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Biomedical subjects

R Spector

Publications and source records attributed to R Spector.

At least 91 records · Page 5Linked to original sources
PubMed1983

Purine and pyrimidine base and nucleoside concentrations in human cerebrospinal fluid and plasma.

Purine and pyrimidine base and nucleoside levels were determined in adult human lumbar (CSF) and plasma by reversed-phase high performance liquid chromatography (HPLC). Guanine, thymine, cytosine and uracil were not detectable (less than 0.1 microM) in human CSF or plasma. Adenine was detectable in plasma (0.3 microM) but was not found in CSF (less than 0.2 microM). Hypoxanthine and xanthine levels in CSF were each approximately 2.5 microM. Plasma levels of hypoxanthine and xanthine were considerably lower (0.4-0.6 microM). Purine and pyrimidine ribonucleosides in human CSF were less than or equal to 0.2 microM with the exception of uridine which was present at concentrations of 2-3 microM. Although low concentrations of thymidine and deoxyuridine (0.2 microM) were present in human plasma, purine and pyrimidine deoxyribonucleosides were less than 0.1 microM in human lumbar CSF.

Chromatography, High Pressure Liquid↗
PubMed1983

Identification and partial characterization of rabbit brain deoxyuridine 5'-triphosphatase.

Adult rabbit brain contains the enzymatic machinery to convert deoxyuridine to deoxyuridine triphosphate (dUTP). Although dUTP as dUMP can be readily incorporated into DNA in place of thymidine monophosphate, we detected no (3H)dUMP in newly synthesized (3H)DNA in adult rabbit brain after the intraventricular injection of (3H)deoxyuridine. Only (3H)thymidine was detected. The probable explanation for the lack of incorporation of uracil into adult rabbit brain DNA is the presence of a specific, high affinity dUTPase which converts dUTP to dUMP and PP. After homogenization and ammonium sulfate fractionation of adult rabbit brain (35 to 75% saturation), a high affinity, specific dUTPase was detected in the dialyzed enzyme preparation. The Km and Vmax of the dUTPase were 0.2 microM and 36 pmol/mg protein/min, respectively. No high affinity dUTPase activity was detectable in liver. In brain, another enzyme hydrolyzed dUTP and dTTP (NTPase( to their respective diphosphates. NTPase, unlike dUTPase, was not sensitive to heating at 65 degrees C for five minutes. Thus, brain, like other tissues, contains a high affinity, specific dUTPase presumably to "sanitize" the cells of dUTP and, thus, protect the integrity of newly synthesized DNA.

Animals↗
PubMed1983

Use of hemoperfusion for treatment of theophylline intoxication.

We review our experience in the management of patients with plasma theophylline concentrations of 30 micrograms/ml or greater. Over a two-and-a-half-year period, 22 patients (Group 1) had plasma theophylline concentrations of 37 +/- 1 micrograms/ml (mean +/- SE) and experienced no severe toxicity (i.e., ventricular extrasystoles or tachycardia, seizures, cardiovascular collapse, or death). Six patients (Group 2) took overdoses of theophylline (92 +/- 12 micrograms/ml) and one died. Eight patients (Group 3) were iatrogenically intoxicated (48 +/- 6 micrograms/ml) and three died. Six patients from Groups 2 and 3 underwent hemoperfusion and did well, except for one patient, in whom seizures developed before hemoperfusion was initiated. We conclude from this experience that charcoal hemoperfusion is a useful procedure for the treatment of theophylline intoxication because of: (1) the serious morbidity and mortality of theophylline intoxication, (2) the prevention of complications with hemoperfusion, and (3) the relative safety of the procedure. We provide tentative guidelines for the initiation of hemoperfusion for the treatment of theophylline intoxication.

Adolescent↗
PubMed1983

Effects of size and frequency of oral doses of charcoal on theophylline clearance.

