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Biomedical subjects

J S Barrett

Publications and source records attributed to J S Barrett.

At least 37 records · Page 2Linked to original sources
PubMed1997

Postural effects on peritoneal transport and systemic uptake of radiolabeled monoclonal antibodies.

To optimize the regional delivery advantage with i.p. administration of monoclonal antibody (mAb) for radioimmunotherapy, it may be possible to delay the rate and extent of mAb absorption from the peritoneal cavity by simply altering the position of a patient after radioantibody administration. It has been shown that the hydrostatic pressure against the diaphragm plays a major role in the rate of egress of radioantibodies from the peritoneal cavity and that fluid removal from the peritoneal cavity can be altered by posture. The current study examined postural effects in normal rats following the i.p. injection of 125I-5G6.4 murine IgG2a anticarcinoma antibody (45 microCi). A 10-ml injection volume of the radioantibody solution was administered to rats restrained in either a supine or inclined (reverse Trendelenburg; feet down at a 45 degrees angle) position. Pharmacokinetic analysis confirmed that the appearance of the radioantibody into the systemic circulation was delayed in the inclined group. The time to peak blood concentration was prolonged from 14.7 (supine) to 19.2 (inclined) hours (P = 0.005). All other pharmacokinetic parameters were equivalent across the treatment groups. The mean half-life of 166 h, mean blood clearance of 9 ml/min, and mean steady-state volume of distribution of 36 ml were consistent with previous experience with this radioantibody in the rat. The intrinsic absorption profile indicated that the mean percentage absorption from the peritoneal cavity to the blood stream was greater in the supine animals from 4 h after i.p. injection until absorption was complete. By 10 h after injection, absorption from the peritoneal cavity was essentially complete in the supine-dosed animals, while those restrained in an inclined position had cleared only 50% of the total absorbed dose. Hence, the regional delivery advantage afforded by intraperitoneal administration of the radioantibody may be further exploited by maintaining an inclined position throughout the absorption phase, a strategy that may be applicable to radioimmunotherapy of patients.

Animals↗
PubMed1997

Selegiline percutaneous absorption in various species and metabolism by human skin.

PURPOSE: A Selegiline Transdermal System (STS) is under development for indications which may not be optimally or safely treated with oral selegiline. Studies were conducted to evaluate the in vitro penetration and skin metabolism of selegiline in order to better understand the toxicological findings and the observed plasma levels of selegiline and its metabolites in animals and man. METHODS: In vitro penetration studies were conducted in four different species (male hairless mice, male and female rats, female dog and male Micropig) and compared to human skin. In another study, viable human skin was used to estimate the extent of metabolism of selegiline by human skin using Franz diffusion cells. RESULTS: Results indicated that female dog and male Micropig skin were reasonable animal models for 24 hour in vitro selegiline penetration through human skin. Penetration of selegiline through rat skin and hairless mouse skin was 2-fold and 3-fold higher than through human skin, respectively. Metabolism was negligible in human skin. Selegiline metabolites (L-methamphetamine and N-desmethylselegiline but not L-amphetamine) were detected at all time points but the extent of selegiline metabolism was negligible. The cumulative 24 hour in vitro selegiline permeation from a 1.83 mg/cm2 STS through human skin was 5.0 mg. This was similar to the in vivo permeation in humans as assessed by residual patch analysis. CONCLUSIONS: The similarity of dog and human skin permeation results support the use of the dog as a species for evaluating the toxicology of transdermally-administered selegiline. Selegiline is not metabolized cutaneously and hence the metabolic profile following STS administration is likely due to hepatic metabolism only.

Animals↗
PubMed1996

Absorption and presystemic metabolism of selegiline hydrochloride at different regions in the gastrointestinal tract in healthy males.

PURPOSE: The absorption and disposition of selegiline (SEL) and its metabolites N-desmethylselegiline (DMS), L-methamphetamine (MET), and L-amphetamine (AMP) were assessed in 8 healthy male volunteers at proximal and distal regions of the intestine relative to oral administration (in the stomach) to determine if intestinal site dependence contributed to the erratic oral absorption of selegiline hydrochloride which is manifest as low and variable bioavailability. METHODS: An open-label, four-way crossover, single dose pharmacokinetic study comparing the bioavailability of 10 mg selegiline hydrochloride administered to healthy young males as a solution by the oral route (in the stomach) and by a nasoenteric tube to the following three sites: duodenum, jejunum and terminal ileum was conducted. Infusions were administered over a 1 minute interval and a two week washout was observed between treatments. Samples were taken over 96 hours and analyzed by LC/MS/MS. RESULTS: Selegiline exposure was greatest following administration to the stomach (approximately 150% > duodenum or jejunum) and least in the terminal ileum (approximately 33% less than duodenum or jejunum). Duodenal and jejunal sites were equivocal based on selegiline absorption and subsequent metabolism. While both AMP and MET exposure was equivalent at all dosing sites, DMS exposure was less (approximately 18%) at the terminal ileum. CONCLUSIONS: The oral absorption of selegiline is neither permeability-limited or intestinal site-dependent. Stomach absorption may bypass presystemic metabolism. The reduced DMS exposure at the terminal ileum is consistent with the theorized presystemic formation of DMS via luminal P450 enzymes and the density of these enzymes in the duodenum and jejunum relative to the ileum. AMP and MET metabolites were insensitive to dosing site consistent with their hepatic formation. The true magnitude of these effects would require multiple dosing as single dose pharmacokinetics do not predict the extent of multiple dose selegiline exposure.

