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Biomedical subjects

R T Curnow

Publications and source records attributed to R T Curnow.

At least 19 recordsLinked to original sources
PubMed2001

A phase II study of the bispecific antibody MDX-H210 (anti-HER2 x CD64) with GM-CSF in HER2+ advanced prostate cancer.

The proto-oncogene HER2 presents a novel therapeutic target. We report results in 25 patients with HER2+ advanced prostate cancer treated with the bispecific antibody MDX-H210 15 microg m(-2)by intravenous infusion plus GM-CSF 5 microg kg(-1)day(-1)by subcutaneous injection for 4 days repeated weekly for 6 weeks. Patients with stable disease or better received further cycles of treatment until disease progression or study withdrawal. 1 patient received no treatment and 4 received less than 1 cycle and are included in the toxicity analysis only. Median duration of follow up was 105+ (range 21-188) days. Toxicity was generally NCI-CTG 0-2. There were 2 grade 4 adverse events (heart failure and dyspnoea) and 1 grade 3 event (allergic reaction) resulting in discontinuation of the study medication. There were 9 further grade 3 events not resulting in trial withdrawal. There were no treatment-related deaths. 7/20 (35%) evaluable patients had a >50% PSA response of median duration 128 (range 71-184+) days. 7/12 (58%) patients with evaluable pain had improvements in pain scores. The PSA relative velocity on therapy decreased in 15/18 (83%) assessable patients compared to pre-study. GM-CSF and MDX-H210 is active in hormone refractory prostate carcinoma with acceptable toxicity; further studies are warranted.

Adenocarcinoma↗
PubMed2001

Pharmacokinetic-pharmacodynamic relationships of the bispecific antibody MDX-H210 when administered in combination with interferon gamma: a multiple-dose phase-I study in patients with advanced cancer which overexpresses HER-2/neu.

INTRODUCTION: MDX-H210 is a Fab'xFab' bispecific antibody (BsAb) constructed chemically by crosslinking Fab' mAb 520C9 (anti-HER-2/neu) and Fab' mAbH22 (anti-CD64). STUDY DESIGN AND OBJECTIVES: This was a dose escalation study of intravenous MDX-H210 (1-70 mg/m(2)), preceded 24 h beforehand by subcutaneous IFNgamma (50 microg/m(2) to up-regulate FcgammaRI) administered three times a week for 3 weeks. We investigated the pharmacokinetic-pharmacodynamic relationships between MDX-H210 C(max) and AUC and (i) MDX-H210 binding to peripheral blood monocytes and neutrophils, (ii) the peak plasma G-CSF, IL-6, IL-8 and TNFalpha concentrations, and (iii) the observed clinical toxicity. RESULTS: 23 patients (19F:4M; median age 51.5; range 25-72 y) with advanced HER-2/neu positive cancers (19 breast, three prostate and one lung) were studied. Plasma MDX-H210 concentrations over time, circulating numbers of monocytes and neutrophils, percent saturation of monocyte and neutrophil FcgammaRI, and plasma concentrations over time of G-CSF, IL-6, IL-8 and TNFalpha were measured and clinical toxicity monitored. The E(max) pharmacodynamic model best fitted the relationship of MDX-H210 C(max) and the maximum percent saturation of both monocytes (E(max)=74.6; EC(50)=0.9 microg/ml) and neutrophils (E(max)=66.2; EC(50)=2.3 microg/ml) on the first day of treatment. On the last day of treatment, day 19, these parameters were E(max)=57.0% and EC(50)=0.46 microg/ml for monocytes and E(max)=61.9% and EC(50)=0.26 microg/ml for neutrophils. No positive relationship was defined between the log MDX-H210 C(max) and the log peak plasma IL-6, G-CSF, TNF or IL-8 concentrations on day 1. On day 19 these plasma cytokine concentrations were undetectable post MDX-H210 therapy. There was no consistent relationship between MDX-H210 C(max) and the observed clinical toxicities. CONCLUSIONS: These data suggest that MDX-H210 C(max) and AUC could be related by the E(max) model to maximum percent FcgammaRI saturation on circulating monocytes and neutrophils in the patients studied. After day 1, the post MDX-H210 therapy cytokine response attenuated over time, consistent with desensitization. We did not find a relationship between log MDX-H210 C(max) and peak plasma cytokine concentrations or clinical toxicities.

