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D A Smith

Publications and source records attributed to D A Smith.

At least 127 records · Page 7Linked to original sources
PubMed1996

Iron-based second-sphere contrast agents for magnetic resonance imaging: development of a model system and evaluation of iron (III) tris (tironate) complex in rats.

RATIONALE AND OBJECTIVES: Iron(III) complexes have been developed as magnetic resonance (MR) contrast agents based on the use of ligands capable of providing coordinative saturation at iron and allowing the second-sphere hydrogen bonding of water molecules. METHODS: Studies of solution-phase binding of a probe ion to a diamagnetic metal catecholate complex and molecular orbital calculations were performed. R1 values were determined. Toxicity studies of iron(III) tris(tironate) were conducted with rats. Excretion studies were performed by analysis of urine samples. MR measurements were made. RESULTS: Second-sphere coordination of a probe ion to a metal catecholate complex occurred in solution. Molecular orbital calculations suggested flexibility in design. Iron(III) tris (catecholate) complexes were shown to have high R1 values. Images of the kidneys and liver showed dose-dependent enhancement in T1-weighted images. The onset of toxicity was at approximately 0.30 mmol/kg. Urine analysis indicated essentially complete clearance (0.1-0.2 mmol/kg) within 24-48 hours. CONCLUSION: Interactions between water molecules and basic sites within a paramagnetic metal-ligand complex allow for application of suitable complexes as T1 agents.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed1996

Pharmacokinetics and pharmacodynamics of cisatracurium in patients with end-stage liver disease undergoing liver transplantation.

We determined the pharmacokinetics and pharmacodynamics of cisatracurium, one of the 10 isomers of atracurium, in 14 patients with end-stage liver disease undergoing liver transplantation and in 11 control patients with normal hepatic and renal function undergoing elective surgery. Blood samples were collected for 8 h after i.v. bolus administration of cisatracurium 0.1 mg kg-1 (2 x ED95). Plasma concentrations of cisatracurium and its metabolites were determined using an HPLC method with fluorescence detection. Pharmacokinetic variables were determined using non-compartmental methods. Neuromuscular block was assessed by measuring the electromyographic evoked response of the adductor pollicis muscle to train-of-four stimulation of the ulnar nerve using a Puritan-Bennett Datex (Helsinki, Finland) monitor. Pharmacodynamic modelling was completed using semi-parametric effect-compartment analysis. Volume of distribution at steady state was 195 (SD 38) ml kg-1 in liver transplant patients and 161 (23) ml kg-1 in control patients (P < 0.05), plasma clearance was 6.6 (1.1) ml kg-1 min-1 in liver transplant patients and 5.7 (0.8) ml kg-1 min-1 in control patients (P < 0.05), but elimination half-lives were similar: 24.4 (2.9) min in liver transplant patients vs 23.5 (3.5) min in control patients (ns). The time to maximum block was 2.4 (0.8) min in liver transplant patients compared with 3.3 (1.0) min in control patients (P < 0.05), but the clinical effective duration of action (time to 25% recovery) was similar: 53.5 (11.9) min in liver transplant patients compared with 46.9 (6.9) min in control patients (ns). The recovery index (25-75% recovery) was also similar in both groups: 15.4 (4.2) min in liver transplant patients and 12.8 (1.9) min in control patients (ns). After cisatracurium, peak laudanosine concentrations were 16 (5) and 21 (5) ng ml-1 in liver transplant and control patients, respectively. In summary, minor differences in the pharmacokinetics and pharmacodynamics of cisatracurium in liver transplant and control patients were not associated with any clinically significant differences in recovery profiles after a single dose of cisatracurium.

Adult↗
PubMed1996

Mechanisms of granuloma formation in murine Mycobacterium avium infection: the contribution of CD4+ T cells.