Administration, Oral↗
PubMed1996

Pharmacokinetics and safety of a selegiline transdermal system relative to single-dose oral administration in the elderly.

This open-label, two-phase cross-over study compared the safety and pharmacokinetics of transdermally administered selegiline and orally administered selegiline hydrochloride in elderly men and women (n = 6/gender). Single oral doses of 10 mg selegiline hydrochloride and single 1/2 and 1 selegiline transdermal system (STS) (delivering similar3.4 and 6.3 mg over 24 h) administered topically were safe and well tolerated in all subjects. Plasma concentrations of selegiline (SEL) and its N-desmethylselegiline (DMS), L-amphetamine (AMP), and L-methamphetamine (MET) metabolites were measured using an HPLC/MS/MS method with lower quantitation limits of 10, 50, 200, and 200 pg/mL, respectively. No significant gender-related differences were observed following single 10-mg oral doses of selegiline hydrochloride or single 24-h applications of 1/2 and 1 STS to elderly males and females. The low level of dermal irritation as assessed by erythema and edema rating scales suggests that the STS was similar to Band-Aid (Johnson & Johnson, Skillman, NJ) controls. The transdermal administration of SEL bypasses the first-pass metabolism, that is significant after oral administration (first-pass extraction >90%). Peak plasma levels of 1.19, 23.22, 4.78, and 14.08 ng/mL were observed for SEL, DMS, AMP, and MET after a single 10-mg oral dose to the elderly. By contrast, peak plasma levels of 2.10, 0.85, 1.06, and 2.71 ng/mL were observed for SEL, DMS, AMP, and MET after a single 24-h application of 1 STS. Comparison of dose-corrected areas under the curve (AUCs) (made under the assumption of linear pharmacokinetics) indicate the SEL exposure after transdermal application was more than 50-fold greater than that obtained orally. This increase in systemic SEL exposure at the expense of metabolite formation that is reduced to <70% of that obtained orally for N-DMS, L-AMP, and L-MET is hypothesized to be of therapeutic value in patients with a variety of neurodegenerative and psychiatric disorders.

Journal Article↗
PubMed1994

Pharmacokinetics and pharmacodynamics of L-703,014, a potent fibrinogen receptor antagonist, after intravenous and oral administration in the dog.

The pharmacokinetics and pharmacodynamics of L-703,014, a fibrinogen receptor antagonist, have been examined in the dog. An analytical method which utilizes methanol precipitation of dog plasma proteins followed by HPLC with an automated column switching technique using the chemical analogue L-704,326 as internal standard was developed for the determination of L-703,014 in dog plasma. The compound was not metabolized in the dog and was eliminated in the kidneys and into bile. Of the administered dose, 68.9 +/- 1.3% (i.v.) and 80.5 +/- 11.9% (p.o.) were recovered in the feces; 20.3 +/- 1.3% (i.v.) and 2.2 +/- 0.2% (p.o.) were recovered in the urine by 72 hr. L-703,014 was 23 +/- 3.4% bound in dog plasma protein and the mean ratio of plasma/whole blood was 1.22 +/- 0.05. The mean terminal half-life was 118 +/- 36 min, the mean steady-state volume of distribution was 0.61 +/- 0.22 L/kg, and the mean plasma clearance was 8 +/- 2 mL/min/kg. Ex vivo platelet aggregation measurements were made by inducing platelet aggregation with 10 micrograms/mL collagen in the presence of 1 microM epinephrine as an agonist. The mean C50 was 44.4 +/- 6.0 ng/mL, and the mean Hill coefficient was 1.5 +/- 0.3. The mean bioavailability was 4.9 +/- 1.4% in dogs administered 2.0 mg/kg (p.o.).

Administration, Oral↗
PubMed1994

NM-Win: a personal computer-based Microsoft Windows front-end to NONMEM IV.

