Biomedical subjects

G M Bright

Publications and source records attributed to G M Bright.

At least 19 recordsLinked to original sources

PubMed1999

Appraisal of growth hormone (GH) secretion: evaluation of a composite pharmacokinetic model that discriminates multiple components of GH input.

Criteria for a diagnosis of GH deficiency include inadequate GH secretion as assessed by provocative testing. The changes in serum GH concentration in such tests, however, do not uniformly predict treatment responses. We questioned whether the changes in serum GH have a uniform dependence among subjects on the mass of secreted GH. We simulated spontaneous GH secretory events with bolus infusions of recombinant human GH (rhGH) in 15 somatostatin-infused adult subjects. Maximum serum GH responses, the GH areas under the curve, and GH mass calculated from deconvolution techniques are all indexes of GH secretion influenced by GH clearance and distribution volume. In this group, these indexes showed a nonuniform dependence on the known GH dose. Despite somatostatin infusion, we found evidence for low level basal GH secretion with oscillatory characteristics that may have influenced the GH concentration dependence on GH dose. We then developed and evaluated a new pharmacokinetic model to account for pulsatile, basal, and oscillatory inputs to the serum GH concentration profile. The new model is comprised of three terms. The first describes plasma GH concentrations from exogenous administration of rhGH according to a one- or a two-compartment model. The second term accounts for basal GH secretion. The third is a cosinor function that describes the oscillatory pattern of basal GH. The composite pharmacokinetic model predicted plasma GH concentrations well (r2 = 0.88-0.97); pharmacokinetic and cosinor parameters had high precision and narrow 95% confidence intervals. The pharmacokinetic parameters were stable and independent. The mean values and coefficients of variance (SD/mean) of GH pharmacokinetic parameters in our 15 subjects were: clearance, 0.236 L/min (24%); volume of distribution, 3.46 L (30%); and terminal half-life, 12.3 min (37%). The values for the cosinor parameters were: basal concentration, 0.22 ng/mL (85%); amplitude, 0.758 (50%); cycle, 121 min (27%); and time shift (acrophase), 60.3 min (53.6%). During the 9-h study, clearance decreased from 0.259 +/- 0.09 to 0.214 +/- 0.06 L/min (P < 0.03), and basal concentration increased from 0.20 +/- 0.22 to 0.33 +/- 0.33 ng/mL (P < 0.5). We conclude that our model can provide useful estimates of GH pharmacokinetics in the presence of basal, oscillating, endogenous concentrations without administering a dose of radiolabeled GH. The substantial inter- and intrasubject variance in pharmacokinetic parameters between subjects negates the assumption of a uniform relationship between GH secretion and serum GH concentration and detracts from the utility of a GH concentration cut-off point in GH testing. These findings have implications to the valid appraisal of GH deficiency states, selection of rhGH treatment candidates, and physiological regulation of the GH axis.

Adult↗

PubMed1999

Growth hormone stimulation test results as predictors of recombinant human growth hormone treatment outcomes: preliminary analysis of the national cooperative growth study database.

Growth hormone (GH) stimulation tests are considered a prerequisite to clinical trials of recombinant human GH (rhGH) therapy, but the test results may not be predictive of the treatment outcomes with rhGH. We examined the GH stimulation test results as a predictor of the treatment outcome in a cohort of prepubertal subjects in the National Cooperative Growth Study. A standard is proposed in which a diagnosis of GH deficiency is considered appropriate when a patient has significant first-year catch-up growth and that a positive stimulation test result predicts this outcome. With this construct, a traditional interpretation of GH stimulation test results correctly identifies 64% of the rhGH treatment outcomes. The analysis shows an upper limit of diagnostic sensitivity of 82% and a lower limit of specificity of 25% in our study population. The results of our recent studies suggest that the sensitivity and specificity of the current GH stimulation tests are attributable in part to broad intersubject variation in GH clearance, rates of GH elimination, and GH volume of distribution. The combined studies suggest that the use of subject-specific pharmacokinetic parameters will improve the diagnostic interpretation of GH stimulation test results and improve rhGH treatment outcomes.growth hormone stimulation tests, recombinant human growth hormone, pharmacokinetic parameters, maximal stimulated growth hormone concentration.

