PubMed Health⌕ Search

Biomedical subjects

S Melethil

Publications and source records attributed to S Melethil.

At least 19 recordsLinked to original sources
PubMed2000

Pharmacodynamics of warfarin in cats.

The overall purpose of this study was to evaluate the pharmacodynamic response to warfarin in cats. The specific aim was to determine if a log-linear indirect response model (Nagashima et al., 1969) used to describe the in vivo effect of warfarin in humans could be applied to cats. The pharmacokinetics of racemic warfarin were described using a non-compartmental approach. The relationship between prothrombin complex activity (PCA) and normalized prothrombin time (PTR) was defined for feline plasma under our experimental conditions, and determined to be: %PCA=12.38+648 e-PTR/0.492. These data were then integrated and used to predict the warfarin dose associated with therapeutic anti-coagulation defined as an International Normalized Ratio (INR) of 2.0-3.0. The maximum prothrombinopenic response to warfarin in cats after a single intravenous dose of 0.5 mg/kg occurred at 24-48 h. Pharmacodynamic modeling suggested that each cat had a narrow therapeutic range of the steady-state concentration of total warfarin required to appropriately block prothrombin complex synthesis (median: 265.2-358.7 ng/mL). The median daily dose range predicted to yield therapeutic concentrations of warfarin was 0.061-0.088 mg/kg per day. Wide inter-individual variations in both pharmacokinetics and pharmacodynamic response suggest that a more optimal dosing of warfarin may be possible with the development of individual pharmacokinetic/pharmacodynamic algorithms, analogous to those currently employed in human patients.

Animals↗
PubMed1996

Aluminum toxicokinetics.

In this study of the toxicokinetics of aluminum we have examined some of the fundamental issues that currently define our understanding of the toxicology of aluminum in humans. There is a vast literature on this subject, and it was not our aim to review this literature but to use it to develop our understanding of the toxicokinetics of aluminum and to identify critical and unresolved issues related to its toxicity. In undertaking this task we have chosen to define the term toxicokinetics to encompass those factors that influence both the lability of aluminum in a body and the sites at which aluminum is known to accumulate, with or without consequent biological effect. We have approached our objective from the classical pharmacological approach of ADME: the absorption, distribution, metabolism, and excretion of aluminum. This approach was successful in identifying several key deficits in our understanding of aluminum toxicokinetics. For example, we need to determine the mechanisms by which aluminum crosses epithelia, such as those of the gastrointestinal tract and the central nervous system, and how these mechanisms influence both the subsequent transport and fate of the absorbed aluminum and the concomitant nature and severity of the biological response to the accumulation of aluminum. Our hope in highlighting these unresolved issues (summarized in Table 1) is that they will be addressed in future research.

Absorption↗
PubMed1996

Standardization in biological analyses of aluminum: what are the needs?

A review of the literature of aluminum (Al) levels in biological samples, particularly Alzheimer's disease (AD) brain, reveals a lack of interlaboratory agreement at both the bulk and microprobe levels. One possible reason for this controversy may be the methods chosen for quantitation and standardization. Currently, the major problem affecting quantitation of Al at the bulk level is the lack of low-Al-concentration, matrix-matched certified standards. Although a number of certified aluminum bulk standards are available, most do not match well in matrix with the samples of interest. A similar situation exists for micro-probe standards in which commercially available pure metal foils and thin films of materials, such as metal oxides, are available but again do not match well in matrix. A review of the current status of quantitation of Al levels in biological analyses at the bulk and microprobe level is presented. Future directions to develop standards include the submission of currently used microprobe standards to a central laboratory for critical analysis and selection of the optimum standard, followed by establishment of interlaboratory and intertechnique comparisons. Other future directions include the adaptation of a standard protocol for the selection of tissue for analysis and criteria for data rejection, as well as the development of a standard system for data normalization and reporting.

Aluminum↗
PubMed1995

Effect of aging on the kinetics of blood-brain barrier uptake of tryptophan in rats.