Adult↗
PubMed1989

Effect of a new synthetic hexapeptide to selectively stimulate growth hormone release in healthy human subjects.

Growth hormone-releasing peptide (GHRP, SK&F 110679) is a hexapeptide (His-DTrp-Ala-Trp-DPhe-LysNH2) that selectively stimulates the release of growth hormone (GH) but not other pituitary hormones in vitro and in vivo in a variety of animal species. GHRP was administered to 17 normal men at doses of from 0.05 to 2.5 micrograms/kg as a 30 min intravenous infusion. Eight of the men were infused with saline as a control. Serum GH increased consistently at doses of 0.25 microgram/kg and above during the infusion of the peptide, peaked at 45 min and then decreased to baseline values by 210 min. The mean peak serum GH concentrations (+/- SE) in response to GHRP infusion were 17.8 +/- 6.1 micrograms/L at a dose of 0.25 microgram/kg (n = 4, p = .03 vs saline), 38.3 +/- 9.2 micrograms/L at 0.5 microgram/kg (n = 4, p = .04 vs saline) and 63.0 +/- 5.4 micrograms/L at 1.0 microgram/kg (n = 4, p = .002 vs saline). Serum LH, FSH, TSH and ACTH were unaffected by GHRP administration. GHRP was safe and well-tolerated in all men. GHRP infusion resulted in a dramatic, selective and dose-dependent increase in serum GH concentrations.

Adrenocorticotropic Hormone↗
PubMed1987

Long term regulation of glycogen metabolizing enzymes by insulin in H4 hepatoma cells.

Insulin alone at concentrations of less than 1 to 5 uU/ml increased the enzyme activities of glycogen synthase, synthase phosphatase, phosphorylase, and phosphorylase phosphatase in hepatoma H4 cells in culture in the presence and absence of serum. Increase in total and active forms of glycogen synthase and phosphorylase were observed. Cycloheximide blocked the action of insulin on glycogen synthase, glycogen synthase phosphatase and phosphorylase phosphatase. The enzymes with the exception of glycogen synthase phosphatase were expressed with greater hormonal sensitivity in the absence as compared to the presence of serum in terms of hormone concentration required and or time of onset. These results demonstrate that these glycogen metabolizing enzymes are under long term control by insulin, with glycogen synthase being the most sensitive of the enzymes studied to the action of the hormone.

Animals↗
PubMed1987

Dichloroacetate inhibits glycolysis and augments insulin-stimulated glycogen synthesis in rat muscle.

The decrease in plasma lactate during dichloroacetate (DCA) treatment is attributed to stimulation of lactate oxidation. To determine whether DCA also inhibits lactate production, we measured glucose metabolism in muscles of fed and fasted rats incubated with DCA and insulin. DCA increased glucose-6-phosphate, an allosteric modifier of glycogen synthase, approximately 50% and increased muscle glycogen synthesis and glycogen content greater than 25%. Lactate release fell; inhibition of glycolysis accounted for greater than 80% of the decrease. This was associated with a decrease in intracellular AMP, but no change in citrate or ATP. When lactate oxidation was increased by raising extracellular lactate, glycolysis decreased (r = - 0.91), suggesting that lactate oxidation regulates glycolysis. When muscle lactate production was greatly stimulated by thermal injury, DCA increased glycogen synthesis, normalized glycogen content, and inhibited glycolysis, thereby reducing lactate release. The major effect of DCA on lactate metabolism in muscle is to inhibit glycolysis.

Acetates↗
PubMed1987

Hexose phosphates as regulators of hepatic glycogen synthase phosphatases.

The activity of glycogen synthase phosphatase from smooth endoplasmic reticulum of liver was stimulated markedly by galactose-6- and fructose-6-phosphates and to a lesser extent by glucose-1- and 2-deoxyglucose-6-phosphates. The synthase phosphatase of liver cytosol showed strong activation by glucose-1-, glucose-6- and fructose-6-phosphates and smaller activation by galactose-6- and 2-deoxyglucose-6-phosphates. Kinetic analysis showed that the activators did not affect the Km for glycogen synthase D, for either enzyme. The mechanism of activation of the two phosphatases by hexose phosphates appears to be by combination of the activator at a specific activator site on the enzyme rather than by substrate modulation. It is concluded that certain hexose phosphates, particularly fructose-6-phosphate and glucose-1-phosphate, can function as regulators of hepatic synthase phosphatase activity, and that this may explain the ability of elevated blood glucose to increase both glycogen synthase I activity and glycogen synthesis in the liver.

