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R Spector

Publications and source records attributed to R Spector.

At least 37 records · Page 2Linked to original sources
PubMed1988

Transport of amantadine and rimantadine through the blood-brain barrier.

The unidirectional transport of amantadine and rimantadine across cerebral capillaries, the anatomical locus of the blood-brain barrier, was measured with an in situ rat brain perfusion technique. Both rimantadine and, to a lesser extent, amantadine were transported principally across the blood-brain barrier by a saturable transport system with a one-half saturation concentration of about 1.0 mM (either rimantadine or amantadine). The permeability surface area constants were 8.5 x 10(-2) sec-1 (rimantadine) and 1.1 x 10(-2) sec-1 (amantadine) with concentrations of less than 1.0 microM in the perfusate. The extraction of rimantadine and amantadine from the perfusate at low concentrations (less than 1.0 microM) was 88 and 26%, respectively, of the extraction of diazepam which is 100% extracted. Amantadine and rimantadine transport through the blood-brain barrier was significantly inhibited by weakly basic drugs (e.g., diphenhydramine) but not choline (10 mM), probenecid (1 mM) or leucine (1 mM). Inasmuch as both the pKa and percentage ionized at pH = 7.4 of rimantadine (10.4 and 99.9%, respectively) are much higher than that of amantadine (pKa = 9.0 and 97.5%, respectively), and inasmuch as rimantadine is transported into brain much more readily than amantadine, our results suggest that the carrier-mediated transport of the ionized moiety is the crucial process determining the penetration of amantadine and rimantadine through the blood-brain barrier.

Adamantane↗
PubMed1987

Clinical pharmacology and therapeutics education for senior medical students.

In many medical schools instruction of students in clinical pharmacology remains informal and may be inadequate. To determine the short-term efficacy of a mandatory senior medical year course in clinical pharmacology, we compared examination scores of senior students in the College of Medicine, University of Iowa, either prior to or following the Clinical Pharmacology and Therapeutics Lecture Series. A significantly higher (P less than .001) mean score was demonstrated by students taking the examination following the course (75 +/- 4% correct) versus those taking the examination prior to the course (55 +/- 4% correct). To determine student acceptance, postcourse questionnaires were completed. Students surveyed immediately postcourse and alumni surveyed up to four years after graduation highly recommended the course and favored retaining it as a mandatory part of the fourth-year curriculum. This study confirms the efficacy and acceptance of senior medical courses in therapeutics and suggests an effective role for clinical pharmacologists in their design and execution.

Curriculum↗
PubMed1987

Transport of quinolinic acid into rabbit and rat brain.

The transport metabolism of [3H]quinolinic acid in the central nervous system of rabbits and rats were studied. In vitro [3H]quinolinic acid was not readily accumulated by isolated choroid plexus. After the intraventricular injection of tracer quantities of [3H]quinolinic acid, the [3H]quinolinic acid did not enter the brain as readily as concurrently injected [14C]mannitol and was not metabolized. The permeability-surface area constant for [3H]quinolinic acid at the rat blood-brain barrier was 1.5 +/- 1.3 X 10(-5) sec-1 compared to 2.8 +/- 0.4 X 10(-5) sec-1 for [3H]mannitol. Our results suggest that: 1) [3H]quinolinic acid is transported in the CNS by passive diffusion and 2) is not metabolized.

Animals↗
PubMed1987

Niacinamide transport through the blood-brain barrier.

The unidirectional influx of niacinamide across cerebral capillaries, the anatomical locus of the blood-brain barrier, was measured with an in situ rat brain perfusion technique employing [14C]niacinamide. Niacinamide was transported rapidly across the blood-brain barrier by a system that was not saturable with 10 mM niacinamide in the perfusate. However, with periods of perfusion longer than 30 seconds, there was substantial backflow of [14C]niacinamide into the perfusate. Niacinamide (1.7 microM) transport through the blood-brain barrier was not significantly inhibited by 3-acetylpyridine. Thus, niacinamide is transported rapidly and bidirectionally through the blood-brain barrier by a high capacity transport system. Although involved in the transfer of niacinamide between blood and brain, this transport system does not play an important regulatory role in the synthesis of NMN, NAD, and NADP from niacinamide in brain.

Animals↗
PubMed1987

Hypoxanthine transport through the blood-brain barrier.

The unidirectional influx of hypoxanthine across cerebral capillaries, the anatomical locus of the blood-brain barrier, was measured with an in situ rat brain perfusion technique employing [3H]hypoxanthine. Hypoxanthine was transported across the blood-brain barrier by a saturable system with a one-half saturation concentration of approximately 0.4 mM. The permeability-surface area product was 3 X 10(-4) sec-1 with a hypoxanthine concentration of 0.02 microM in the perfusate. Adenine (4 mM) and uracil and theophylline (both 10 mM), but not inosine (10 mM) or leucine (1 mM), inhibited hypoxanthine transfer through the blood-brain barrier. Thus, hypoxanthine is transported through the blood-brain barrier by a high-capacity, saturable transport system with a half-saturation concentration about 100 times the plasma hypoxanthine concentration. Although involved in the transport hypoxanthine from blood into brain, this system is not powerful enough to transfer important quantities of hypoxanthine from blood into brain.