A Microsoft Windows-based front-end, NM-Win, has been written to provide a more user-friendly environment to do nonlinear mixed effect modeling with the NONMEM program. NM-Win utilizes an object-oriented interface design which allows users to view and edit control, PRED, and/or data files using Windows Notepad. In addition, calls made to the Microsoft FORTRAN compiler and linker which generate the final NONMEN executable are performed simply by clicking the "Run NONMEN" button. During the executive step, interactions can be viewed in a window to check the progress of the run. Errors encountered while NONMEN or NM-TRAN is running are brought to a window for ease in debugging. Advanced options allow the user the flexibility of compiling user-written PRED files and creating linker response files. While the PC platform is not optimal for large data set or complex models, it does permit easier debugging and offers multitasking while Windows is running.

Algorithms↗
PubMed1994

Pharmacokinetics and pharmacodynamics of MK-383, a selective non-peptide platelet glycoprotein-IIb/IIIa receptor antagonist, in healthy men.

MK-383 (L-tyrosine, N-(n-butylsulfonyl)-O-[4-butyl(4-piperidinyl)], monohydrochloride monohydrate) is a potent and specific platelet fibrinogen receptor antagonist that may be useful in preventing processes that lead to occlusive thrombus formation in the lumen of the blood vessel. Two placebo-controlled phase I trials were completed in 56 healthy volunteers to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of MK-383 administered as 1- and 4-hour infusions in the presence and absence of aspirin. When administered to healthy male subjects by constant infusions up to 0.4 microgram/kg/min over 1 hour or up to 0.2 microgram/min over 4 hours, it provided a well-tolerated reversible means of inhibiting platelet function. At infusion rates of 0.25 and 0.15 microgram/kg/min for 1 and 4 hours, respectively, MK-383 extended baseline bleeding time by 2.0- to 2.5-fold and inhibited adenosine diphosphate (ADP)-induced platelet aggregation by at least 80%. The pharmacokinetics of MK-383 include a mean plasma clearance of 329 ml/min, steady-state volume of distribution of 76 L, and half-life of 1.6 hours. The percentage of dose excreted in the urine was 37%. Correlations between MK-383 plasma concentration (C) and inhibition of platelet aggregation were examined by fitting with a sigmoid maximum-effect model. The plasma concentration yielding 50% inhibition (C50) for MK-383 in healthy volunteers is approximately 13 ng/ml, with a Hill coefficient > 5. Based on a naive pooled analysis, an exponential empirical model best describes the MK-383 C-extension of template bleeding time (BTE) relationship. The model indicates that the MK-383 plasma concentration necessary to double BTE is approximately 30 ng/ml (i.e., 2.5-fold greater than the C50 for ADP-induced inhibition of platelet aggregation). The pharmacokinetics of MK-383 was unaffected by pretreatment with 325 mg aspirin 1 day before and 1 hour before infusion. Conversely, aspirin pretreatment reduced C50 and increased bleeding time extension, suggesting that aspirin may have an additive effect with respect to inhibition of platelet function. Based on the putative role of the fibrinogen receptor in thrombotic processes and an acceptable human pharmacokinetic-pharmacodynamic profile, MK-383 should be evaluated in patients with unstable angina.

Analysis of Variance↗
PubMed1993

NONMEM version III implementation on a VAX 9000: a DCL procedure for single-step execution and the unrealized advantage of a vectorizing FORTRAN compiler.

There is great interest within the FDA, academia, and the pharmaceutical industry to provide more detailed information about the time course of drug concentration and effect in subjects receiving a drug as part of their overall therapy. Advocates of this effort expect the eventual goal of these endeavors to provide labeling which reflects the experience of drug administration to the entire population of potential recipients. The set of techniques which have been thus far applied to this task has been defined as population approach methodologies. While a consensus view on the usefulness of these techniques is not likely to be formed in the near future, most pharmaceutical companies or individuals who provide kinetic/dynamic support for drug development programs are investigating population approach methods. A major setback in this investigation has been the shortage of computational tools to analyze population data. One such algorithm, NONMEM, supplied by the NONMEM Project Group of the University of California, San Francisco has been widely used and remains the most accessible computational tool to date. The program is distributed to users as FORTRAN 77 source code with instructions for platform customization. Given the memory and compiler requirements of this algorithm and the intensive matrix manipulation required for run convergence and parameter estimation, this program's performance is largely determined by the platform and the FORTRAN compiler used to create the NONMEM executable. Benchmark testing on a VAX 9000 with Digital's FORTRAN (v. 1.2) compiler suggests that this is an acceptable platform. Due to excessive branching within the loops of the NONMEM source code, the vector processing capabilities of the KV900-AA vector processor actually decrease performance. A DCL procedure is given to provide single step execution of this algorithm.

