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Biomedical subjects

M A Root

Publications and source records attributed to M A Root.

At least 19 recordsLinked to original sources
PubMed1986

Proinsulin radioimmunoassay in the evaluation of insulinomas and familial hyperproinsulinemia.

Two new radioimmunoassays for human proinsulin (hPI) have been developed and used to study patients with islet cell tumors and familial hyperproinsulinemia. Both antisera were adsorbed against human C-peptide conjugated to Sepharose, following which cross-reactivity to insulin and C-peptide was less than 0.001%. Antiserum 18D recognized the junction between the insulin B-chain and C-peptide and provided fivefold greater sensitivity than our previously reported hPI assay. Antiserum 11E recognized a determinant which includes or is adjacent to the A-chain-C-peptide junction or which is specified by the tertiary structure. In all 20 patients studied with surgically confirmed islet cell tumors, fasting plasma proinsulinlike material (PLM) was abnormal (greater than 3 SD from the mean measured in either lean or obese subjects) in both assays. This provided better discrimination than has been reported for PLM measured by gel filtration (abnormal in 13 of 14 of the present samples) with a considerably less laborious procedure. Samples from two families in which a mutant proinsulin is present in the circulation have immunoreactivity in the two assays consistent with previous identification of the molecule as an A-chain-C-peptide-linked intermediate of proinsulin conversion. The immunoreactivity of a sample from another family in which large amounts of proinsulin circulate are consistent with an intact molecule being the predominant form. This assay will be useful for confirming the diagnosis of insulin-secreting tumor in patients suspected of recurrent fasting hypoglycemia and in physiologic studies of proinsulin secretion.

Adenoma, Islet Cell↗
PubMed1985

A radioimmunoassay for circulating human proinsulin.

A radioimmunoassay for human proinsulin (hPl) has been developed using biosynthetic hPl prepared by recombinant DNA technology as immunogen, standard, and tracer. The antiserum was raised in a guinea pig and then adsorbed against insulin and C-peptide conjugated to Sepharose to improve its specificity. After adsorption of the antiserum, the cross-reactivities to insulin and C-peptide were each less than 0.2%. Competition studies using in vitro enzymatically split forms of proinsulin demonstrated that the major antigenic determinant recognized was the junctional region between the B-chain of insulin and the C-peptide. The range of the assay extended from 10 to 150 fmol/tube, with a 50% displacement of 45-55 fmol/tube. This sensitivity proved suitable for measurements of serum hPl concentrations during infusion of biosynthetic hPl into normal subjects and type I diabetic subjects. Eighty-five of 89 serum samples from the normal subjects and each of 20 samples from diabetic subjects diluted in parallel with the hPl standard. Since the direct assay sensitivity was not sufficient for measurement of endogenous hPl levels, a simple procedure for quantitative extraction of proinsulin-like material (PLM) from up to 40 ml of plasma on insulin antibody-Sepharose columns was developed. Logit-log slopes were calculated for dilutions of extracts of samples collected in the fasting state and 60 min after 75 g or oral glucose from eight healthy subjects. The slopes of 15 of the 16 samples did not differ significantly from the slope of the hPl standard.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Human proinsulin standards.

Two new batches of pancreatic human proinsulin have been compared with biosynthetic human proinsulin. Standards of these three proinsulin preparations were made on the basis of quantitative amino-acid analyses and compared in two proinsulin radioimmunoassays with a proinsulin standard prepared 14 years ago. The curves of the new standards were superimposable. However, they differed considerably from the curve of the old standard which proved to be only one-third of the strength of the new standards, thereby leading to a threefold over-estimation of proinsulin concentrations when the old standard is used. We conclude that the new standards should replace previously used standards.

Amino Acids↗
PubMed1983

Dopamine agonist-induced hyperglycemia in rats: structure-activity relationships and mechanisms of action.

The concentration of blood glucose was measured in rats after administration of a number of drugs characterized as dopamine agonists. Compounds that cause release of dopamine, or agents that block the reuptake of dopamine, did not elevate blood glucose. Some direct dopamine receptor stimulants (lergotrile, bromocriptine, apomorphine) caused hyperglycemia, but other agonists (e.g. pergolide) did not. Further experiments with lergotrile, the most active hyperglycemic dopamine agonist, revealed that the blood glucose increase was accompanied by a marked elevation in liver glycogen, indicating a gluconeogenic effect of the compound. This hypothesis was supported by using inhibitors of gluconeogenesis (L-tryptophan or 3-mercaptopicolinic acid) to block lergotrile's hyperglycemic action. Structure-activity relationships among close analogues of lergotrile suggest that the cyano moiety in the lergotrile molecule may be of importance in the hyperglycemic action of lergotrile. These results indicate that central dopamine stimulation per se does not cause hyperglycemia in rats.

Animals↗
PubMed1983

Action of somatostatin on stomach, pancreas, gastric mucosal blood flow, and hormones.

