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Biomedical subjects

K W Hunter

Publications and source records attributed to K W Hunter.

At least 37 records · Page 2Linked to original sources
PubMed1986

Acute titration and chronic follow-up with captopril in hypertension. A one-year safety profile on combination therapy with captopril and a diuretic.

The present study examines acute titration with captopril and chronic follow-up data on captopril and a diuretic in patients with all forms of hypertension. Captopril was initiated in those patients in whom previous antihypertensive agents either failed to control high blood pressure or produced adverse reactions. Acute titration was done in 88 patients in whom average diastolic blood pressure was equal to or more than 95 mm Hg. Initial titration dosage was decided on the basis of initial blood pressure recordings. During initial titration, 5 patients received 12.5 mg, 51 received 25 mg, 28 received 50 mg, and the remaining 4 received 100 mg of captopril. Post-captopril blood pressure data were normalized by using pre-captopril data as 100% for each patient. The blood pressure-lowering effect of captopril on both systolic and diastolic blood pressure in all 88 patients was statistically significant (p less than 0.05), within forty-five minutes of captopril administration irrespective of the doses. No adverse reactions were seen during the acute titration. After the initial titration, in all 88 patients a diuretic was added to obtain a synergistic effect. Eleven patients were dropped from the study, for they could not follow the requirements of the protocol. In 77 patients the data for a one-year safety profile with captopril and diuretic were available. There were no overall significant statistical changes in serial white blood cell count, serum potassium, and serum creatinine values in those 77 patients. In 31 patients the initial and maintenance dosage of captopril and the diuretic remained unaltered for one year. Post-captopril blood pressure and heart rate data were normalized, pre-captopril data being considered as 100% in those 31 patients. The blood pressure data following captopril and a diuretic therapy compared with the pre-captopril data were statistically significant (p less than 0.05) throughout the study period. However, no significant changes in heart rates were observed during the study period. In all other patients, diuretic therapy was continued throughout the study period. In 6 severely hypertensive patients, an additional beta-blocker was needed for further control of high blood pressure. In 3 severe hypertensives with renal failure, besides a diuretic and a beta-blocker, minoxidil was needed to normalize their high blood pressure. In 4 of 77 patients, verapamil was used for treatment of either vasospastic angina or paroxsysmal supraventricular arrhythmia.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic beta-Antagonists↗
PubMed1985

Preparation and characterization of monoclonal antibodies to the trichothecene mycotoxin T-2.

Two mouse immunoglobulin G1 monoclonal antibodies that bind to the trichothecene mycotoxin T-2 were prepared. These antibodies, designated 12C12 and 15H6, had affinities for T-2 of 3.5 X 10(6) and 5.8 X 10(7) liters/mol, respectively. A competitive inhibition enzyme immunoassay that employed these antibodies had a sensitivity for T-2 of 50 ng per assay. Both antibodies bound to the metabolite HT-2 but not to the related trichothecenes monoacetoxyscirpenol, diacetoxyscirpenol, deoxynivalenol, and deoxyverrucarol. Evidence is presented that T-2-protein conjugates inhibit protein synthesis in lymphoid cells and that this apparent immunotoxicity may be due to the release of T-2 from the protein carrier.

Animals↗
PubMed1985

Monoclonal antibodies to T-2 toxin. In vitro neutralization of protein synthesis inhibition and protection of rats against lethal toxemia.

A murine monoclonal antibody (15H6) against the trichothecene mycotoxin T-2 was capable of neutralizing the in vitro protein synthesis inhibitory effect of T-2 toxin in human B lymphoblastoid cultures. It was further shown that 15H6 given to rats (250 mg/kg) 30 min before or 15 min after a lethal dose (1 mg/kg) of T-2 toxin conferred 100% survival. A lower dose of 15H6 (125 mg/kg), given 15 min after the lethal dose of T-2 toxin, protected 25% of the rats. An increased time to death and 45% survival was seen in rats given the full dose of 15H6 antibody 60 min after lethal toxin. These data are the first demonstration of effective prophylaxis and therapy for T-2 toxemia.

Animals↗
PubMed1985

Structural and stereochemical specificity of mouse monoclonal antibodies to the organophosphorous cholinesterase inhibitor soman.

