Biomedical subjects

D D Allen

Publications and source records attributed to D D Allen.

31 records · Page 2Linked to original sources

PubMed1996

The pharmacokinetics and blood-brain barrier permeation of the chelators 1,2 dimethly-, 1,2 diethyl-, and 1-[ethan-1'ol]-2-methyl-3-hydroxypyridin-4-one in the rat.

The 3-hydroxypyridin-4-ones (HPs) are iron and aluminum chelators. Their ability to enter the brain had not previously been directly determined. To determine whether they cross the blood-brain barrier (BBB), three HPs possessing a wide range of lipophilicity were examined: 1-[ethan-1'ol]-2-methyl-HP (CP40), 1,2-dimethyl-HP (CP20, L1, deferiprone), and 1,2-dimethyl-HP (CP94, EL1NEt). Their pharmacokinetics were determined in rats to establish dosing parameters for microdialysis studies of BBB permeation. Studies were then conducted with microdialysis probes in the blood, frontal cortex, and lateral ventricle to determine the rate and extent of HP BBB permeability. All three HPs were detectable in brain dialysate samples collected 0-7 min after HP injection, demonstrating rapid entry into the brain. The extent of unbound distribution (an indicator of the mechanism of BBB permeation) was 0.9 and 1.2 for the frontal cortex and lateral ventricle for CP20, and was 1.1 and 1.6 for CP94, suggesting diffusion across the BBB. The extent of unbound distribution of CP40 was 0.2 for both the frontal cortex and lateral ventricle, suggesting the presence of a transporter moving it out of brain extracellular fluid. Introduction of cyanide into the brain did not affect the brain to blood CP40 ratio, suggesting that the transporter is not energy-dependent. Both CP94 and CP40 caused death due to respiratory failure, whereas CP20 did not. The ability of less toxic bidentate HP chelators, such as CP20, to enter the brain may enable their use in the treatment of metal-induced diseases and iron-facilitated oxidative injury involving the central nervous system.

Animals↗

PubMed1996

Hippocampal acetylcholine increases during eyeblink conditioning in the rabbit.

The classically conditioned rabbit nictitating membrane reflex (NMR) is modulated by the septohippocampal cholinergic system. Disruption of this system retards NMR acquisition. Aluminium (Al) is a neurotoxin that interferes with hippocampal acetylcholine (ACh) synthesis and release. Using microdialysis, this study tested the hypothesis that NMR acquisition in the rabbit is associated with hippocampal ACh release. This was conducted by measuring ACh release in control and A1-intoxicated rabbits during NMR training. NMR training consisted of four sessions of 100 conditioning trials/session in a delay paradigm. The percentage of conditioned responses (CRs) increased with each conditioning session for both groups, although percent CRs was significantly greater in the control group. Acetylcholine release in the ventral hippocampus increased significantly over baseline in the control group during the second and third conditioning sessions. In the Al-intoxicated group, ACh release did not increase significantly during any conditioning session. A separate group of rabbits was pseudoconditioned, receiving the same conditioning stimuli, although explicitly unpaired. This group did not acquire the CR. Acetylcholine release did not significantly increase during any conditioning session, suggesting that the increase in ACh release observed in the control group was not merely a product of conditioning stimuli presentation. The lack of increased ACh release in the Al-intoxicated rabbits was associated with a CR acquisition deficit. The results of this study are consistent with a role of hippocampal cholinergic function in NMR acquisition in the rabbit.

Acetylcholine↗

PubMed1996

Evaluation of 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid in the inhibition of rouleaux formation.

BACKGROUND: DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid) inhibits the formation of serum-or plasma-induced rouleaux through its ability to bind to band 3 on red cell membranes. This property of DIDS was evaluated in the serologic testing of specimens exhibiting rouleaux. STUDY DESIGN AND METHODS: Optimal test conditions for DIDS treatment of reagent red cells were determined by varying the volume and concentration of DIDS solution and the incubation temperature and duration and comparing the results of antibody screening procedures using specimens that exhibit macroscopically visible rouleaux. Blind titration studies compared untreated and DIDS-treated red cells to evaluate the maintenance of antigen integrity. The use of DIDS-treated red cells for antibody detection and identification was evaluated by comparing the results in donor specimens containing antibodies with those in untreated and DIDS-treated selected panel cells. In addition, 4-percent (wt/vol) dextran in serum was used to induce rouleaux formation as a way of determining the capability of DIDS to resolve ABO serum grouping discrepancies. RESULTS: Complete inhibition of rouleaux formation occurred when reagent red cells were treated by incubation at 37 degrees C for 10 minutes with 150 microliter (approx. 5 drops) of 0.05 mg per mL of DIDS in 0.9-percent NaCl. There were no significant differences in titration scores of untreated and DIDS-treated red cells tested with the 19 antisera used to assess antigen integrity. Antibody identification studies showed that DIDS-treated reagent red cells reacted similarly to untreated reagent red cells. In addition, DIDS resolved dextran-induced ABO serum grouping discrepancies. CONCLUSION: DIDS effectively resolved the serologic problems associated with the presence of rouleaux, without affecting the results of the test system itself. Implementation of this method to inhibit the rouleaux-forming properties of serum and plasma specimens can be useful in serologic testing.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed1995

Evidence for energy-dependent transport of aluminum out of brain extracellular fluid.