Animals↗
PubMed1986

Polyuria among patients with psychosis.

Using the criterion of early morning urinary specific gravity (SPGR) of 1.008 or less to define the presence of polyuria, we identified 26 of 72 male (36 percent) and 14 of 31 female (45 percent) institutionalized chronically psychotic patients as polyuric during a comprehensive survey of one of the chronic care units at a State mental hospital. Factors including diagnosis, sex, age, weight, and serum sodium did not distinguish the polyuric from the nonpolyuric patients. For men, administration of lithium was associated with polyuria. Urinary creatinine concentration (UCR) correlated well with SPGR, and UCR may provide an alternate index to separate polyuric from nonpolyuric patients. The clinical implications of our findings are discussed.

Adult↗
PubMed1986

Prevention of diabetes in BB rats. I. Evidence suggesting a requirement for mature T cells in bone marrow inoculum of neonatally injected rats.

Injection of major histocompatibility complex (MHC)-compatible bone marrow cells from normal animals into neonatal BB rats resulted in a striking decrease in incidence of diabetes and restoration of concanavalin A (ConA) and mixed lymphocyte responses. However, injection of bone marrow cells pretreated with anti-rat thymocyte antiserum plus complement to remove mature T cells had no effect on incidence of disease, suggesting that mature T cells in the bone marrow inoculum were responsible for prevention of diabetes. Because the decreased incidence of diabetes in rats injected with untreated bone marrow appeared to be unrelated to the extent of lymphopenia in these animals, the involvement of T cells in the onset of diabetes must reflect a defect in the normal function of these cells rather than their absolute number. Approximately 50% of the W3/13+ cells in the spleens of BB rats lacked the OX-8 and W3/25 T cell subset markers. The identity of this W3/13+, OX-8-, W3/25- blank subset remains to be established. Our results, interpreted in light of studies from the other laboratories, suggest the existence of multiple abnormalities in the BB rat, including the presence of T cells as effector or helper cells that augment onset of disease and the absence of a regulatory T cell circuit that could prevent the disease.

Animals↗
PubMed1985

Multiple forms of synthase D phosphatase and phosphorylase a phosphatase in liver and regulatory effects of metabolites on their activities.

The smooth endoplasmic reticulum (ER) and cytosol fractions of liver homogenates exhibit phosphoprotein phosphatase activity towards glycogen synthase D and phosphorylase a. The following observations suggest that liver contains multiple forms of these phosphatases. Synthase phosphatase activity in either fraction was more readily inactivated by heating than phosphorylase phosphatase activity. Both synthase phosphatase and phosphorylase phosphatase activities in smooth ER were non-competitively inhibited by Mg2+, but were activated by this ion in the cytosol. Synthase phosphatase activities in cytosol and smooth ER were stimulated by a number of sugar phosphates, particularly glucose-1-phosphate, galactose-6-phosphate and fructose-6-phosphate. Erythrose-4-phosphate stimulated synthase phosphatase activity in the cytosol, but inhibited the microsomal enzyme. Phosphorylase phosphatase activities in either fraction were inhibited by most sugar phosphates. Adenosine mono-, di- and tri-phosphates inhibited phosphatase activities in both fractions. Low concentrations of AMP and ADP inhibited phosphorylase phosphatase activities to a greater extent than synthase phosphatase activities. Chromatography of the smooth ER fraction on DEAE-cellulose resulted in the separation of synthase phosphatase from phosphorylase phosphatase, as soluble proteins. The elution profile for the microsomal phosphatase was different from that for the cytosol enzymes. It is concluded that: both synthase phosphatase and phosphorylase phosphatase in liver have at least two isoenzyme forms; synthase phosphatase and phosphorylase phosphatase are separate enzymes; the different behaviour of microsomal and cytosol phosphatases towards divalent cations and sugar phosphates provides a potential mechanism for the differential regulation of these activities in liver.