To test the usefulness of immunotherapy in organophosphate poisoning, two mouse monoclonal antibodies were prepared to the chemical warfare agent soman. The antibodies bound reversibly to soman and afforded considerable protection to acetylcholinesterase in vitro. However, they were only marginally effective in preventing the consequences of soman poisoning in mice (these data have been published elsewhere). Since potential for immunotherapeutic usefulness resides in antibody affinity and specificity, we conducted experiments to define these parameters to enable us to maximize them in the production of later antibodies. Interaction of the antibodies (CC1 and BE2) in affinity-purified form with a series of soman analogs in a competitive inhibition enzyme immunoassay was used to assess the contribution to binding affinity of each functional group on the soman molecule. Neither antibody interacted with the -P = S analog of soman or methylphosphonic acid. A decrease in the number of methyl groups on the pinacolyl side chain reduced or eliminated binding with both antibodies while increasing the size of this group had a mixed result. The major metabolite of soman, its basic hydrolysis product, interacted weakly with BE2 and failed to interact with CC1. Alkyl ester group substitution at the fluorine position increased antibody binding up to the symmetrical dipinacolyl analog. Stereochemical specificity was determined by measuring the apparent decrease in the rate of inhibition of cholinesterases (acetylcholine acetylhydrolase, EC 3.1.1.7, or acylcholine acylhydrolase, EC 3.1.1.8) by pure soman stereoisomers in the presence of increasing concentrations of each antibody. CC1 demonstrated specificity that varied as C(+)P(+) less than C(-)P(+) less than C(-)P(-) less than C(+)P(-). Although affinities were much lower, BE2 also showed a preference for the more toxic P(-) isomers.

Acetylcholinesterase↗
PubMed1984

Leishmanial differentiation in vitro: induction of heat shock proteins.

During temperature-induced in vitro differentiation from the promastigote to the amastigote form of the parasitic protozoan Leishmania mexicana, seven actively synthesized proteins were identified. These proteins corresponded precisely in molecular weight to the well-known heat shock proteins seen in species such as Drosophila. The minimal DNA synthesis observed in the differentiating parasites indicated that little cell division occurs during this process. The absence of RNA synthesis during early temperature-induced differentiation suggests that the leishmanial heat shock proteins are post-transcriptionally regulated. Heat shock proteins may play an adaptive role in the transition of Leishmania from arthropod to mammalian host.

Animals↗
PubMed1984

Intravenous immunoglobulin in neonatal group B streptococcal disease. Pharmacokinetic and safety studies in monkeys and humans.

Numerous studies have suggested that opsonic antibody is important in neonatal immunity to group B streptococci. Immunoglobulin G is primarily transferred from the mother to the fetus across the placenta in the last few weeks of pregnancy. Premature babies may, therefore, not acquire sufficient opsonic antibody to protect them from infection with group B streptococci. Although maternal immunization may provide adequate maternal opsonic antibody, premature infants with antibody deficiency may remain susceptible to infection. Intravenous immunoglobulin administered to term pregnant rhesus monkeys did not provide reliable levels of serum opsonic activity to group B streptococci in their offspring. Pharmacokinetic and safety studies were also performed in human neonates. Significant elevations in group B streptococcal-specific IgG did occur in human neonates given 500 mg/kg intravenous immunoglobulin and the infusions appeared safe and well tolerated. The availability of intravenous immunoglobulin with functional activity against group B streptococci may provide a rapid and effective method of delivering opsonic antibody to neonates.

Adult↗
PubMed1984

A micro-method for the detection of butyrylcholinesterase secreted by hepatocytes in vitro.

A new assay has been developed for detection of butyrylcholinesterase (EC 3.1.1.8) activity based upon the change in absorbance of phenol red, caused by the release of butyric acid from the substrate. Using commercially available enzyme prepared from horse serum, linear, dose-related decreases in absorbance were obtained, generally with correlation values of 0.965 or greater. The assay was modified and used to detect enzyme activity in the supernatants from primary cultures of mouse hepatocytes. The enzyme-mediated response was inhibited by NN'-diisopropylphosphorodiamidic anhydride, a specific inhibitor of butyrylcholinesterase.