Child↗

PubMed1998

Metabolism and excretion of a new anxiolytic drug candidate, CP-93, 393, in healthy male volunteers.

CP-93,393 [(7S,9aS)-1-(2-pyrimidin-2-yloctahydropyrido[1,2-a] pyrazin-7-ylmethyl)pyrrolidine-2,5-dione] is a new anxiolytic drug with highly selective serotonin 5-hydroxytryptamine 1A autoreceptor agonist, alpha2-adrenergic antagonist, and dopamine D2 agonist properties. The excretion, biotransformation, and pharmacokinetics of CP-93,393 were investigated in six healthy male volunteers after oral administration of a 5-mg dose of [14C]CP-93,393. The administered radioactivity was excreted predominantly in the urine. One week after administration of the dose, cumulative excretion amounted to 67.8 +/- 2.5% in the urine and 22.0 +/- 5.6% in the feces. In total, 89.8 +/- 5.7% of the radioactive dose was recovered in urine and feces. Mean maximum plasma concentration values for unchanged CP-93,393 were 10.92 and 1.02 ng/ml for poor metabolizers (PMs) and extensive metabolizers (EMs) of dextromethorphan, respectively. AUC0-infinity values for unchanged CP-93,393 were also greater for PMs than for EMs, whereas the mean maximum plasma concentration and AUC0-infinity values for total radioactivity were similar for the two phenotypes. Less than 0.5% of the dose was excreted in urine as unchanged drug for both EMs and PMs, suggesting extensive metabolism of CP-93,393 in both phenotypes. Hydroxylation at the 5-position of the pyrimidine ring was identified as the main metabolic pathway. 5-Hydroxy-CP-93,393 (M-15) and its glucuronide and sulfate conjugates (M-7 and M-13, respectively) accounted for approximately 51% of the administered dose in excreta of both PMs and EMs. Hydrolysis of the succinimide ring, in combination with 5-hydroxylation and/or conjugation or not, accounted for approximately 9% of the dose. A novel metabolite, apparently resulting from oxidative degradation of the pyrimidine ring, was characterized as the amidine analog M-18. M-15 (47-62%), its sulfate conjugate (M-13, approximately 9%), and the pyrimidine ring-cleaved product (M-18, 7-13%) were identified as the major circulating metabolites for both EMs and PMs. Therefore, CP-93,393 undergoes metabolism by three primary pathways, i.e. 1) aromatic hydroxylation followed by conjugation with glucuronic acid and sulfuric acid, 2) oxidative degradation of the pyrimidine ring, and 3) hydrolysis of the succinimide ring. The identified metabolites accounted for approximately 90, 91, and 92% of the total radioactivity present in urine, plasma, and feces, respectively. The major in vivo oxidative metabolites were also observed after in vitro incubations with human liver microsomes.

Administration, Oral↗

PubMed1995

Corticosteroid-binding globulin modulates cortisol concentration responses to a given production rate.

In most clinical situations, the ability of the adrenal to produce cortisol is studied with measurements of cortisol concentration. The validity of this assumes the existence of a predictable relationship between cortisol production and plasma cortisol concentration. This assumption was tested by determining if production rates, as simulated by constant cortisol infusions, were predictive of the resultant plasma and urine cortisol concentrations in dexamethasone-suppressed subjects. Additional attempts to predict simulated cortisol production rates were made with infusions of [9,12,12-2H3]cortisol. Thirty-six 8-h cortisol infusions were performed in 24 subjects. Although there was a tendency to achieve a higher plasma cortisol concentration response at a higher cortisol infusion rate (P < 0.04), the known cortisol infusion rate was a poor predictor of plasma cortisol responses (r2 = 0.12). Addition of corticosteroid-binding globulin concentration (CBG) as a covariate greatly improved the predictability of plasma cortisol responses (r2 = 0.52). Urine free cortisol, normalized to inulin excretion, had a predictable relationship to cortisol infusion rate (r2 = 0.82). Isotope-enrichment data from a group of 6 subjects receiving multiple cortisol infusions during administration of [9,12,12-2H3]cortisol gave the most accurate predictions of the known cortisol infusion rates (r2 = 0.93). It is concluded that: 1) cortisol infusion (production) rate and plasma cortisol concentration are poorly correlated; 2) CBG is an important modulator of concentration responses to a given production rate; and 3) short (8-h) infusions of [9,12,12-2H3]cortisol may be used to determine cortisol production rates in humans. The mechanisms by which CBG modulates cortisol concentration responses are elaborated in a companion report.