Adenine Nucleotides↗
PubMed1985

Regulation of hepatic glycogen metabolism: effects of diabetes, insulin infusion, and pancreatic islet transplantation.

Insulin-deficient diabetes mellitus results in diminished capacity of the liver to accumulate glycogen. One site of metabolic lesion in the diabetic liver is at the level of the synthase-activating enzyme, synthase phosphatase. This activity is progressively diminished with increasing severity of chemically induced diabetes in both soluble and smooth endoplasmic reticulum (SER) associated subfractions. Insulin administration via an implanted miniosmotic pump or via intrahepatic islet transplantation increased synthase phosphatase activity, particularly in SER. Hepatic glycogen synthesis and accumulation was enhanced as well. The data support a role for insulin in maintenance of the ability of the liver to synthesize and accumulate glycogen mediated either directly or indirectly through SER-synthase phosphatase activity.

Animals↗
PubMed1985

Patterns of urinary excretion among patients with self-induced water intoxication and psychosis.

Parameters of water metabolism were measured serially in nine patients with the syndrome of self-induced water intoxication and psychosis (SIWIP). Clinical and laboratory findings indicated that SIWIP patients are type A of the syndrome of inappropriate antidiuresis. Estimated 24-hour urinary excretion of creatinine and early morning urinary creatinine concentration measurements were used to calculate 24-hour urine volumes. Polyuria was considered present for male patients when excretion was estimated to be greater than 2,600 ml of urine/24 hours or early morning urinary specific gravity was less than or equal to 1.003. Male patients with a specific gravity of less than or equal to 1.003 predictably excreted 28,000 ml of urine/day. Severe hyposthenuria may be a biological marker for a population at risk to develop complications of SIWIP, including seizures, coma, and death.

Adult↗
PubMed1984

Effects of dexamethasone administration on hepatic glycogen synthesis and accumulation in adrenalectomized fasted rats.

Adrenalectomized 24-h fasted rats lack the ability to synthesize and accumulate hepatic glycogen. In addition, the ability of liver glycogen synthase to respond to acute glucose administration is muted. The defect has been localized to the level of smooth endoplasmic reticulum-associated synthase phosphatase activity which is greatly reduced in adrenalectomized fasted rat liver. In vivo exposure to dexamethasone increases hepatic glucose output and hepatic glycogen synthesis and accumulation by 2-6 h after administration. Smooth endoplasmic reticulum synthase phosphatase activity is increased, and activation of glycogen synthase is restored. Ambient insulin concentrations are increased by steroid administration and appear to have a role in restoration of the ability to activate glycogen synthase, and consequently to restore the ability to synthesize and accumulate hepatic glycogen.

Adrenalectomy↗
PubMed1983

The role of insulin and glucocorticoids in the regulation of hepatic glycogen metabolism: effect of fasting, refeeding, and adrenalectomy.

The roles of insulin, adrenal corticol hormones, and nutritional factors in the regulation of hepatic glycogen metabolism were investigated by means of fasting and refeeding normal and adrenalectomized (ADX) rats. More specifically, the hypothesis in question in this study is that certain hepatic phosphoprotein phosphatases are targets of insulin action in liver. In anesthetized rats, the hepatic glycogen concentration and the activities of hepatic glycogen synthase, glycogen synthase phosphatase, glycogen phosphorylase, and phosphorylase phosphatase were correlated with peripheral plasma glucose and immunoreactive insulin levels. Hepatic phosphatase activities were measured in (soluble) the high speed supernatant and smooth endoplasmic reticulum (SER). Fasting resulted in expected diminutions in circulating glucose and insulin levels and loss of hepatic glycogen. These changes were greater in ADX rats. The percentage of hepatic glycogen synthase in the active or I form increased with fasting in normal rats, but did not change in ADX rats. Hepatic synthase phosphatase activities were decreased in SER by fasting in both normal and ADX rats, but to a much greater extent in the latter; soluble synthase phosphatase was much less affected by fasting. The percentage of phosphorylase in the active or a form was significantly decreased in normal, but not ADX, rats. Phosphorylase phosphatase activities were not significantly changed by fasting in any of the subcellular fractions in normal liver, but were increased in the hepatic SER of ADX rats. Refeeding fasted rats for 2 and 6 h resulted in increased hepatic glycogen, activation of glycogen synthase, and increased circulating levels of both insulin and glucose. Refeeding also caused increases in SER-associated synthase phosphatase activity in ADX animals. SER phosphorylase phosphatase activities were significantly increased by refeeding in normal rats, but were decreased in ADX rats. Regression analysis of the data suggested statistically significant positive correlations between insulin levels and SER synthase phosphatase activity in ADX animals, on the one hand, and SER synthase phosphatase and the percentage of synthase in the I form, on the other. No statistically significant correlation between insulin levels and phosphorylase phosphatase activities could be demonstrated. These results are compatible with the hypothesis that glycogen synthase phosphatase activity in liver, especially that associated with SER, is subject to physiological regulation by circulating levels of insulin. In contrast, phosphorylase phosphatase activity seems to be much less influenced by changes in the circulating insulin level. The results are compatible with the proposition that SER-associated phosphoprotein phosphatases are physiologically relevant in the regulation of hepatic glycogen metabolism.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenalectomy↗
PubMed1983