The effect of size and frequency of oral doses of activated charcoal on theophylline kinetics was studied. Six fasting, healthy men received intravenous infusions of aminophylline (6 mg/kg) over 1 hr, followed by either no activated charcoal as a control, 5 gm activated charcoal every 2 hr for 6 doses, 10 gm every 2 hr for 6 doses, 10 gm every hr for 12 doses, 20 gm every 2 hr for 6 doses, or 40 gm every 4 hr for 3 doses. Five grams every 2 hr decreased serum theophylline t 1/2 from the control of 9.1 +/- 0.7 to 5.6 +/- 0.4 (SE) hr and decreased the AUC from the control of 123 +/- 11 to 79 +/- 6 mg X hr/l. The regimen of 20 gm every 2 hr further decreased theophylline t 1/2 to 4.3 +/- 0.4 hr and decreased AUC to 62 +/- 6 mg X hr/l. When a 120-gm dose of activated charcoal was given as a regimen of 40 gm every 4 hr or as a regimen of 10 gm every hr, there were small differences in serum theophylline t 1/2 (5.4 +/- 0.3 and 4.3 +/- 0.2 hr) and in AUC (73 +/- 5 and 60 +/- 4 mg X hr/l). Repeated small doses of oral activated charcoal enhanced the total body clearance of theophylline, and larger doses induced a relatively small further increase. There was little difference between the effects of the same total dose every 4 hr vs every hour.

Adult↗
PubMed1983

Enhancement of theophylline clearance by oral activated charcoal.

A randomized crossover trial of the effect of oral activated charcoal on the kinetics of intravenous theophylline was carried out in six normal male subjects. After intravenous aminophylline (6 mg/kg), subjects received water or water with activated charcoal (140 gm) in divided doses over 12 hr. Serum theophylline concentrations were measured from 0 to 24 hr after the aminophylline infusion. Treatment with activated charcoal decreased the serum t 1/2 from 6.4 +/- 1.2 to 3.3 +/- 0.4 (SEM) hr and the serum AUC from 78 +/- 14 to 42 +/- 4 mg . hr/l. Percent decrease in AUC after treatment with charcoal correlated positively with the endogenous theophylline serum t 1/2 (r = 0.94). These results suggest that oral activated charcoal (1) enhanced the total body clearance of theophylline and (2) may be efficacious in the treatment of theophylline poisoning, especially in patients with prolonged serum t 1/2s of theophylline.

Adult↗
PubMed1983

Identification, development, and regional distribution of ribonucleotide reductase in adult rat brain.

The development and regional distribution of ribonucleotide reductase (EC 1.17.4.1) were determined in rat brain. Ribonucleotide reductase was partially purified by ammonium sulfate fractionation (20-40% saturation). Enzyme activity was measured by a specific radiochemical assay. This method involved the reduction of [14C]cytidine diphosphate (CDP) to [14C]deoxycytidine diphosphate with subsequent hydrolysis and separation of the product ([14C]deoxycytidine) from substrate ([14C]cytidine) by Dowex-1-borate ion-exchange chromatography. The specific activity of ribonucleotide reductase in whole brain of newborn rats was 3.78 +/- 0.55 units (pmol/h)/mg protein (SEM; n = 6) and declined to 0.17 +/- 0.01 units/mg protein (n = 7) at 10-12 weeks of age, with a further decline to 0.11 +/- 0.01 units/mg protein (n = 3) at 1 year. Ribonucleotide reductase activity in rat liver decreased from 4.58 +/- 0.62 units/mg protein (n = 3) in newborn animals to 0.06 +/- 0.01 units/mg protein (n = 7) at 10-12 weeks and was present at trace levels at 6 months of age. The decline in specific activity with age was not due to a change in the Km for CDP. The Km for CDP in brain of newborn and adult rats was 80-90 microM. In 10- to 12-week-old rats, the specific activity of ribonucleotide reductase was similar in the various regions of the brain tested except for the brainstem, which had 50% lower specific activity than the whole brain. These results indicate that ribonucleotide reductase activity is present and widely distributed in adult rat brain.

Aging↗
PubMed1983

Deoxycytidine transport and metabolism in the central nervous system.

