the cause of cardiac arrest is potentially reversible.

Animals↗
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

Quinidine-digoxin interaction: time course and pharmacokinetics.

The time course of the rise in serum digoxin concentration was followed in 18 patients treated with digoxin as quinidine treatment was started with a loading dose. The mean serum digoxin levels rose significantly during the first 24 hours after administration of quinidine was begun, and reached a new steady state concentration after about 48 hours. Digoxin kinetics were studied in two groups of normal volunteers: Group 1 (n = 7) received a small dose of quinidine, 800 mg/day, and group II (n = 8) received 1,600 mg/day. There was no significant mean change in the apparent volume of distribution of digoxin in either group. In group I (small dose), quinidine reduced the digoxin clearance values: total clearance by 30 percent, renal clearance by 32 percent and nonrenal clearance by 29 percent. In group II (large dose), quinidine reduced digoxin total clearance by 36 percent, renal clearance by 54 percent and nonrenal clearance by 22 percent. The reduction in digoxin volume of distribution and renal clearance during quinidine treatment were a function of the serum quinidine concentration. The change in nonrenal clearance of digoxin was independent of serum quinidine concentration.

Adult↗
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

Effect of quinidine on the digoxin receptor in vitro.

To investigate the basis for a clinically important digitalis-quinidine interaction that is characterized by increases in serums digoxin concentrations when quinidine is administered to digoxin-treated patients, we have studied in vitro the interaction of quinidine with the digoxin receptor. Evidence has been obtained that quinidine is capable of decreasing the affinity for digoxin of cardiac glycoside receptor sites on purified Na,K-ATPase and on intact human erythrocyte membranes. As others have shown, quinidine is capable of inhibiting Na,K-ATPase activity, and evidence has been obtained in the current study that, while quinidine can reduce the affinity of the enzyme for digoxin, it is also capable of acting together with digoxin in inhibiting enzyme activity to a degree greater than the inhibitory effect of digoxin alone. The concentrations of digoxin and quinidine used in this study were considerably greater than their therapeutic serum concentrations. Nevertheless, these observations are consistent with the hypothesis that the increases in serum digoxin concentrations and the decreases in volumes of digoxin distribution observed clinically when quinidine is administered to digoxin-treated patients may reflect, at least in part, a decrease in the affinity of tissue receptors for digoxin. The possibility must also be considered that enhanced cardiac effects of digoxin may occur clinically as the result of an augmentation, by quinidine, of digoxin effects, which more than compensates for the modest reduction in digoxin binding.

Biological Transport, Active↗