Aluminum (Al) can cause CNS toxicity. The mechanism of its blood-brain barrier (BBB) permeation is poorly understood. In this study, microdialysis was used to determine extracellular fluid (ECF) unbound aluminum distribution between frontal cortex (FC) and blood during steady-state aluminum concentrations. The brain/blood aluminum ratio was determined. Over a 16-fold range of aluminum concentrations (dosed as aluminum citrate), brain/blood aluminum ratios were 0.10-0.15, consistently and significantly < 1. Aluminum diffusion cannot account for these results, suggesting the presence of a carrier that moves aluminum out of brain extracellular fluid. These aluminum brain/blood ratios (BBRs) were not significantly different over the range of concentrations studied, suggesting an inability to saturate the carrier. Brain/blood aluminum ratios obtained with four aluminum-hydroxypyridinones were also significantly < 1 (0.1-0.3), and were generally significantly different among themselves and from the aluminum citrate BBR. Movement of a BBB permeability marker from blood into brain extracellular fluid suggested partial BBB opening. The aluminum BBRs obtained (all << 1), in the presence of a partially opened BBR, suggest an efficient carrier moving aluminum out of brain ECF. Addition of cyanide to the brain microdialysis probe solution significantly increased the Al (citrate) BBR to 1. These results suggest the presence of an efficient, energy-dependent carrier that removes aluminum from brain ECF, either into brain cells or blood.

Aluminum↗

PubMed1994

Pharmacokinetics of aluminum 3-hydroxypyridin-4-one complexes: implications for aluminum redistribution subsequent to chelation therapy.

The pharmacokinetics of selected aluminum-hydroxypyridinone (Al-HP complexes were determined in rats to better understand the relationship between their disposition and elimination parameters and the safety of HPs in the chelation therapy of Al intoxication. Five complexes were administered as i.v. bolus doses of Al-HP (0.25 mmol/kg Al-0.75 mmol/kg HP). The Al-HP steady state volumes of distribution ranged from 220 to 871 ml/kg, suggesting that each complex distributed out of the vascular compartment (which should have been approximately 65 ml/kg). Systemic clearances ranged from 189 to 906 ml/h per kg. Elimination half-lives (t1/2) and mean residence times ranged from 0.36 to 0.84 and 0.52 to 1.20 h, respectively. The Al-CP20 complex had a short t1/2 and a midrange volume of distribution. It demonstrated no apparent toxicity, whereas myoclonic seizures were observed after Al-CP22, Al-CP24 and Al-CP94 administration. The most appropriate choice for Al chelation among the HPs tested may be CP20. Characterization of the distribution and elimination of Al-HP complexes improves the understanding of potential toxicity that may be associated with HP therapy of Al intoxication.

Aluminum↗

PubMed1994

Studies of aluminum neurobehavioral toxicity in the intact mammal.

1. Aluminum (Al) has been implicated in neurotoxic syndromes in several conditions, including Alzheimer's disease (AD). The developmental stage of the mammalian brain most susceptible to Al was determined in rabbits systematically exposed to Al during the prenatal, postnatal, or second month or for 1 month as adults or as aged subjects. Eyeblink reflex classical conditioning showed an Al-induced learning deficit only in the adult and aged rabbits. 2. 4-Aminopyridine, which was reported to improve learning in AD subjects, attenuated the Al-induced learning deficit. 3. Conditioned eyeblink acquisition is slower in AD subjects than controls, supporting the Al-loaded rabbit as a model of some AD effects. 4. To determine if the Al-loaded rabbit modeled the AD cholinergic deficit, acetylcholine (Ach) overflow was measured in rabbit hippocampus using microdialysis. Aluminum pretreatment reduced basal and potassium-stimulated Ach overflow compared to controls. 5. Acetylcholine overflow increased as control rabbits acquired the conditioned eyeblink reflex, then subsequently decreased, although conditioned eyeblink performance continued. In contrast, Al-loaded rabbits showed a delay in conditioned eyeblink acquisition and greatly attenuated Ach overflow. The Al-induced attenuation of Ach overflow may contribute to the Al-induced learning deficit. 6. Brain Al entry was studied using microdialysis of blood, brain, and lateral ventricle. Aluminum rapidly entered the brain and lateral ventricle. Frontal cortical Al was greater than lateral ventricular Al, suggesting that Al primarily enters the brain through the cerebral microvasculature. 7. The brain/blood Al ratio was always significantly less than 1. This ratio was influenced by the Al form administered, brain site and animal species. Thus, there appears to be an active process moving Al out of brain extracellular fluid (ECF). 8. Brain and blood dialysate Ach concentrations were not different after cyanide addition to the dialysate, supporting the conclusion that an active process moves Al out of brain ECF.