Adult↗

PubMed1995

Corticosteroid-binding globulin influences kinetic parameters of plasma cortisol transport and clearance.

In an accompanying study, we reported a very poor correlation between the magnitude of a continuous cortisol infusion in dexamethasone-suppressed adults and the resultant steady state plasma cortisol concentration (r2 = 0.13). The concentration of corticosteroid-binding globulin (CBG) was found to explain an additional 39% of the variance in cortisol response. We hypothesized that CBG might act by altering kinetic parameters of cortisol transport. According, the rate of cortisol disappearance (Kd), volume of distribution (V), and pool size (P) were determined after bolus injection of a stable isotope of cortisol in two groups of healthy female subjects with both normal and elevated CBG concentrations. The bolus studies were performed during continuous cortisol infusion and steady state conditions of plasma cortisol concentration. Two models were used to generate the kinetic parameters. The kinetic parameters thus generated were able to predict the known cortisol infusion rate with 4-16% error. The goodness of fit of modeled to experimental data was excellent in all cases (> 0.93). In both models, Kd had a negative correlation to the CBG concentration (P < 0.05), a negative correlation to the volume of distribution (P < 0.03), and a positive correlation (P < 0.03) to pool size. Excellent correlations were noted between both models in estimates of kinetic parameters (r2 = 0.82-0.97; P < 0.01). We conclude that CBG, in addition to its role of transport protein, plays an active role in determining the disposition of cortisol in humans.

Adult↗

PubMed1993

Gas chromatographic-mass spectrometric method for measuring stable isotope enrichments of underivatized cortisol from small plasma volumes.

Isotope dilution methods utilizing quantification of stable enrichment by mass spectrometry has been used recently to determine cortisol production rates in humans. Studies of steroid production and utilization rates require frequent blood sampling, and while stable isotopes are safe for pediatric and perinatal use, the required blood volumes may be problematic using published methodologies. We have developed methods to isolate and quantify the plasma enrichment of cortisol with its stable isotope, [9,12,12-2H3]cortisol using a simple four-step isolation procedure and gas chromatography-mass spectrometry. Isolation is semi-quantitative, but reproducible (mean recovery; 51.5 +/- 5.4% coefficient of variation) and the method does not require derivation. In human studies, this method can determine plasma enrichments between 1 and 10 mol% at plasma concentrations of 2 micrograms/dl or more; only 1 ml of plasma is required. The concentrations of labelled cortisol added to plasma are low (0.2-0.5 micrograms/dl) and are not expected to interfere with the sensitive hypothalamic-pituitary-adrenal feedback system. We conclude that reproducible quantification of stable cortisol isotope enrichment can be achieved from small plasma volumes.

Chromatography, Thin Layer↗

PubMed1992

Quantification of islet cell antibodies by microscope photometry and antibody titration compared.

Islet cell antibodies can predict eventual insulin-dependent diabetes mellitus. In the standard method used by the Immunology of Diabetes Workshop (IDW), predictive power depends on antibody titer as determined by testing multiple serum dilutions. Here I report use of a microscope-based photometry system (MPS) to test whether islet fluorescence intensities from undiluted sera can predict IDW results. MPS testing of 120 undiluted IDW specimens correctly identified 27 of 31 positive and 84 of 89 negative specimens. The relationship between IDW consensus values and MPS readings of undiluted sera is: IDW = 2.45 MPS - 1.44 (r = 0.67, P less than 0.001). Thus, corrected islet intensities from undiluted sera correlated well with IDW values. However, the ability of MPS to predict high IDW consensus values is limited, which may reflect the variable antigenic content of pancreas specimens; moreover, background correction as currently applied is incomplete; nonspecific immunofluorescence appears to emanate from within the islet.