In dogs gastric secretion induced by tetragastrin and pancreatic secretion induced by secretin and/or cholecystokinin were inhibited by somatostatin at doses of 0.06-1 microgram X kg-1 X h-1 and 0.06-1 microgram X kg-1 X 0.5 h-1, respectively. Inhibition was a linear function of the logarithm of dose. Basal and 2-deoxy-D-glucose-induced gastric acid secretion was also significantly inhibited by low doses of somatostatin. Results in this study differ from those reported previously by clarifying the action of somatostatin as follows. 1) The inhibitory effect of somatostatin on pancreatic protein secretion was significantly greater than that on water and bicarbonate production. Somatostatin was more effective on cholecystokinin- than secretin-induced pancreatic secretion. 2) Although gastric mucosal blood flow (MBF) was affected by somatostatin, the reduction of MBF was not the primary mechanism responsible for its inhibitory action. 3) The low doses of somatostatin used in this study significantly inhibited gastric and pancreatic secretion without affecting the basal plasma concentrations of insulin, glucagon, growth hormone, gastrin, or secretin in the dogs, suggesting that the inhibitory action was not mediated by changes or reduction in plasma concentration of these hormones.

Animals↗
PubMed1980

Hepatic insensitivity to glucagon in ob/ob mice.

Hepatic cAMP concentration of normal mice increased 40 fold within 10 min after a single dose of glucagon (2 mg/kg, IP). In contrast, hepatic cAMP increased only 2 fold in ob/ob mice. Glucagon induced hepatic L-phenylalanine:pyruvate aminotransferase and stimulated glycogenolysis in normal mice but failed to elicit these cAMP-mediated responses in ob/ob mice. The insensitivity of ob/ob mice to glucagon was not ameliorated by fasting or by theophylline.

Animals↗
PubMed1979

Clinical pharmacokinetics of vindesine.

The pharmacokinetics of vindesine were investigated in five patients with advanced cancer who were described by a triphasic serum decay curve compatible with a three-compartment open mammillary model. Serum half-lives were 2 min, 50 min, and 24 h for the fast, middle, and slow phases, respectively. The volume of the central compartment approximated the plasma volume in all patients studied. Distribution occurred quickly into a superficial tissue compartment in fairly rapid equilibrium with the plasma compartment, and also into a deep tissue compartment with slower redistribution to the central compartment. The large apparent volume of distribution and long elimination half-live suggest extensive tissue sequestration or delayed excretion of the drug in man. The slightly increased serum half-life of vindesine compared with published results for vinblastine may account for the greater degree and longer duration of marrow suppression seen clinically with vindesine.

Dose-Response Relationship, Drug↗
PubMed1977

Pharmacokinetics of vindesine and vincristine in humans.

Vindesine, a new Phase 1 Vinca alkaloid congener, exhibited serum pharmacokinetic behavior in humans compatible with a three-compartment, open mammilary model. The kinetic parameters included: t1/2 alpha=3.24+/-1.14 min, t1/2beta=99.0+/-44.5 min, t1/2gamma=1213+/-493 min, Vc (Valpha)=4.81+/-2.12 liters, Vbeta=58.2+/-50.5 liters, Vgamma=598+/-294 liters. Vincristine, studied only for the first 4 hr, behaved like a two-compartment system, with values of t1/2 alpha=3.37+/-0.72 min, t1/2beta=155+/-18 min, Valpha=4.53+/-0.49 liters, and Vbeta=57.3+/-21.1 liters. Urine excretion data demonstrated that most drug elimination occurred within the first 24 hr and amounted to 13.2+/-5.9% for vindesine and 9.5+/-5.1% for vincristine.

Humans↗
PubMed1976

The immunogenicity of insulin preparations.

Patients who had never received insulin were administered porcine or bovine Lente insulins prepared from either conventional USP-grade insulin, "single-peak" insulin (SPI), or "single-component" insulin (SCI) in an attempt to determine if insulin immunogenecity was related to the purity of various insulin preparations. Serum insulin antibody titers were monitored by a sensitive I125-insulin binding procedure. All six groups of patients had some degree of antibody formation after six months of continuous insulin administration. Based upon the percent of I125-insulin bound by the serum, the least immunogenic insulin preparation was the porcine SCI. The most immunogenic insulins were the bovine preparations, all three of which gave comparable antibody responses. The patients who received porcine USP insulin and porcine SPI had similar antibody titers, both of which were significantly higher than the titers from the patients on porcine SCI, but significantly lower than the antibody titers from the patients treated with any of the bovine preparations. The immunogenicity of bovine SCI was significantly reduced by administering multiple daily doses of the neutral regular form instead of one or two daily injections of the Lente form, Although these purer insulin preparations (SPI and SCI) are still associated with various degrees of immunogenecity, they are significant improvements for the treatment of insulin lipoatrophy and insulin allergy.

Adolescent↗