PURPOSE: The purpose of this investigation was to examine the effect of aging on the blood-brain barrier (BBB) transport of tryptophan. METHODS: A well established in-situ brain perfusion technique was used to examine brain uptake of 14C-tryptophan in 2-, 12- and 24-month old Sprague-Dawley rats; perfusate tryptophan concentrations ranged from 0.00175 to 2 mM. Uptake data were modeled using non-linear regression analysis. RESULTS: Permeability-surface area product (PA) for tryptophan was significantly lower in 12- and 24-month old rats, as compared to the 2-month old animals. A transport model consisting of both saturable (Michaelis-Menten type) and non-saturable components best described brain uptake of tryptophan in all 3 age groups. However, age-dependent differences in BBB transport parameters of tryptophan were observed. For the saturable component, both Vmax and Km were significantly lower in the 12- and 24-month old rats, as compared to the youngest group of rats. These results suggest that transporter mobility, number and affinity for tryptophan are altered in older rats. Values for Kd, the rate constant for non-saturable brain tryptophan transport, were also significantly lower in animals of the two older age groups. Interestingly, PA values for thiourea, a compound believed to be transporter across BBB by diffusion, were also lower in these two age groups. CONCLUSIONS: Aging decreases the ability of the BBB to transport the neutral amino acid tryptophan.

Aging↗
PubMed1994

Evaluation of hepatic metabolism of salicylic acid in perfused rat liver.

Hepatic metabolism of salicylic acid was studied using a single-pass liver perfusion technique. Livers obtained from male, Sprague-Dawley rats (200-300 g) were perfused with Krebs-Henseleit bicarbonate buffer containing the drug (50-100 micrograms/mL) and glycine (0.5 or 5 mM) or glucose (5.5 mM) or bovine serum albumin (0.33%). Effluent samples over a 30-50 min interval were analyzed for salicylic acid and its metabolites (gentisic acid, salicyluric acid, and salicyl acyl and salicyl phenolic glucuronides). Effluent concentrations of salicylic acid did not differ from those in the perfusate, indicating that the liver is not a site for the metabolism of this drug. Hepatic uptake studies are needed to confirm this finding.

Animals↗
PubMed1993

Increased blood-brain barrier permeability of amino acids in chronic hypertension.

A previous communication from this laboratory reported that brain uptake of libenzapril, a small polar molecule, was enhanced in chronic hypertension (1). The objective of this investigation was to determine if this was a more generalized phenomenon. Therefore, experiments were undertaken to examine the effect of chronic hypertension on the brain uptake of tryptophan (an amino acid with high brain permeability) and glutamic acid (one with low permeability). Brain concentrations of these two amino acids were 5- to 12-fold greater in chronic hypertensive rats, as compared to normotensive rats; the corresponding brain uptake index (BUI) values were 2- to 5-fold higher in the former group. Since blood-brain barrier transport of amino acids involve both saturable (carrier) and non-saturable (most likely, diffusion via pores) mechanisms, data from this study show that hypertension can enhance BBB transport of amino acids by affecting one or both of these pathways.

Animals↗
PubMed1992

Kinetics of aluminum in rats. III: Effect of route of administration.

Male Fischer rats received 0.1 mg/kg (bolus) of elemental aluminum as the sulfate salt via the portal (n = 4) or systemic (n = 4) route of administration. Blood and bile were serially sampled over an 8-h period, postadministration. Aluminum was determined by flameless atomic absorption spectrophotometry. Blood aluminum concentrations declined in a monoexponential fashion, with half-lives of 0.7 h (portal) and 1.08 h (systemic) (p less than 0.05). The corresponding systemic clearances were 48.9 +/- 10.6 and 35.1 +/- 3.64 mL/(h.kg) (p less than 0.05). The systemic availability following portal administration was 0.66, indicating a significant "first-pass" effect. Biliary aluminum recovery (% dose) was negligible following both routes [0.83 +/- 0.062% (portal) versus 1.3 +/- 0.22% (systemic), p less than 0.05]. Bile flow decreased approximately 40% (p less than 0.05) immediately upon injection of aluminum via the portal route only; flow remained suppressed throughout the study. This decrease in bile flow was most likely responsible for the lower biliary recovery with this route. In contrast, liver recovery of aluminum at 8-h postadministration was higher with the portal route (65.4 +/- 4.1 versus 39.4 +/- 2.52%). These results show that reported values for oral "bioavailability" of aluminum, often calculated by the standard AUC ratio method, underestimate the true extent of absorption. One mechanism of aluminum-related jaundice observed clinically may be due to cholestasis.