4-Aminopyridine↗

PubMed1994

Effect of including a clinical example on the ability of physical therapists to apply information in a technical research report.

BACKGROUND AND PURPOSE: The purpose of this study was to determine whether an example in a technical research report would affect application of content to hypothetical patient problems and to future patients. SUBJECTS: Subjects were 69 physical therapists who routinely used isokinetic equipment in the treatment of patients with knee joint pathologies. METHODS: Thirty-five subjects (group 1) read a research report that described mathematical models for predicting preinjury quadriceps femoris and hamstring muscle performance. The report included an example of applying the information. The remaining 34 subjects (group 2) read the same research report with the example omitted. Subjects were asked to select appropriate prediction models and determine preinjury knee torques for two hypothetical patients. Subjects were also contacted 6 to 12 weeks after initial data collection to determine whether they had applied research report results in their treatments of patients. RESULTS: Chi-square analyses indicated manuscript type was not related to the selection of correct models, but group 1 subjects computed correct torque values more frequently than did group 2 subjects. Insufficient data were available regarding application of research report content to patients. CONCLUSION AND DISCUSSION: The results indicate application of technically oriented research reports may be enhanced by including examples of applications. (Gross MT, Sekerak DK, Allen DD. Effect of including a clinical example on the ability of physical therapists to apply information in a technical research report.

Adult↗

PubMed1994

Pharmacokinetics and distribution of tris(maltolato)aluminum(III) into the central nervous system.

The maltolate compound of aluminum (Al), tris(maltolato)aluminum(III), has been demonstrated to be quite toxic after central administration and in cell cultures. However, reports of peripheral Al-maltolate administration in vivo demonstrated unimpressive neurological effects. We found no reports of Al-maltolate pharmacokinetics or its distribution into the central nervous system (CNS) after systemic administration. In the present study, we evaluated Al pharmacokinetics in serum and Al distribution into brain extracellular fluid (ECF) in rats following Al-maltolate administration. The pharmacokinetic studies revealed that systemic clearance, elimination half-life and mean residence time were 42 (+/- 5) ml/hr/kg, 2.2 (+/- 0.5) hr and 3.1 (+/- 0.7) hr [mean +/- SD), respectively. The steady state volume of distribution (Vss) for Al-maltolate was 130 ml/kg. This Vss suggests that Al-maltolate may exhibit limited distribution outside the vascular compartment, which is estimated to be approximately 80 ml/kg in these rats. Previously, we used microdialysis (MD) probes to assess Al-citrate distribution into the CNS. MD was utilized in the present study to evaluate the CNS distribution of Al as a result of Al-maltolate administration. MD probes were implanted into the frontal cortex (FC) and jugular vein to sample Al from brain and blood ECF, respectively. Al was not measurable in FC MD probe dialysates after a 0.5 mmol/kg Al (as maltolate) bolus, but could be measured after steady state blood and brain ECF Al concentrations had been achieved. The Al brain/blood ration calculated from Al-maltolate steady state brain and blood MD samples was 0.04, significantly less than those calculated for other Al salts at equimolar Al doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Antipyrine as a dialyzable reference to correct differences in efficiency among and within sampling devices during in vivo microdialysis.

Antipyrine was investigated as a dialyzable substance that could be used to quantitate relative differences in the efficiency of dialysis among multiple microdialysis probes and by a single probe over time. The contribution of effective membrane surface area to recovery variability was tested by the introduction of air into microdialysis probes. Reduction of effective membrane surface area reduced antipyrine recovery. Dialysates from probes implanted in the jugular vein, brain, and liver of rats receiving antipyrine demonstrated differences in antipyrine concentration among probes within the same rat. These results suggest dissimilar efficiencies of the probes to recover antipyrine, which should be uniformly distributed throughout body water. Dialysates from blood, brain, and liver probes in rats that received both antipyrine and tritiated water (3H2O) showed differences in antipyrine and 3H2O concentrations among probes. Variability of antipyrine and 3H2O concentrations over time within a probe were positively correlated, suggesting that the cause(s) of temporal variability affected both of these markers of body water. Correction of antipyrine tissue/blood ratios, using 3H2O blood/tissue ratios from the same sampling period, reduced the variability in antipyrine tissue/blood ratios, producing ratios closer to the expected value of 1. Differences in probe efficiency contributing to the variability of antipyrine and 3H2O recovery would also be expected to influence the recovery of other substances during microdialysis. The administration of antipyrine during microdialysis experiments is suggested to enable reduction of temporal and site-related differences in substance recovery that are due to differences in probe efficiency. Other methods are necessary to determine the actual extracellular concentration of dialyzed substances and the integrity of the blood-brain barrier.