Autoantibodies↗

PubMed1990

Adrenal autoantibodies bind to adrenal subcellular fractions enriched in cytochrome-c reductase and 5'-nucleotidase.

A quantitative assay for human adrenal autoantibodies has been developed to aid in the detection and isolation of human adrenal antigens. To define the subcellular location(s) of the antigen(s) capable of binding with these antibodies, we have quantitated both antibody binding to various adrenal subcellular fractions and the adrenal autoantibody binding inhibition caused by each subcellular fraction. To further define the subcellular location of the autoantibody binding, each fraction was assayed for organelle-specific marker enzyme activities. Enzyme activities were correlated to adrenal autoantibody binding to each fraction by linear regression. Of the materials tested, both antibody binding and inhibition of binding were most highly correlated with adrenal subcellular fractions enriched with cytochrome-c reductase and 5'-nucleotidase (r = 0.98; P less than 0.05). Thus, our data support the localization of adrenal autoantigen(s) in the microsomes, plasma membrane, or both.

5'-Nucleotidase↗

PubMed1989

In vitro and in vivo uptake of azithromycin (CP-62,993) by phagocytic cells: possible mechanism of delivery and release at sites of infection.

Azithromycin, a novel azalide antibiotic, concentrated in human and mouse polymorphonuclear leukocytes (PMNs), murine peritoneal macrophages, and mouse and rat alveolar macrophages, attaining intracellular concentrations up to 226 times the external concentration in vitro. In murine peritoneal macrophages, azithromycin achieved concentration gradients (internal to external) up to 26 times higher than erythromycin. The cellular uptake of azithromycin was dependent on temperature, viability, and pH and was decreased by 2,4-dinitrophenol. Azithromycin did not decrease phagocyte-mediated bactericidal activity or affect PMN or macrophage oxidative burst activity (H2O2 release or Nitro Blue Tetrazolium reduction, respectively). Azithromycin remained in cells for several hours, even after extracellular drug was removed. However, its release was significantly enhanced by phagocytosis of Staphylococcus aureus (82 versus 23% by 1.5 h). In vivo, 0.05 micrograms of azithromycin was found in peritoneal fluids of mice 20 h after oral treatment with a dose of 50 mg/kg. Following caseinate-induced PMN infiltration, there was a sixfold increase in peritoneal cavity azithromycin to 0.32 micrograms, most of which was intracellular. Therefore, the uptake, transport, and later release of azithromycin by these cells demonstrate that phagocytes may deliver active drug to sites of infection.

Animals↗

PubMed1989

Variability in islet cell antibody determination: a quantitative assessment.

The source of variability in the outcome of islet cell antibody (ICA) determinations due to pancreas and serum were independently assessed with a quantitative assay. The effect of choice of pancreatic substrate and serum specimen was assessed by testing for parallelism among twenty-five dilution curves of five sera from diabetic subjects and five pancreata. The five by five format allowed for five tests of pancreatic variability (one serum against five pancreata) and five tests of serum variability (one pancreas against five sera). Analyses of variance and covariance of these dilution curves indicate that test outcome is affected by both the sera (5 tests, p values 10(-6) to 10(-7) and the pancreas (5 tests, p values 10(-3) to 10(-5)). The data support heterogeneity among islet cell antibody isotypes and raise the possibility of diversity of islet cell antigens. Antigenic diversity of pancreatic substrates may interfere with inter- and intra-laboratory comparisons of islet cell antibody determinations. The strong effect of pancreas type on ICA outcome infers possible heterogeneity of the islet cell antigen(s) capable of reacting with human islet cell antibodies.

Autoantibodies↗

PubMed1988

Synthesis, in vitro and in vivo activity of novel 9-deoxo-9a-AZA-9a-homoerythromycin A derivatives; a new class of macrolide antibiotics, the azalides.