Adenine↗
PubMed1987

The effect of sorbitol and activated charcoal on serum theophylline concentrations after slow-release theophylline.

The effect of the addition of sorbitol to an oral regimen of multiple doses of activated charcoal on serum theophylline concentrations was studied after the ingestion of slow-release theophylline in nine healthy male volunteers. At 6, 7, 8, 10, and 12 hours after Theo-24 (1200 mg/70 kg) ingestion, each subject received, in a randomized crossover design, either 300 ml water, 20 gm activated charcoal in water, or 20 gm activated charcoal in water plus 75 ml 70% sorbitol at 6 and 8 hours only. The serum AUCs from 6 to 30 hours after Theo-24 ingestion during the water, charcoal, and charcoal plus sorbitol phases were 305 +/- 16, 113 +/- 6, and 85 +/- 10 mg-hr/L (mean +/- SE), respectively. We conclude that the addition of sorbitol to an oral regimen of multiple doses of activated charcoal decreased the serum theophylline concentrations after therapeutic doses of slow-release theophylline to a significantly greater extent than did the activated charcoal regimen alone.

Adult↗
PubMed1987

The effect of dietary protein-calorie restriction on the renal elimination of cimetidine.

The renal elimination of the weak-base cimetidine was studied in five healthy male subjects during normal and restricted (low-protein, low-calorie) diets in a randomized crossover fashion. An intravenous dose of cimetidine, 7 mg/kg, was administered on day 7 of the normal (100 gm/70 kg protein/day) and the restricted (19 gm/70 kg protein/day) diets. The renal clearance of cimetidine was unchanged by the dietary restriction; however, the fractional excretion of cimetidine increased from 3.06 to 3.94 (P less than 0.05), indicating an apparent increase in net tubular secretion of cimetidine during the restricted diet. We conclude that cimetidine dosage adjustments are apparently not necessary for patients with acutely restricted nutrient intake, although other weakly acidic and basic drugs may require dosage changes.

Adult↗
PubMed1987

Sustained reductions in oxipurinol renal clearance during a restricted diet.

The renal clearance of oxipurinol, the major metabolite of allopurinol, was studied in six healthy subjects during normal and restricted (low protein and low calorie) diets. A 600 mg oral dose of allopurinol was administered after 7 days of a normal diet (100 mg protein/day) and again after 2 and 4 weeks of a restricted diet (19 gm protein/day). The renal clearance of oxipurinol was reduced from 19.6 +/- 1.5 ml/min during the normal diet to 10.9 +/- 0.8 and 12.0 +/- 0.9 ml/min (both P less than 0.001) during the restricted diet at 2 and 4 weeks, respectively. These changes in oxipurinol renal clearance paralleled changes in uric acid renal clearance. Furthermore, the plasma oxipurinol half-life was increased from 27.0 +/- 1.7 hours during the normal diet to 51.1 +/- 4.3 and 45.7 +/- 3.7 hours (both P less than 0.001) during the restricted diet at 2 and 4 weeks, respectively. We conclude that dietary protein and calorie restriction cause a sustained reduction in the elimination of oxipurinol.

3-Hydroxybutyric Acid↗
PubMed1987

Digoxin toxicity in patients with high serum digoxin concentrations.

A retrospective study of the clinical course and outcome of patients with serum digoxin concentrations (SDCs) greater than 3 ng/mL was conducted to determine the probability of a patient without initial signs or symptoms of digoxin toxicity subsequently developing signs or symptoms. Of 123 patients with SDCs greater than 3 ng/mL, 54 had no apparent signs or symptoms of toxicity at the time the index SDC was determined (group 1). Of these 54, two patients developed definite digoxin toxicity, although neither suffered significant morbidity. Digoxin administration was reduced or discontinued in all patients but one in group 1. There were no significant differences between the patients who had no signs or symptoms of digoxin toxicity (group 1) and those who did have signs or symptoms (group 2) in the mean SDC (3.9 +/- 0.1 vs 4.2 +/- 0.2 ng/mL, respectively), the serum creatinine (2.9 +/- 0.2 vs 3.4 +/- 0.4 mg/dL), or the incidence of atrial fibrillation (29/54 vs. 35/69) and coronary artery disease (21/54 vs. 18/69). The authors conclude that clinically stable patients receiving digoxin who have elevated SDCs but are without signs or symptoms of digoxin toxicity are at low risk of developing serious digoxin toxicity and do not generally require treatment beyond the discontinuation of digoxin therapy.

Aged↗
PubMed1987

Biotin transport through the blood-brain barrier.