Animals↗

PubMed1992

4-Trimethylammonium antipyrine: a quaternary ammonium nonradionuclide marker for blood-brain barrier integrity during in vivo microdialysis.

The well-controlled microdialysis (MD) study of substance permeation into brain extracellular fluid (ECF) and cerebrospinal fluid requires consideration of blood-brain barrier (BBB) integrity, which might be compromised by microdialysis probe implantation. Others have assessed BBB integrity with radionuclide markers. A nonradionuclide marker may be desirable in many studies. A charged antipyrine analogue may be useful to determine BBB integrity with concomitant antipyrine characterization of probe efficiency (Yokel et al., 1992, J Pharmacol Toxicol Methods 27:135-142), and may not require another analytical technique. We synthesized, validated, and evaluated 4-trimethylammonium antipyrine (4TMA-AP) as a BBB integrity marker. BBB permeation was determined by calculation of a BBB integrity percentage (Pi) from brain/blood concentrations. The PiS of Evan's blue, which does not permeate the intact BBB, and 4TMA-AP were not significantly different in rats without known BBB disruption, suggesting a lack of 4TMA-AP permeation through the intact BBB. When MD probes were slowly implanted into the frontal cortex, 4TMA-AP PiS were usually zero. Intracarotid oleic acid injection to open the BBB significantly increased 4TMA-AP PiS, suggesting that 4TMA-AP entered brain ECF when the BBB was compromised. Rapid probe implantation produced increased 4TMA-AP PiS, suggesting BBB disruption. The predicted appearance of 4TMA-AP in brain ECF suggests that it is a BBB integrity marker.

Animals↗

PubMed1992

Dissimilar aluminum and gallium permeation of the blood-brain barrier demonstrated by in vivo microdialysis.

Aluminum (Al) and gallium (Ga) permeations of the blood-brain barrier (BBB) were assessed in rats. Unbound extracellular Al and Ga concentrations were ascertained at the two potential sites of BBB permeation, cerebral capillaries and choroid plexuses, by implantation of microdialysis probes in the frontal cortex and lateral ventricle, respectively. A microdialysis probe implanted in the jugular vein revealed unbound blood Al or Ga concentrations. Al or 67Ga citrate was administered via the femoral vein. Peak Al and Ga concentrations were seen within the first 10 min at all three sites. Area under the curve (concentration vs. time to final sample) values were calculated using RSTRIP. Within-rat overall frontal cortical/blood and lateral ventricular/blood ratios [brain/blood ratios (oBBRs)] were calculated from area under the curve values. Aluminum frontal cortical oBBRs were significantly higher than those for the lateral ventricle. Ga oBBRs were not significantly different between the two sites. Al and Ga oBBRs were significantly different in the lateral ventricle. These results suggest that the primary site of A1 permeation across the BBB is at cerebral capillaries, whereas Ga permeation across the BBB does not significantly differ between cerebral capillaries and choroid plexuses. The use of Ga as a model to study Al pharmacokinetics may not be appropriate in the elucidation of the site or mechanism of Al entry into the brain.

Aluminum↗

PubMed1991

Heterologous introns can enhance expression of transgenes in mice.

In a previous study we showed that genomic constructs were expressed more efficiently in transgenic mice than constructs that were identical except for the lack of introns. Using the mouse metallothionein promoter-rat growth hormone gene construct as a model, we show that the first intron of the rat growth hormone gene is essential for high-level expression, whereas the other three introns are less effective. Several heterologous introns placed 3' of the coding region of an intronless rat growth hormone gene are also ineffective. However, insertion of some heterologous introns between the metallothionein promoter and the growth hormone gene improves expression. To determine whether addition of heterologous introns would provide a general strategy for improving expression, we have tested them in conjunction with other intronless genes and with different promoters.

Animals↗

PubMedDate not supplied

The blood-brain barrier and brain drug delivery.

The present report encompasses a thorough review of drug delivery to the brain with a particular focus on using drug carriers such as liposomes and nanoparticles. Challenges in brain drug delivery arise from the presence of one of the strictest barriers in vivo-the blood-brain barrier (BBB). This barrier exists at the level of endothelial cells of brain vasculature and its role is to maintain brain homeostasis. To better understand the principles of brain drug delivery, relevant knowledge of the blood-brain barrier anatomy and physiology is briefly reviewed. Several approaches to overcome the BBB have been reviewed including the use of carrier systems. In addition, strategies to enhance brain drug delivery by specific brain targeting are discussed.

Blood-Brain Barrier↗