Animals↗
PubMed1984

Studies using a monoclonal antibody against soman.

The production of antibodies against the organophosphorus hapten soman has been undertaken in vivo in rabbits and in vitro by employing monoclonal techniques. The polyclonal rabbit antibodies did not cross-react with soman but were inhibited by soman analogs in a competitive inhibition enzyme immunoassay ( CIEIA ). In contrast the monoclonal antisoman antibodies were inhibited specifically by soman in the CIEIA but not by sarin nor the hydrolysis products of soman. The monoclonal antibodies were able to compete with acetylcholinesterase (AChE) for soman when the antibody was present in a molar concentration equal to the antibody-soman dissociation constant, resulting in a retardation of the rate of inhibition of AChE by soman. When monoclonal antibodies were administered to mice in a passive immunization regimen, the times-to-death increased twofold at an LD70 or LD90 dose level. These results suggest that the monoclonal antibodies have proper characteristics for use as an immunocytochemical reagent of high specificity. The ability of the antisoman monoclonal antibodies to compete with AChE for soman in vitro and the preliminary in vivo data indicate that selected monoclonal antibodies may prove useful in a therapeutic or prophylactic mode for organophosphorus poisoning.

Acetylcholinesterase↗
PubMed1984

Improved detection of bacterial antigens by latex agglutination after rapid extraction from body fluids.

Nonspecific agglutination of antibody-coated latex particles, unrelated to the presence of specific bacterial antigens, is a major difficulty with commercial latex particle agglutination tests. Rheumatoid and other factors are known to interfere with latex tests. We studied the use of six chelating, reducing, and anticoagulatory reagents in a rapid extraction of antigen procedure to free heat-stable antigens of Haemophilus influenzae type b and group B streptococcus which had been added to human sera. We also screened sera for the incidence of nonspecific agglutination from the three following groups: 123 patients with positive serology tests, 112 hospitalized patients, and 87 blood donors. The rapid extraction of antigen procedure involved a 1:4 dilution of the sera with each of the six reagents, incubation at 100 degrees C for 3 min, and centrifugation at 13,000 X g for 5 min. Two commercial latex kits were tested (Bactigen and Wellcogen). Nonspecific agglutination was entirely eliminated by each of the six extraction reagents. Sera from 52% of the patients with positive serology tests, 29% of the hospitalized patients, and 28% of the blood donors showed nonspecific agglutination with Bactigen before extraction. Nonspecific agglutination was eliminated in all but one sample after the rapid extraction of antigen procedure. This simple, rapid extraction procedure eliminated nonspecific reactions in cerebrospinal fluids and amniotic fluids and reduced this problem in urines and sera with each commercial kit used on clinical specimens.

Agglutination↗
PubMed1983

Measurement of monoclonal antibody concentrations in hybridoma cultures: comparison of competitive inhibition and antigen capture enzyme immunoassays.

Competitive inhibition and antigen capture enzyme immunoassays were compared for the measurement of mouse monoclonal IgGl antibody produced by a hybridoma culture. Both methods yielded standard curves that were linear over several orders of magnitude, and both were comparable in sensitivity (10 ng/ml). However, the slope of the antigen capture curve was flatter than the slope for competitive inhibition. This difference in slope, coupled with a larger average standard deviation for each point on the standard curve for antigen capture, resulted in a significantly larger range of variability in IgGl levels. It is concluded that the competitive inhibition enzyme immunoassay method is better suited to the precise quantification of mouse monoclonal antibodies in hybridoma culture supernatants.

Animals↗
PubMed1983

Functional antibacterial activity of a human intravenous immunoglobulin preparation: in vitro and in vivo studies.

The functional antibacterial activity of an intravenous immunoglobulin preparation (Swiss Red Cross Immunoglobulin, SRK-Ig) was tested both in vitro and in vivo. Using type III group B streptococci as a model system, the intravenous immunoglobulin preparation was shown to enhance phagocytosis and killing of the bacteria by human neutrophils. There was good activity to several type III strains, and for efficient opsonization both antibody and complement were required. In an animal model of neonatal group B streptococcal sepsis, passively administered immunoglobulin enhanced survival with 27/37 (73%) treated animals surviving compared to only 3/16 (19%) controls. These studies demonstrate that the intravenous immunoglobulin preparation SRK-Ig has retained functional activity and may have potential value for prophylaxis or therapy of certain bacteria infections.