Aluminum↗
PubMed1992

Aluminum-induced acute cholinergic neurotoxicity in rat.

In the present study the acute effect of intravenous aluminum chloride (1 mg/kg) on choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities of rats was investigated. Aluminum was found to cross the blood-brain barrier (BBB) as indicated by the detection of aluminum in the cerebrospinal fluid (CSF) 30 min after femoral vein injection. Two hours following aluminum injection, ChAT activity in the basal forebrain and hippocampus was significantly reduced by 30% and 22%, respectively, whereas no change was observed in the caudate nuclei. On the other hand, AChE activity was significantly increased by 45% in the caudate nuclei, whereas little change was observed in other brain areas. This report demonstrates that rapid transport of Al across the BBB, and the acute nature of Al neurotoxicity in rats.

Acetylcholinesterase↗
PubMed1992

Kinetics of aluminum in rats. IV: Blood and cerebrospinal fluid kinetics.

Aluminum causes central nervous system (CNS) toxicities in both humans and various animal species. Although blood aluminum concentrations are monitored in the clinic, very little is known regarding the relationship between such concentrations and corresponding CNS aluminum content. As a first step in that direction, this study was undertaken to simultaneously determine blood and CSF kinetics of this element. Following intravenous injection of aluminum (1 mg/kg), there was a rapid (within 30 min, post injection) increase in CSF aluminum; peak concentrations (38-45 ng/ml) were achieved between 2-3 h. While peak blood aluminum concentrations increased about 58-fold from the pre-dose value (from 256 +/- 120 to 14,730 +/- 388 ng/ml), corresponding increases in CSF aluminum were only about 20-fold. Blood and CSF aluminum concentrations declined monoexponentially with half-lives of 2.77 and 3.45 h, respectively (P < 0.05). Results from these showed that blood and CSF compartments achieve equilibrium and indicated the feasibility of determining brain aluminum content using blood concentrations.

Aluminum↗
PubMed1992

Effect of chronic hypertension on the blood-brain barrier permeability of libenzapril.

Very little information is available on the permeability of the blood-brain barrier (BBB) to small polar drugs in chronic hypertension. The blood and cerebrospinal fluid (CSF) pharmacokinetics of libenzapril (LZP), a potent angiotensin converting enzyme inhibitor, were investigated in hypertensive (SH) and normotensive (SD) rats. Following intravenous bolus administration of this hydrophilic drug, the terminal rate constant for elimination (beta), steady-state volume of distribution (Vdss), and systemic clearance (CL) were similar in these two animal groups. Other pharmacokinetic parameters (Cpo, alpha, k12, and k21) were significantly (P less than 0.05) greater in the hypertensive group, except for the volume of the central compartment (Vc) and ratio of Vc to Vdss, which were smaller in SH rats. The ratio of area under the concentration-time curve (AUC) in CSF to blood was about twofold higher in SH rats compared to normotensive rats, showing increased BBB permeability in hypertensive rats. An acute brain uptake study was also performed in SH, SD, and WK rats by intracarotid administration of 14C-LZP along with 3H2O as a reference marker. Both LZP and water transport was found to be significantly higher (about two- to five-fold) in six of the seven different brain regions in SH rats as compared to the normotensive (SD and WK) controls. Because of this simultaneous increase in concentrations of both the drug and the reference marker, BUI values were not affected. Regional brain concentrations in SH rats were also linearly correlated with the mean arterial pressure (MAP) values, providing further evidence of the systemic pressure related increase in BBB permeability.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Kinetics of aluminum in rats. II: Dose-dependent urinary and biliary excretion.