Infection with the virulent Mycobacterium avium strain TMC 724 caused progressive infection in C57BL/6 and BALB/c mice, while infection with a less virulent strain (M. avium SE 01) resulted in chronically persistent bacterial loads. Livers of mice infected with TMC 724 were characterized by progressively expanding tumor-like infiltrations of epithelioid macrophages, while SE 01 induced well-developed, compact epithelioid granulomas that remained constant in size and number for at least 4 months. When C57BL/6 mice were depleted of CD4+ T cells by i.p. administration of specific mAb at the time of infection, their capacity to initiate granuloma formation was completely abrogated during the first 4 weeks of infection. Semi-quantitative competitive RT-PCR of liver homogenates obtained 3 weeks after infection revealed that depletion of CD4+ T cells was accompanied by a 25-fold reduced expression of IFN-gamma mRNA and a 5-fold reduced expression of tumor necrosis factor (TNF)-alpha mRNA when compared to control infected mice. Granuloma morphology in response to either TMC 724 or SE 01 was similar in immunodeficient SCID mice to that observed in syngeneic BALB/c mice. However, SCID mice developed granulomas in a delayed fashion and were less efficient in surrounding infected Kupffer cells with an inflammatory infiltration. The delayed kinetics of granuloma initiation in infected SCID mice was paralleled by a lower mRNA expression for IFN-gamma and TNF-alpha compared to that observed in infected BALB/c mice. mAb-mediated neutralization of IFN-gamma in BALB/c mice significantly reduced inflammatory infiltrations and granuloma formation. These data support the conclusion that CD4+ T cells accelerate granuloma formation by enhancing the production of TNF-alpha and IFN-gamma at the site of infection.

Animals↗
PubMed1996

Alanine germination receptors of Bacillus subtilis.

The alanine-stimulated spore germination responses of Bacillus subtilis 168 have been dissected by combining physiological and genetical approaches. From the analyses the authors infer that there are three classes of alanine response. Two of the responses are mediated via the GerA proteins, with and without germinal adjuncts, the third is mediated via the GerB proteins and obligately requires adjuncts.

Alanine↗
PubMed1996

Behavioural vigilance in schizophrenia. Evidence for hyperattentional processing.

BACKGROUND: Despite 30 years of research, some surprisingly fundamental gaps remain in our understanding of schizophrenic input dysfunctions. METHOD: In a provisional test of a 'hyperattention' hypothesis, schizophrenic patients and control subjects performed a behavioural test that was adapted from a paradigm originally developed for characterising vigilance or sustained attention in animals. On this computerised operant testing procedure, subjects discriminated between signals of various salience and non-signal presentations. Hits and correct rejections resulted in monetary rewards while misses and false alarms entailed monetary costs. RESULTS: Data from in-patients with schizophrenia and age, education and gender-matched controls support hypotheses not only about hyperattentional dysfunctions in schizophrenia with respect to overall signal detectability but also in terms of resistance to the vigilance decrement that normally occurs over trials. CONCLUSIONS: The theoretical importance of impairments of this sort are discussed with respect to the cognitive and perceptual consequences of hypervigilance and 'input dysfunction'.

Adult↗
PubMed1996

Pharmacokinetics and metabolism of zamifenacin in mouse, rat, dog and man.

1. Zamifenacin was rapidly metabolized in vitro by liver microsomes from rat, dog, and man. 2. Zamifenacin exhibited extensive plasma protein binding with human plasma showing 20 and 10-fold higher binding that that in rat and dog respectively. 3. Following oral administration to animals, metabolic clearance resulted in decreased bioavailability due to first-pass metabolism in rat and mouse. Oral clearance in man was low as a result of increased metabolic stability and increased plasma protein binding compared with animals. 4. Metabolism was the major route of clearance of zamifenacin with the primary metabolic step resulting in opening of the methylenedioxy ring to yield the catechol. In man, this metabolite was excreted as the glucuronide conjugate, whereas in the animal species it was further metabolized by mono-methylation of the catechol.

Animals↗
PubMed1996

Pharmacokinetics of a series of bis(methanesulphonamido-arylalkyl)amines in the beagle dog.

1. The pharmacokinetics of three closely related analogues of dofetilide have been investigated in the beagle dog. These have been compared with those of dofetilide and related to physicochemical properties and structural features of the molecules. 2. Following intravenous administration, the four compounds exhibit elimination half-lives ranging from 4.6 to 19 h. This range is due to changes in both volume of distribution and plasma clearance across the series. 3. In vitro plasma protein shows a relationship to lipophilicity within this series. Protein binding increasing from 54% for dofetilide, the least lipophilic compound (log D7.4 = 0.73) to 92% for the most lipophilic analogue (log D7.4 = 2.07). There is a trend for a decrease in the volume of distribution with increased plasma protein binding. 4. Plasma clearance values range from 2.4 to 10.2 ml/min/kg and are comprised of renal and non-renal components. Renal clearance ranges fro 0.11 to 2.9 ml/min/kg and shows an inverse correlation with and lipophilicity of the compounds. Values for the renal clearance of unbound drug suggest that only the most lipophilic derivative (III), has sufficient membrane affinity to undergo tubular reabsorption. 5. Non-renal clearance of either total or free drug shows no relationship with lipophilicity. Highest values are observed for the two compounds with a methyl substituent on the tertiary amine and lowest values for the two compounds in which the tertiary amine is incorporated into a 7-membered ring. In vitro metabolism in dog liver microsomes also shows increased lability for the two N-methyl compounds. The N-desmethyl metabolite is the major product in both cases.