The unidirectional influx of biotin across cerebral capillaries, the anatomical locus of the blood-brain barrier, was measured with an in situ rat brain perfusion technique employing [3H]biotin. Biotin was transported across the blood-brain barrier by a saturable system with a one-half saturation concentration of approximately 100 microM. The permeability-surface area products were 10(-4) s-1 with a biotin concentration of 0.02 microM in the perfusate. Probenecid, pantothenic acid, and nonanoic acid but not biocytin or biotin methylester (all 250 microM) inhibited biotin transfer through the blood-brain barrier. The isolated rabbit choroid plexus was unable to concentrate [3H]biotin from medium containing 1 nM [3H]biotin. These observations provide evidence that: biotin is transported through the blood-brain barrier by a saturable transport system that depends on a free carboxylic acid group, and the choroid plexus is probably not involved in the transfer of biotin between blood and cerebrospinal fluid.

Animals↗
PubMed1987

Transport of diphenhydramine in the central nervous system.

The transport and metabolism of diphenhydramine was studied in vitro in the isolated rabbit choroid plexus and in vivo in New Zealand white rabbits and Sprague-Dawley rats. In vitro, [14C] diphenhydramine was accumulated by a saturable, energy-requiring system in choroid plexus. In vivo, 20 min after intraventricular injection into rabbits, [14C]diphenhydramine was cleared from cerebrospinal fluid much more rapidly than [3H]sucrose, a molecule transported in the central nervous system by simple diffusion. In vivo, employing the in situ rat brain perfusion technique, [14C]diphenhydramine was cleared from the cerebral perfusion fluid as rapidly as [14C]diazepam. However, the clearance of [14C]diphenhydramine, but not [14C]diazepam, was inhibited by the addition of 10 mM unlabeled diphenhydramine to the perfusate. These in vivo and in vitro results show that diphenhydramine, unlike diazepam, is transported between blood, brain and cerebrospinal fluid, in part, by saturable, carrier-mediated transport processes at both the blood-brain and blood-cerebrospinal fluid barriers.

Animals↗
PubMed1987

Plasma and cerebrospinal fluid nucleosides and oxypurines in acute liver failure.

Concentrations of pyrimidine nucleosides (with the possible exception of uridine) and oxypurines in mammalian plasma and cerebrospinal fluid (CSF) are maintained relatively constant by potent homeostatic mechanisms. To test the importance of the intact liver in maintaining homeostasis of pyrimidine nucleosides and oxypurines in plasma and CSF, we performed a greater than 90% or sham hepatectomy on New Zealand white rabbits. At 1, 6, 12, or 24 hours after real or sham hepatectomy, plasma and CSF nucleosides and oxypurines were measured by high-performance liquid chromatography. At all times after hepatectomy, the concentrations of the pyrimidine deoxyribonucleosides (deoxycytidine, deoxyuridine, and thymidine) were increased approximately threefold in plasma and CSF compared with sham-operated controls. Twenty-four hours after hepatectomy, the concentrations of uridine and cytidine in plasma were decreased by 70% and 50%, respectively, and in CSF by 50% and 40%, respectively, when compared with the concentrations in the sham-operated controls. Hypoxanthine concentrations in CSF were increased approximately twofold at 6, 12, and 24 hours after hepatectomy. These results suggest that liver function is essential for the maintenance of normal concentrations of pyrimidine nucleosides in plasma and CSF. That pyrimidine nucleoside concentrations are disrupted in plasma and CSF in this model of acute liver failure suggests that pools of pyrimidine nucleotides in some tissues (e.g., brain) may be altered by liver failure.

Animals↗
PubMed1986

Leukotriene C4 transport and metabolism in the central nervous system.

The transport and metabolism of radiolabeled leukotriene (LT) C4 in the CNS were investigated after intraventricular injection. Under thiopental (Pentothal) anesthesia, New Zealand white rabbits were injected intracerebroventricularly with 0.2 ml of artificial CSF containing 2.5 microCi of [3H]LTC4 (36 Ci/mmol), 0.3 microCi of [14C]mannitol, and, in some cases, 0.9 mg of probenecid, 1.8 mg of cysteine, 1.4 micrograms of unlabeled LTC4, or 2 mg of tolazoline HCl. After 2 h, the conscious rabbits were killed, and the quantity and nature of the 3H and 14C were determined in CSF, choroid plexus, and brain. The [3H]LTC4 recovered in CSF and brain was not extensively metabolized, as greater than 70% of the 3H remained [3H]LTC4, although some spontaneous conversion to 11-trans-[3H]LTC4 occurred. Oxidized forms of [3H]LTC4, [3H]LTD4, and [3H]LTE4 did not exceed 18% in CSF and brain. After intraventricular injection of [3H]LTC4, 3H was transferred from the CSF to blood by a probenecid-sensitive, but tolazoline-insensitive, transport system in the CNS much more rapidly than mannitol. Cysteine decreased the retention of [3H]LTC4 in brain. These results are consistent with previous in vitro observations that [3H]LTC4 is transferred from CSF into blood by an efficient transport system for LTC4 in choroid plexus.

Animals↗