Previous iv studies from our laboratories have shown that the disappearance half-life of blood aluminum increased with dose. Experiments were initiated to determine if saturation of biliary and/or urinary excretion could be responsible for this dose-dependent behavior. Biliary aluminum excretion (0-12 h) accounted for less than 1% of the injected amount at 0.1- and 1.0-mg/kg doses. During the same interval, urinary excretion accounted for 16.7 +/- 2.66 and 8.85 +/- 2.2% of administered dose at the low and high doses, respectively (p less than 0.05); corresponding long term (0 to 13 or 22 days) urinary recoveries were 37.6 +/- 3.67 and 28.4 +/- 1.88% of the injected dose (p less than 0.05), with most (66-70%) of the excretion occurring in the first 24 h. This is consistent with many previous reports showing that urinary excretion is one major elimination pathway for aluminum. Both biliary and urinary clearances decreased with increasing blood aluminum concentration; the biliary and urinary clearance values at low concentrations (500-900 ng/mL) were approximately four- and threefold higher than the corresponding values at higher concentrations (10,000-12,000 ng/mL), respectively. It appears that this apparent saturability of biliary clearance may be due to concentration-dependent of transfer from blood to liver, rather than from liver to bile. In vitro ultrafiltration studies support the hypothesis that decreases in urinary clearance were due to decreased filterability of aluminum at the glomerulus as its blood concentration was increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Aluminum↗
PubMed1991

The pharmacokinetics of aspirin in rats and the effect of buffer.

Aspirin (acetylsalicyclic acid) was administered to rats intravenously, orally, and intraintestinally at different doses or in different dosage forms. The distribution and elimination kinetics of aspirin in rats following intravenous administration were best described by a two-compartmental open system and were dose independent up to 15 mg/kg. The terminal elimination half-life following intravenous dosing (10 mg/kg) was 3.36 +/- 0.85 min (n = 15) with the clearance being 8.40 +/- 1.24 L/(kg.hr). Intravenous distribution and elimination kinetics of aspirin in rats were not influenced by an orally administered buffered solution with a buffer capacity of 0.933 mEq ANC (acid neutralizing capacity) per kg of body weight. However, this orally buffered solution did change the gastrointestinal absorption kinetics of aspirin in rats. The absolute bioavailable dose of aspirin was 56.6 +/- 10.4% (n = 6) following its administration in an unbuffered solution while it was only 31.8 +/- 8.0% (n = 6) following administration in the buffered solution. The corresponding values of the absolute bioavailable doses were 43.4 +/- 3.7% and 25.5 +/- 1.8% following intraintestinal administration. The lower systemic availability of aspirin in the presence of buffer is attributed to a greater fraction of the administered dose becoming available for absorption from the intestine where the extraction efficiency is higher than that in the stomach.

Administration, Oral↗
PubMed1990

Simultaneous sampling of blood, bile, and urine in rats for pharmacokinetic studies.

A method for simultaneous serial sampling of blood, bile, and urine from rats is described. Techniques for cannulation of jugular and femoral veins, bile duct, and bladder are described that make serial sampling of these three fluids possible. A saline infusion regimen was developed that prevents dehydration and maintains constant hematocrit values throughout the experiment. Accuracy of timed-samples can be easily controlled along with complete collection of voided urine. This method also allows for economy in terms of cost (number of animals used) and time in pharmacokinetic investigations involving the rat where extensive sampling of blood, bile, and urine are needed. In addition, interanimal variability, which can be quite high in such studies, is avoided by sampling all these three fluids in a single rat. While the kinetic parameters of blood aluminum obtained from this anesthetized animal model compare well with those in unanesthetized rats reported from this laboratory, this method is most useful for comparative studies.

Aluminum↗
PubMed1990

Evaluation of the interaction of lithium and alprazolam.

A potential pharmacokinetic interaction between lithium and alprazolam was studied in 10 normal subjects. Pharmacokinetic parameters were determined from the following regimens: single-dose alprazolam, multiple-dose lithium, and multiple-dose alprazolam with lithium. Steady-state alprazolam clearance during multiple dosing with lithium was not different from that with the single dose of alprazolam. Lithium renal clearance decreased when it was coadministered with alprazolam (31.2 vs. 22.4 ml/minute, p less than 0.05). There was a small but significant increase in the steady-state area under the curve for lithium in the presence of alprazolam (10.3 vs. 11.1 mEq/hour/liter). The small increase in the serum lithium concentrations and decrease in lithium renal clearance was probably the result of lower urine flow rates (1.46 vs. 0.98 ml/minute, p less than 0.05) with the combination of the drugs. This is supported by a weak but significant linear relationship between urine flow rates and lithium renal clearance (N = 57, r = 0.353, p = 0.007). The percent of daily lithium dose recovered at steady-state from the 24-hour urine collection decreased significantly from 93.6% to 78.2% in the presence of alprazolam. This suggests that alprazolam may decrease lithium absorption. The results of this study do not support a definitive interaction of lithium and alprazolam and there is little clinical significance to the small rise in serum lithium concentrations.