Animals↗
PubMed1996

A comparison of performance in added-purpose occupations and rote exercise for dynamic standing balance in persons with hemiplegia.

OBJECTIVES: Adding purpose to daily occupations to promote performance is a basic premise of occupational therapy. This study investigated the hypothesis that in persons with hemiplegia, two added-purpose occupations would elicit more exercise repetitions than a rote exercise. METHOD: In a counterbalanced order, 21 subjects with hemiplegia, aged 51 to 78 years, experienced all three conditions of a dynamic standing balance exercise that involved bending down, reaching, standing up, and extending the arm. One condition of added purpose involved the use of materials (small balls and target); a second added-purpose condition involved the subjects' imagination of the small balls. The third condition was the rote exercise without added purpose. RESULTS: A one-way analysis of variance for related measures indicated that the subjects performed significantly differently in each of the three conditions (p < .001). A Tukey multiple comparison test revealed that the subjects did significantly more exercise repetitions in the added-materials condition and in the imagery-based condition than in the rote exercise condition (p < .05). CONCLUSION: This study demonstrates how added purpose can enhance motor performance in persons with hemiplegia. Purpose may be effectively added to an exercise through the use of materials or imagery.

Aged↗
PubMed1996

Use of medians and "average of normals" of patients' data for assessment of long-term analytical stability.

Using results from patients, we studied several methods for long-term (years) monitoring of the analytical stability of various chemistry tests. For each test, we obtained on a bimonthly basis histograms of > or = 200 to approximately 2000 data points and determined the median, mean, and mean of those data points in the reference range ("average of normal" or AON). Examining approximately 4 years' data, we found that the medians and AON are extremely stable for most tests, and that all observed shifts in the medians or in the AON could be explained by expected or unexpected changes in the laboratory. The means and peak values of the Erlang (gamma) distribution were less useful, owing to shifts caused by extreme outliers, especially for enzymes in serum. We assumed that the underlying patient population and testing patterns were stable. We recommend the use of medians or the AON of patients' data under defined conditions for monitoring the long-term analytical stability of certain tests involving serum or whole blood.

Ammonia↗
PubMed1996

Putative active site template model for cytochrome P4502C9 (tolbutamide hydroxylase).

Binding of substrates to the active site of cytochrome P450 enzymes largely relies on hydrophobic interactions. However, other binding interactions can take place giving the enzyme high regioselectivity and even stereoselectivity. For instance, within the major human cytochrome P450s involved in drug metabolism, cytochrome P4502D6 (CYP2D6) relies on an ion-pair interaction as a major binding factor. There are now a number of substrates reported that have routes of metabolism ascribed specifically to cytochrome P4502C9 (CYP2C9), the isoform mainly responsible for tolbutamide hydroxylation. Although chemically diverse, these substrates have the capability to be hydrogen bond donors (or acceptors). The substrate specificity has been rationalized in terms of a hydrogen bond donor/acceptor model and, by use of molecular modeling, an active site template model for CYP2C9 has been generated. The substrates modeled were phenytoin, warfarin, ibuprofen, naproxen, diclofenac, delta 1-tetrahydrocannabinol, 58C80, and tolbutamide. In addition to the substrates, the potent, selective inhibitor sulfaphenazole was also included in the modeling. An initial hydrogen bond donor site (N2) was identified on phenytoin, the most rigid of the substrates. Corresponding hydrogen bond donation sites were then identified on all of the molecules studied. Using molecular modeling, the site of metabolism and the hydrogen bond donation sites of the molecules were then overlaid on phenytoin to produce the putative active site model. The resultant model is described by a, the distance between the site of metabolism (Y), and the hydrogen bond donor heteroatom (X) and C, the angle between this and the hydrogen bond. The mean dimensions (+/- SD) for the nine substrates and one inhibitor (a = 6.7 +/- 1.0 A, C = 133 +/- 21 degrees) illustrate the degree of overlap achieved.