Animals↗
PubMed1983

Enhanced survival in Pseudomonas aeruginosa septicemia associated with high levels of circulating antibody to Escherichia coli endotoxin core.

We studied the relationship between serum antibodies to the cross-reactive endotoxin core of Escherichia coli and survival following Pseudomonas aeruginosa septicemia. Core glycolipid was purified from the outer cell membrane of a uridine diphosphate galactose 4-epimerase-deficient rough mutant E. coli (J5 strain), characterized, and used as the antigen in a quantitative enzyme-linked immunosorbent assay (ELISA) to measure core-specific IgG and IgM antibodies. 43 patients with Pseudomonas septicemia, among whom there was a mortality of 42%, were evaluated. Core-specific antibody concentrations in acute sera ranged from 1 to 49 micrograms/ml in the case of IgG and from 1 to 200 micrograms/ml for IgM. Core-specific antibodies of both isotypes were higher in patients who survived compared with those who succumbed to their septicemias (mean, microgram/ml +/- SEM, 26 +/- 3 vs. 14 +/- 4, P = 0.005 for IgG, and 55 +/- 12 vs. 18 +/- 5, P = 0.009 for IgM). Although total IgG levels were also higher in acute sera from survivors compared with nonsurvivors (mean, mg/dl +/- SEM, 1,120 +/- 99 vs. 694 +/- 119, P = 0.004), total IgM levels were virtually identical in the two groups (146 +/- 23 vs. 148 +/- 48, P = 0.52). Conversely, patients with core-specific IgG levels greater than 10 micrograms/ml at the onset of septicemia had better survival than those with levels less than 10 micrograms/ml (79 vs. 14%, P less than 0.001), and patients with core-specific IgM levels greater than 30 micrograms/ml had better survival than those with levels less than 30 micrograms/ml (81 vs. 44%, P = 0.01). In comparison, patients with total IgG levels greater than 1,000 mg/dl also had better survival than those with levels less than 1,000 mg/dl (82 vs. 42%, P = 0.01), while those with total IgM levels greater than 150 mg/dl showed somewhat less improvement in survival compared with those with levels less than 150 mg/dl (71 vs. 50%, P = 0.12). Core-specific IgM was highly correlated with core-specific IgG (r = 0.52), but not with type-specific anti-lipopolysaccharide (r = 0.13) or anti-toxin A (r = 0.12) antibodies, or with total IgG (r = 0.28) or IgM (r = 0.31). In contrast, core-specific IgG correlated somewhat more closely with type-specific antibodies (r = 0.36), and with total IgG (r = 0.51) and IgM (r = 0.52). Stepwise linear discriminant analysis indicated that type-specific antibody levels were the best predictor of outcome, among those antibodies examined, followed by anti-core IgM. Although anti-core IgG, anti-toxin A, and total IgG levels all correlated individually with survival, none augmented the prognostic power of type-specific antibodies in combination with anti-core IgM, which together predicted outcome accurately 73.5% of the time. Host factors not significantly associated with anti-core antibody levels included rapidly fatal underlying disease, age, sex, leukopenia, and prior treatment with cytotoxic drugs. In contrast, prior steroid therapy was associated with low levels of both core-specific IgG and IgM (P < 0.05). These data suggest cross-protective activity against P. aeruginosa septicemia of naturally occurring antibodies to the endotoxin core of E. coli. Anti-core antibodies, particularly of the IgM isotype appear to augment the more specific protective immunity engendered by antibodies to the O-specific side chains of Pseudomonas lipopolysaccharides. This cross-protective immunity likely applies to other Gram-negative pathogens as well.

Antibodies, Anti-Idiotypic↗
PubMed1983

Murine malaria: cellular interactions in the immune response.