A series of erythromycin A-derived semisynthetic antibiotics, featuring incorporation of a basic nitrogen atom into a ring expanded (15-membered) macrocyclic lactone, have been prepared and biologically evaluated. Semisynthetic modifications focused upon (1) varied substitution at the macrocyclic ring nitrogen and (2) epimerization or amine substitution at the C-4'' hydroxyl site within the cladinose sugar. In general, the new azalides exhibit improved Gram-negative potency, expanding the spectrum of erythromycin A to fully include Haemophilus influenzae and Neisseria gonorrhoeae. When compared to erythromycin A, the azalides exhibit substantially increased half-life and area-under-the-curve values in all species studied. The overall in vitro/in vivo performance of N-methyl, C-4'' epimers 3a and 9; and C-4'' amine 11 identify these compounds as the most interesting erythromycin A-superior agents. Compound 3a has been advanced to clinical study.

Animals↗

PubMed1987

Serositis with autoimmune endocrinopathy: clinical and immunogenetic features.

Twenty patients with autoimmune endocrinopathies experienced 45 episodes of pleural and/or pericardial serositis. Seventeen of these patients were women and 15 had clinical or serologic evidence of 2 or more endocrinopathies. Idiopathic primary hypoadrenalism (10 cases), Graves' disease (8 cases), Hashimoto's disease (4 cases), atrophic thyroiditis with hypothyroidism (3 cases), idiopathic primary hypogonadism (3 cases), transient thyroiditides (2 cases), and type I diabetes mellitus (1 case) were diagnosed at a mean age of 24 years. Serositis recurred after asymptomatic intervals of months to years even in patients treated for endocrine dysfunction. Fourteen of 16 Caucasians had circulating immune complexes, including all 9 patients with a C4AQ0 (C4A null) phenotype and including all 12 patients with HLA antigens B8 and DR3, antigens associated with systemic lupus and with autoimmune endocrinopathies. Serositides associated with autoimmune endocrinopathies can occur with chest pain, fever, and exudative effusions in young Caucasian women with the HLA B8 DR3 C4AQ0 phenotype. These serositides may have a common pathophysiologic mechanism.

Adolescent↗

PubMed1987

Quantitative assay for human cytoplasmic islet cell antibodies.

An assay for human islet cell antibodies (ICAs) in serum yielding numerical values and amenable to statistical evaluation has been developed utilizing fluorescence spectrophotomicroscopy (FSPM). The results of the blinded trials by FSPM were compared with those by standard indirect immunofluorescence (IFL). No false-positive or false-negative readings were obtained in 258 observations when the results by FSPM were compared with those by IFL. The intra- and interassay variabilities encountered were not enough to misclassify a specimen. The presence of anti-thyroid, anti-adrenal, or anti-nuclear antibodies did not produce false-positive readings. Twenty-eight additional specimens from diabetic children were also analyzed via three blood group type O pancreases. There was complete agreement concerning the presence or absence of ICA between IFL and FSPM analyses. Analysis of the three pancreases yielded different numbers of results positive for ICA (14/28 vs. 22/28 vs. 15/28, P = .008) in both assays. Thus, selection of pancreatic substrate may influence the outcome of assays for ICA. A matrix of fluorescent microspheres has been devised that allows calibration of the FSPM system. Now, reproducible and comparable readings for ICA values can be obtained from the various reporting laboratories. Should an international reference serum for ICA become available, the remaining problem in the ICA assay, that of substrate (pancreas) variability, should be resolved.

Autoantibodies↗

PubMed1985

Ambulatory management of adolescent alcohol and drug abuse.

The foregoing description of program concept forms the philosophic basis for our ambulatory management of adolescents alcohol and drug abuse. The malleability of the adolescent and young adult is an advantage in helping him to adapt to a treatment program that is structured, consistent, and fair. The possibility of alternatives within that framework allows significant chances for success, thereby changing a negative lifestyle to one that meets the needs of the individual as required by his environment.