Impaired glycogenic substrate activation of glycogen synthase is associated with depressed synthase phosphatase activity in diabetic rat liver.

Glucose and gluconeogenic substrates promote the activation of hepatic glycogen synthase in vivo and in vitro; activation occurs as inactive glycogen synthase D is dephosphorylated to active glycogen synthase I by glycogen synthase phosphatase. Impairments of glycogen accumulation and glycogen synthase activation in diabetes have been attributed to decreased glycogen synthase phosphatase activity. To determine the role of glycogen synthase phosphatases associated with cytosol and smooth endoplasmic reticulum in the impairment of glycogen synthase activation, livers of normal and streptozotocin-diabetic fed rats were sampled by freeze-clamping before and after perfusion with a mixture of 25 mM glucose, 10 mM glutamine, 4 mM lactate, and 1 mM pyruvate. Perfusion induced activation of glycogen synthase in normal rats, but activation was reduced in the diabetic rats in proportion to the severity of insulin deficiency (r = 0.72, P less than 0.0001). There was also a close correlation between insulin levels and glycogen synthase phosphatase activities of both cytosol (r = 0.76, P less than 0.0001) and SER (r = 0.71, P less than 0.0001) fractions. In contrast, glycogen phosphorylase phosphatase activity and inactivation of glycogen phosphorylase during perfusion were normal in the diabetic livers. This is the first demonstration that glycogen synthase phosphatase activities in both soluble and SER fractions of liver cells are closely related to circulating insulin levels, and that the impairment of glycogen synthesis in diabetes may result from deficient glycogen synthase phosphatase activity in both cell compartments.

Animals↗
PubMed1983

Plasmapheresis in thyroxine overdose: a case report.

Thyrotoxicosis from an overdose of medicinal thyroid is a condition which may be associated with a significant delay in onset of toxicity. We report a case treated with plasmapheresis, and conclude that the amount of thyroid hormone removed was insignificant compared to the total ingestion. We also note that the plasma half-life of thyroxine is apparently reduced in an acute massive ingestion.

Adult↗
PubMed1980

Impaired glycogen synthase activating system in human diabetic polymorphonuclear leukocytes.

The effects of diabetes mellitus on glycogen synthase and its activating system (synthase phosphatase) were studied using human polymorphonuclear leukocytes (PMN). PMN were obtained from control subjects and diabetic patients by a gradient sedimentation technique. Enzyme activities of endogenous synthase-l and total synthase were not statistically different in diabetic and control cells. For measurement of endogenous synthase phosphatase, cells were sonicated in 50 mM Tris buffer (pH 7.5) and incubated at 30 degrees C. Conversion of synthase-D to -l and the maximum percent synthase-l attained were decreased in homogenates of diabetic cells. There was no correlation between the plasma glucose concentration and the rate of conversion of synthase-D to -l. Synthase phosphatase activities were also measured using a purified synthase-D substrate. Under these experimental conditions, glycogen synthase phosphatase activities did not differ in control and diabetic cells. These results are consistent with a diabetes-induced defect in conversion of endogenous synthase-D to -l at the level of the synthase enzyme rather than at that of the activating phosphatase.

Adolescent↗