Aryl Hydrocarbon Hydroxylases↗
PubMed1996

Impact on USAF tuberculosis detection and control program given a low facility tuberculosis prevalence rate.

Isoniazid prophylaxis is a major part of the U.S. Air Force tuberculosis (TB) screening program and is closely tied to the efforts to eliminate TB. If a facility has a low prevalence rate of TB and there is no sound epidemiological evidence to rule out a false-positive TB skin test, a higher threshold for what constitutes a positive reaction in a given population may be appropriate. Criteria for preventive treatment in Air Force Instruction 48-115, para 3.4.2 and 3.4.5, should be expanded to incorporate the positive-predictive rate of the tuberculin skin test as recommended by the Centers for Disease Control and Prevention.

Antitubercular Agents↗
PubMed1996

Cellulitis versus positive purified protein derivative? A case report and review of the literature.

The tuberculin skin test is one of the most widely used diagnostic aids ever developed and remains the only technique of detecting Mycobacterium tuberculosis infection other than actually culturing the organism. False-positives are an acknowledged problem, especially among health care workers (HCW), in whom rescreening can raise more questions than answers. A HCW presented with a severe response to an annual screening test and was retested 6 weeks later with normal results (non-reactive). Causes of false-positives (not including cross-reactivity) are discussed. Readers of the purified protein derivative reaction need to consider alternative explanations for a significant response than infection with tuberculosis, given the medical history and nature of response.

Adult↗
PubMed1996

Significance of metabolism in the disposition and action of the antidysrhythmic drug, dofetilide. In vitro studies and correlation with in vivo data.

Dofetilide, a class III antidysrhythmic agent, undergoes both renal and metabolic clearance. Characterization of the metabolism in vitro allows explanation of species differences, whereas identification of the human enzymes involved permits assessment of potential drug interaction. In liver microsomes, the rate of oxidative metabolism of dofetilide is in the order: male rat > female rat > dog > humans, which correlates with the metabolic clearance seen in vivo. In vitro products of oxidative metabolism, formed by N-dealkylation, are the same as those formed in vivo, with the N-desmethyl being the major product. This route of dofetilide metabolism is mediated by cytochrome P450 (CYP). In humans, N-demethylation has a high KM of 657 +/- 116 microM, indicating low affinity for the enzyme's active site. In a number of human liver microsomal preparations, this rate correlated (r = 0.903) with the activity of CYP3A4. There was no correlation with the activities of other isozymes. Specific isozyme inhibitors also indicated the involvement of CYP3A4, with partial inhibition being observed with ketoconazole and troleandeomycin, whereas the activator, alpha-naphthaflavone, caused increased turnover. No inhibition was observed with specific inhibitors or competing substrates for other isozymes. Dofetilide did not significantly inhibit CYP2C9, CYP2D6, or CYP3A4 at concentrations up to 100 microM in vitro. In contrast, amiodarone (IC50, 25 microM) and flecainide (49 microM) inhibited CYP2C9 and quinidine (0.26 microM), and flecainide (0.44 microM) inhibited CYP2D6. Many antidysrhythmic drugs have active, circulating metabolites, complicating the relationship of dose and clinical response. In vitro pharmacology studies allow assessment of the potential contribution to the pharmacological profile by metabolites. Potency of dofetilide and metabolites has been compared for class III (K+ channel blockade) and class I (Na+ channel blockade) antidysrhythmic activities. Three of the metabolites of dofetilide displayed class III activity, but at concentrations at least 20-fold higher than dofetilide. Dofetilide N-oxide showed class I activity, but only at high concentration. Neither resting membrane potential or action potential amplitude were affected by any metabolite. This lack of biologically relevant activity is in accord with the close correlation between plasma concentrations of dofetilide and pharmacological response.

Action Potentials↗
PubMed1995

Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson's disease.