Adaptation, Psychological↗

PubMed1984

Autoimmunity in congenital rubella syndrome.

Two hundred one deaf adolescents with congenital rubella syndrome and 83 age-matched deaf control subjects were evaluated for the presence of organ-specific antibodies directed against thyroid microsomes, thyroglobulin, pancreatic islets, adrenal cortex, and gastric parietal cells. Positive thyroid microsomal or thyroglobulin antibodies were found in 23.3% (47/201) of the rubella group and in 12.0% (10/83) of control subjects. Nine of 46 (19.6%) in the rubella group and two of nine (22.2%) control subjects with thyroid autoimmunity had thyroid gland dysfunction as indicated by elevated serum TSH concentrations. Neither islet cell nor adrenal cortical antibodies were detected in any subject tested; parietal cell antibodies were detected in 5.5% (8/146) of those in the rubella group and 8.8% (6/68) of control subjects tested, but occurred most frequently in subjects with thyroid autoimmunity (6/36, 16.7% vs 8/178, 4.5%; P less than 0.05). It is recommended that all patients with congenital rubella syndrome be screened for thyroid autoimmunity and that those with positive antibody titers be evaluated for the presence of thyroid dysfunction.

Adolescent↗

PubMed1984

The effect of exogenous growth hormone on insulin requirements during closed loop insulin delivery in insulin-dependent diabetes mellitus.

The amount of insulin required to maintain similar blood glucose concentrations during an eight hour infusion of either saline or growth hormone (2 micrograms/kg/hr) was determined in five fed, insulin-dependent diabetic subjects during closed-loop insulin delivery. Elevations of serum growth hormone concentrations to levels previously observed in poorly controlled diabetic subjects were not accompanied by differences in the amount of insulin required to maintain blood glucose concentrations at levels comparable to those observed during the saline infusion. Specifically, no early insulin-like nor late anti-insulin effects of physiologic increases in serum growth hormone concentrations (10.27 +/- 0.23 mg/ml vs 5.69 +/- 1.5 mg/ml, P less than 0.05) on mean hourly blood glucose levels or mean hourly insulin requirements were observed. These studies suggest that serum growth hormone concentrations similar to those observed in poorly controlled diabetics do not affect the insulin requirements of well-insulinized diabetic subjects.

Adolescent↗

PubMed1984

Synthesis and biological activities of 4"-deoxy-4"-sulfonamido-oleandomycin derivatives.

Chemical modification of the macrolide antibiotic oleandomycin (C-1) is described. Reductive amination of 11-acetyl-4"-deoxy-4"-oxo-oleandomycin (C-6) with ammonium acetate provides amino-oleandomycin derivative C-7 in which the 4"-amine is oriented in the axial configuration. The structure-activity relationship of a series of 4"-sulfonamide analogs prepared from amino-oleandomycin derivative C-7 is discussed. Noteworthy is the significant in vitro potency enhancement of the para-chlorobenzenesulfonamide analog C-12 over that of the parent oleandomycin. The absolute configuration of the 4"-amino-oleandomycin derivative C-7 was established through X-ray analysis of the para-iodobenzenesulfonamide analog C-14.

Animals↗

PubMed1983

Naloxone attenuates recovery from insulin-induced hypoglycemia in normal man.

The effect of the opioid antagonist, naloxone, on recovery of serum glucose concentrations from insulin-induced (0.1 U/kg) hypoglycemia was determined in five normal adult men. Each subject was studied on 2 separate days, at least 2 weeks apart, during an infusion of either normal saline (6.5 ml/h) or naloxone (0.8 mg/h). The order of the infusions was randomized and double blinded. Although glucose recovery was complete by 120 min after insulin administration during each study, the fractional rate of glucose recovery as determined by analysis of covariance was significantly slower during the naloxone infusions (P = 0.008). Plasma glucagon, serum cortisol, and serum GH concentrations were not different during glucose recovery on either study day. These studies suggest that endogenous opioids contribute to glucose recovery from insulin-induced hypoglycemia and therefore may be important to glucose homeostasis in normal man.

Blood Glucose↗