The cellular and humoral interactions that contribute to protective immunity in Plasmodium yoelii malaria were studied by adoptive transfer of selective cell populations or hyperimmune serum into sublethally irradiated syngeneic C57BL/6 mice. For some experiments pools of mononuclear spleen cells were depleted of T or B lymphocytes and cells that take up silica were inactivated by standard procedures. Unfractionated immune spleen cells, but not nonimmune spleen cells, protected recipients from lethal P. yoelii challenge. Analysis of the protective capacity of subpopulations of immune spleen cells showed that levels of immunity similar to those seen after transfer of unfractionated immune cells were present only in those instances where immune macrophages, i.e., cells not previously inactivated with silica, were transferred concomitantly with either immune T (supplemented with nonimmune B) or immune B (supplemented with nonimmune T) cells. The requirement for immune macrophages could not be met by transferring mononuclear cells from a nonimmune donor. The results support the hypothesis that an immune 5,000 R-radioresistant, silica-inactivated, non-T, non-B cell, probably a macrophage, must act in concert with immune T and B lymphocytes in the optimal expression of transferred immunity to P. yoelii.

Animals↗
PubMed1982

Antibacterial activity of a human monoclonal antibody to haemophilus influenzae type B capsular polysaccharide.

Human splenic lymphocytes were fused with a new mutant human myeloma cell line (HFB-1) to produce hybridomas that secrete human monoclonal antibodies. A cloned hybridoma line was selected that secretes IgG antibodies reactive with Haemophilus influenzae type b polyribosylribitolphosphate (PRP) capsular polysaccharide. This human monoclonal antibody was active in an in-vitro neutrophil-mediated bactericidal assay, and provided significant protection in an animal model of H. influenzae type b disease. Human monoclonal antibody to H. influenzae type b may have prophylactic value in man, particularly in infants who do not produce protective antibody after active immunisation with PRP.

Antibodies, Monoclonal↗
PubMed1982

Detection and quantification of the organophosphate insecticide paraoxon by competitive inhibition enzyme immunoassay.

A competitive inhibition enzyme immunoassay (EIA) was developed to detect and quantify levels of the organophosphate insecticide paraoxon in body fluids. Protein-conjugated paraoxon served as an immunogen for the production of rabbit heteroantiserum, from which affinity purified IgG anti-paraoxon antibodies were isolated using a heterologous protein-paraoxon-conjugated immunoabsorbent. In the competitive inhibition EIA a standard curve was generated for the inhibition of binding of anti-paraoxon IgG to a solid-phase bound heterologous protein-paraoxon conjugate by various concentrations of free paraoxon. Binding was proportionate to the color change of an appropriate substrate generated by an enzyme-conjugated second antibody specific for the rabbit IgG anti-paraoxon. The assay detected paraoxon levels as low as 10(-10)M (28 pg/ml) in buffer, and serum paraoxon levels as low as 10(-9)M. In addition to its sensitivity, this technique is ideally suited to the simultaneous processing of large numbers of samples in less than 2 hr. The competitive inhibition EIA is cost effective and should facilitate environmental surveillance using sentinel animals, expand laboratory toxicology studies, and improve clinical detection capabilities.

Animals↗
PubMed1982

Functional characteristics of a modified immunoglobulin preparation for intravenous administration: summary of studies of opsonic and protective activity against group B streptococci.

Group B streptococci (GBS) remains a major cause of morbidity and mortality in newborn babies, despite antibiotic therapy, Recent studies suggest that phagocytosis and killing of GBS is ineffective due to a deficiency in anti-GBS antibody. Using an opsonophagocytic bacterial assay and a suckling rat model of GBS sepsis, we analyzed a modified human immunoglobulin for opsonic and protective antibody. Immune globulin (IGIV) prepared for intravenous use (Gamimune, Cutter Laboratories, Inc.) was highly protective in this experimental GBS model. Using the opsonophagocytic assay, antibody activity to several strains of types Ia, II, and III GBS were also demonstrated with IGIV. To ensure that the IGIV activity was in fact antibody, globulin from IGIV was isolated and analyzed. Purified IgG retained opsonic activity in vitro and also provided protection in experimental GBS disease. Variation in the quantity of IgG necessary for protection was observed in different GBS strains. Since IGIV has opsonic and protective activity against several strains and serotypes of GBS, its intravenous administration may provide a valuable adjunct to standard antibiotic therapy for neonatal GBS infections.

Animals↗