The mechanisms by which deoxycytidine enters and leaves brain, choroid plexus, and CSF were investigated by injecting [3H]deoxycytidine intraarterially, intravenously, and intraventricularly. After intracarotid injection of deoxycytidine (1.0 microM) into rats, deoxycytidine did not pass through the blood-brain barrier at a faster rate than sucrose. [3H]Deoxycytidine, either alone or together with unlabeled deoxycytidine, was infused at a constant rate into conscious adult rabbits. At 130 min, [3H]deoxycytidine readily entered CSF, choroid plexus, and brain. In brain, approx. 60% of the nonvolatile radioactivity was attributable to [3H]deoxycytidine phosphates. The addition of 0.22 mmol/kg unlabeled deoxycytidine to the infusion syringe decreased the phosphorylation of [3H]deoxycytidine in brain by approx. 50%; the addition of 2.2 mmol/kg of unlabeled deoxycytidine to the infusion syringe decreased the relative entry of [3H]deoxycytidine into CSF and brain by approx. 50 and 75%, respectively. Two hours after the intraventricular injection of [3H]deoxycytidine, [3H]deoxycytidine was rapidly cleared from CSF, in part, to brain, where approx. 65% of the [3H]deoxycytidine was converted to [3H]deoxycytidine phosphates. The intraventricular injection of unlabeled deoxycytidine with the [3H]deoxycytidine decreased the phosphorylation of [3H]deoxycytidine in the brain significantly and also decreased the clearance of [3H]deoxycytidine from the CSF. These results were interpreted as showing that the entry of deoxycytidine from blood into CSF occurs by a saturable transport system within the choroid plexus. Once within the CSF, the deoxycytidine can enter brain, undergo phosphorylation to deoxycytidine phosphates, and subsequently be incorporated into DNA.

Animals↗
PubMed1983

Development and regional distribution of deoxyuridine 5'-triphosphatase in rabbit brain.

The development and regional distribution of deoxyuridine 5'-triphosphatase (dUTPase) in rabbit brain was studied. After partial purification of the dUTPase activity, newborn brain and liver activities fell from Vmax values of 1.0 and 6.9 nmol/mg protein/min, respectively, to adult levels of 0.1 (brain) and less than 0.01 (liver). The dUTPase activity was evenly distributed throughout the entire adult rabbit brain, and there was no difference in the Km of dUTPase in newborn and adult brain (0.1 microM). The low level of dUTPase in adult brain and the lack of activity in adult liver were not due to inhibitors or phenylmethylsulfonyl fluoride-sensitive proteases. dUTPase in brain, as in other tissues, probably inhibits the misincorporation of uracil into DNA.

Aging↗
PubMed1983

Deoxycytidine transport and metabolism in choroid plexus.

In vitro, the transport into and release of [3H]deoxycytidine from the isolated choroid plexus, the anatomical locus of the blood-cerebrospinal fluid barrier, were studied separately. By use of the ability of nitrobenzylthioinosine (NBTI) to inhibit deoxycytidine efflux from choroid plexus, the transport of 1 microM [3H]deoxycytidine into choroid plexus at 37 degrees C was measured. Deoxycytidine was transported into choroid plexus against a concentration gradient by a saturable process that depended on intracellular energy production, but not intracellular binding or metabolism. The Michaelis-Menten constant (KT) for the active transport of deoxycytidine into choroid plexus was 15 microM. The active transport system for deoxycytidine was inhibited by naturally occurring nucleosides and deoxynucleosides, but not by 1 mM probenecid and 2-deoxyribose or 100 microM cytosine and cytosine arabinoside. With less than 1 microM [3H]deoxycytidine in the medium, the choroid plexus accumulated [3H]deoxycytidine against a concentration gradient. However, approximately 50% of the [3H]deoxycytidine was phosphorylated to [3H]deoxycytidine nucleotides at a low extracellular [3H]deoxycytidine concentration (6 nM) in 15-min incubations. This accumulation process depended, in part, on saturable intracellular phosphorylation. These studies provide further evidence that the choroid plexus contains an active nucleoside transport system of low specificity for deoxynucleosides and ribonucleosides, and a separate, saturable efflux system for deoxynucleosides which is very sensitive to inhibition by NBTI.