Adult↗
PubMed1990

Mechanism of aluminum-induced inhibition of hepatic glycolysis: inactivation of phosphofructokinase.

Aluminum, an abundant element in the earth's crust, has been implicated in various pathological disorders and low concentrations of this element have recently been shown to inhibit brain glycolysis. However, despite the fact that aluminum accumulates in high concentrations in the liver, potential effects of this metal on hepatic intermediary metabolism have not been explored. In perfused livers from untreated rats, maximal rates of production of lactate plus pyruvate (glycolysis) were 93 +/- 15 mumols/g/hr. Glycolysis was severely inhibited in livers from aluminum-treated rats (0.5 mg/kg, 6 hr before experiment) with maximal rates of only 23 +/- 4 mumols/g/hr. In contrast, glucose production (glycogenolysis) and hepatic oxygen uptake were not altered significantly by prior treatment with aluminum. In livers from fasted rats, pretreatment with aluminum did not influence gluconeogenesis or production of lactate and pyruvate from fructose (5 mM). This finding indicates that pyruvate kinase is not inhibited by aluminum and implicates phosphofructokinase, hexokinase and/or glucokinase as sites for the inhibitory effect of aluminum on glycolysis. In liver homogenates from untreated rats, increasing concentrations of aluminum did not show any appreciable effect on hexokinase or glucokinase activity but did cause progressive decreases in phosphofructokinase activity. Therefore, aluminum-induced inhibition of liver phosphofructokinase, an important control site in the glycolytic pathway, is most likely responsible for aluminum-induced inhibition of hepatic glycolysis.

Adenosine Triphosphate↗
PubMed1989

Kinetics of aluminum in rats I: Dose-dependent elimination from blood after intravenous administration.

Aluminum (Al) kinetics after intravenous bolus administration were studied in the rat. The animals received either 0.1 or 1.0 mg/kg (n = 6 at each dose) of elemental Al as the sulfate salt. The Al content of serial blood samples was determined by flameless atomic absorption spectrophotometry. Blood and plasma Al-time profiles after both doses were monoexponential in most cases. Increasing the administered dose increased the elimination half-life (mean +/- SD) from 1.20 +/- 0.25 to 2.41 +/- 0.26 h. A corresponding decrease in systemic clearance was observed (49.6 +/- 11.0 to 18.4 +/- 4.6 mL/kg.h). Both changes were significant (p less than 0.05). Significant differences were also observed in the volume of distribution, the values of which were 78.3 +/- 17.2 and 58.9 +/- 8.5 mL/kg at the low and high doses, respectively. At both doses, blood:plasma ratios ranged from 0.8 to 1.0, indicating considerable uptake/binding of the element by blood cells.

Aluminum↗
PubMed1987

Elevation of serum aluminum in humans on a two-day sucralfate regimen.

Serum aluminum concentrations were determined in ten healthy subjects treated with phenytoin 500 mg and with sucralfate and phenytoin in a crossover fashion. Each subject received four 1,000-mg sucralfate tablets between 8 AM and 10 PM one day before the study, and this was repeated during the study day. A total of eight doses of sucralfate was administered over the two-day period. Serum samples were drawn at 0, 2, 4, 8, 12, 24, 32, and 48 hours after administration. The areas under the serum aluminum concentration-time curves before and after sucralfate (mean +/- SD) were 496.0 +/- 80.9 and 770.9 +/- 146.6 hr-ng/mL, respectively. This increase is statistically significant (P less than .01), indicating that serum aluminum levels are elevated even after two days of treatment with sucralfate. The results from this study are not in agreement with the only other report on this subject.

Adult↗