BACKGROUND: Trials are under way to determine whether fetal nigral grafts can improve motor function in patients with Parkinson's disease. Some studies use fluorodopa uptake on positron-emission tomography (PET) as a marker of graft viability, but fluorodopa uptake does not distinguish between host and grafted neurons. There has been no direct evidence that grafts of fetal tissue can survive and innervate the striatum. METHODS: We studied a 59-year-old man with advanced Parkinson's disease who received bilateral grafts of fetal ventral mesencephalic tissue in the postcommissural putamen. The tissue came from seven embryos between 6 1/2 and 9 weeks after conception. The patient died 18 months later from a massive pulmonary embolism. The brain was studied with the use of tyrosine hydroxylase immunohistochemical methods. RESULTS: After transplantation, the patient had sustained improvement in motor function and a progressive increase in fluorodopa uptake in the putamen on PET scanning. On examination of the brain, each of the large grafts appeared to be viable. Each was integrated into the host striatum and contained dense clusters of dopaminergic neurons. Processes from these neurons had grown out of the grafts and provided extensive dopaminergic reinnervation to the striatum in a patch-matrix pattern. Ungrafted regions of the putamen showed sparse dopaminergic innervation. We could not identify any sprouting of host dopaminergic processes. CONCLUSIONS: Grafts of fetal mesencephalic tissue can survive for a long period in the human brain and restore dopaminergic innervation to the striatum in patients with Parkinson's disease. In the patient we studied, clinical improvement and enhanced fluorodopa with uptake on PET scanning were associated the survival of the grafts and dopaminergic reinnervation of the striatum.

Brain Tissue Transplantation↗
PubMed1995

Bilateral fetal nigral transplantation into the postcommissural putamen in Parkinson's disease.

We performed fetal nigral transplantations in 4 Parkinson's disease (PD) patients. Solid grafts were bilaterally implanted into the postcommissural putamen using 3 to 4 donors per side aged 6 1/2 to 9 weeks postconception. Transplant deposits were separated by no more than 5 mm in three dimensions. Cyclosporine was employed for a total of 6 months. Patients were evaluated at baseline and at 1, 3, and 6 months postoperatively. Striatal 18-fluorodopa uptake was assessed by positron emission tomography at baseline and at 6 months postoperatively. The procedure was well tolerated in all patients. One patient had a clinically asymptomatic superficial cortical hemorrhage along the needle tract and a second had transient postoperative confusion and hallucinations. All patients experienced clinically meaningful benefit. Significant improvement (p < 0.05) was detected in total UPDRS score during the "off" state, Schwab-England disability score during the "off" state, percent "off" time, and percent "on" time with dyskinesia. Increased striatal fluorodopa uptake was observed bilaterally in each patient, with mean increases of 53% on the right (p = 0.01) and 33% on the left (p = 0.08). Our study demonstrated clear and consistent improvement in clinical features and striatal fluorodopa uptake following fetal tissue transplantation in patients with advanced PD whose condition was not improved preoperatively by drug manipulation. These preliminary results are encouraging and support further studies to evaluate grafting strategies as a therapy for PD.

Adult↗
PubMed1995

Antibodies against human CD63 activate transfected rat basophilic leukemia (RBL-2H3) cells.

CD63 is a widely expressed glycoprotein member of the transmembrane 4 superfamily (TM4SF) that is present on activated platelets, monocytes and macrophages and many non-lymphoid cells. It has been proposed that CD63 and other members of the TM4SF couple to intracellular signal transduction pathways and may have a role in cellular adhesion, proliferation and activation. We have investigated the functions of human CD63 by expression in the rat basophilic leukemia cell line, RBL-2H3, which has previously been reported to respond to antibodies against the rat homolog of CD63. Using a panel of antibodies against human CD63 we have shown that high levels of granular secretion from transfected RBL cells can be stimulated by some, but not all, of the antibodies. The specificity of this response suggests that these activating antibodies may be mimicking a natural ligand for CD63. The secretory response to crosslinking of the high affinity IgE receptor and also that to non-receptor stimuli (phorbol ester and calcium ionophore) is inhibited by an antibody that appears to recognise both human and rat homologs of CD63. These results suggest that stimulus-secretion coupling can occur through human CD63 and that RBL cells transfected with this protein will constitute a valuable tool in elucidating its function.

Animals↗
PubMed1995

Identification of multiple transition structures on the potential energy hypersurface for [2+2] electrocyclization of the pentadienyl cation bearing a phosphorus in the 3-position.

Ab initio molecular orbital investigations of the [2+2] electrocyclization of 3-substituted pentadienyl cations, where the substituents are BH2, AlH2, OH, SH, NH2, PH2, or H, show significant substituent effects on the ground state conformations, transition structures, and energies of activation. Locating the transition structure for the cyclization of the PH2-substituted system was particularly troublesome due to the tendency of the phosphorus group to undergo inversion. The AVS Chemistry Viewer, a data flow environment-based application for the analysis, visualization, and animation of molecular modeling results, proved useful in mapping the potential energy hypersurface and understanding the transition structures for this system.

Cations↗