Animals↗
PubMed1983

Characterization, development, and localization of the deoxycytidine phosphorylating systems in mammalian brain.

The accumulation of deoxycytidine by rabbit and mouse brain was studied in vitro. Brain slices from brain stem, cerebellum, and forebrain of rabbits of various ages (1 day to 2.5 years) and forebrain from adult mice were incubated for various times in artificial CSF containing 6 nM [3H]deoxycytidine at 37 degrees C under 95% O2/5% CO2. Rabbit and mouse brain slices of all ages accumulated [3H]deoxycytidine by a saturable system (IC50 = 4 microM) and converted it to [3H]deoxycytidine phosphates and [3H]DNA. When slices from all brain regions of 1-day-old rabbits were incubated in 6 nM [3H]deoxycytidine for 30 min, tissue-to-medium ratios of 3H were between 1.2 and 2.5 and declined with age, except in cortex; the percentages of total 3H in perchloric acid homogenates of brain slices as [3H]DNA were 10-24% and declined to low levels in middle age. However, at all ages and in all regions tested, 30-85% of the [3H]deoxycytidine within the slices was phosphorylated. After homogenization and subcellular fractionation of the brain slices incubated in [3H]deoxycytidine for 30 min, the highest percentage of [3H]deoxycytidine phosphates plus [3H]DNA was present in the nuclear and mitochondrial fractions of all brain regions. Deoxycytidine phosphates were synthesized from deoxycytidine in all brain regions tested into middle age.

Aging↗
PubMed1982

Acceleration of the body clearance of phenobarbital by oral activated charcoal.

We investigated the effect of multiple oral doses of activated charcoal on the pharmacokinetics of intravenously administered phenobarbital in a randomized crossover trial. Six healthy men volunteered to take 200 mg of phenobarbital sodium per 70 kg of body weight intravenously on two separate occasions. On one occasion, each subject received oral activated charcoal (180 g) in divided doses over three days after the infusion of phenobarbital. Serum levels of phenobarbital were measured in all subjects up to 96 hours after the infusion, and urinary excretion of phenobarbital was measured in two subjects 24 to 96 hours after the infusion. A pharmacokinetic analysis showed that the charcoal decreased the serum half-life of phenobarbital form 110 +/- 8 to 45 +/- 6 hours (S.E.M.) (P less than 0.01), increased the total body clearance of phenobarbital from 4.4 +/- 0.2 to 12.0 +/- 1.6 ml per kilogram per hour (P less than 0.01), and increased the nonrenal clearance from 52 to 80 per cent of the total body clearance. We conclude that oral administration of activated charcoal enhances the nonrenal clearance of phenobarbital.

Administration, Oral↗
PubMed1982

Therapeutic use of albumin: 2.

It has previously been shown that albumin costs in a Veterans Administration Hospital constituted a large portion of the pharmacy drug budget and that much albumin was prescribed inappropriately. Therefore, a program of education and use monitoring was instituted to improve understanding and prescribing of this product. Inappropriate use declined from 41% to 26% of total albumin units and, more dramatically, total cost of albumin used had decreased by 90% one year after this program was initiated. Projected yearly savings from decreased use was more than $85,000. These results demonstrate that such a program can promote more appropriate use of albumin and effect a cost savings for hospitals.

Albumins↗
PubMed1982

The impact of an educational program on gentamicin use in a teaching hospital.

We evaluated the effectiveness of a structured educational program in improving the gentamicin prescribing pattern of physicians in the hospital. Predetermined criteria for acceptable use were based upon the specific indications for initiating the drug therapy, the dosage regimen, and the precautions taken to avoid toxicity. In the preeducation review period, 57 of 109 courses of gentamicin (52 percent) were found acceptable. Following the educational program, 93 of 120 courses (78 percent; p less than 0.001) were acceptable; indications for gentamicin use that were found unacceptable decreased from 11 percent to 5 percent (p less than 0.005) and the incidence of excessive doses declined from 21 to 7 percent (p less than 0.005). We conclude that a structured educational program may improve the prescribing pattern of physicians.

Adolescent↗