Algorithms↗
PubMed1993

Growth hormone response in man to L-692,429, a novel nonpeptide mimic of growth hormone-releasing peptide-6.

L-692,429, a substituted benzolactam, is a novel nonpeptide mimic of the GH secretagogue, GH-releasing peptide-6. The safety and GH secretory activity of L-692,429 (0.001-1.0 mg/kg, i.v.) were investigated in 24 healthy nonobese young (18-26 yr old) male volunteers who demonstrated a GH response of 7 micrograms/L or more after 1 microgram/kg, i.v. GH-releasing hormone [GH-releasing hormone-(1-29)NH2]. L-692,429 was administered as a 15-min iv infusion in an incremental dose, double blind, placebo-controlled, alternating panel fashion to 3 panels of 8 subjects each. Dose-dependent GH secretion was observed with a threshold dose of 0.05 mg/kg (4 of 6 subjects responded with peak GH > 7 micrograms/L), and 0.2 mg/kg produced a response in all 14 subjects tested (mean +/- SE peak GH, 41.0 +/- 6.3 micrograms/L). The maximum dose of 1.0 mg/kg L-692,429 resulted in a pronounced GH response (peak GH, 82.5 +/- 14.9 micrograms/L; n = 8). The GH peak was seen 30-45 min after initiation of the infusion. Small transient increases in cortical and PRL were observed (increases in cortical averaged 182.1 +/- 33.1 nmol/L and peak PRL was 21 +/- 2.6 micrograms/L after 1.0 mg/kg L-692,429, respectively), whereas no significant changes occurred in LH, FSH, TSH, insulin, or glucose concentrations. Plasma pharmacokinetic analysis revealed dose-related increases in plasma concentrations of L-692,429 and a half-life of 3.8 +/- 0.2 (+/- SE) h, a plasma clearance of 214 +/- 67 mL/min, and a steady state volume of distribution of 14.2 +/- 4.8 L. Facial flushing or a warm sensation were reported in 4 subjects, primarily at dose levels of 0.2 mg/kg L-692,429 or more, but no other clinical or laboratory adverse experiences appeared related to drug treatment. L-692,429, synthesized as a specific nonpeptide mimic of GH-releasing peptide-6, is thus a well tolerated, highly effective, and selective GH secretagogue in man.

Adolescent↗
PubMed1992

Vampire bat salivary plasminogen activator promotes rapid and sustained reperfusion without concomitant systemic plasminogen activation in a canine model of arterial thrombosis.

The efficacy of recombinant vampire bat salivary plasminogen activator (bat-PA) as a thrombolytic agent was compared with that of human tissue-type plasminogen activator (t-PA) in a canine model of arterial thrombosis. An occlusive thrombus was formed in the femoral artery by insertion of a thrombogenic copper coil; femoral arterial blood flow was monitored with a Doppler flow meter. Bat-PA and t-PA, when administered by 5-minute intravenous infusion (14 nmol/kg), reperfused seven out of eight and four out of eight dogs, respectively. The median reperfusion times in the bat-PA and t-PA groups were 24 and greater than or equal to 131 minutes, respectively. The mean reperfusion times (+/- SEM) in the recanalized bat-PA- and t-PA-treated dogs were similar (20 +/- 5 and 11 +/- 2 minutes, respectively, p = NS). Maximal blood flow after reperfusion was greater with bat-PA than with t-PA (80 +/- 10% and 41 +/- 15% of control flow, respectively, p less than 0.05). Furthermore, the median reocclusion time was markedly delayed in the bat-PA group relative to the t-PA group (131 versus 34 minutes, respectively, p less than 0.05). Plasma fibrinogen and plasminogen were not significantly depleted by the administration of t-PA or bat-PA. However, plasma alpha 2-antiplasmin activity was moderately depressed in the t-PA group relative to the bat-PA group (p less than 0.05). The clearance profile for t-PA was monoexponential, with a half-life (t1/2) of 2.4 +/- 0.3 minutes and a mean residence time of 3.5 +/- 0.4 minutes. The clearance profile for bat-PA was biexponential, with a t1/2 alpha of 0.9 +/- 0.2 minutes, a t1/2 beta of 20.2 +/- 2.7 minutes, and a mean residence time of 21.3 +/- 4.3 minutes. The steady-state volume of distribution displayed by bat-PA was 16-fold greater than that of t-PA. Zymography of serial plasma samples from the bat-PA-treated dogs failed to demonstrate the apparent generation of a complex between bat-PA and plasminogen activator inhibitor-1; the corresponding complex with t-PA was observed in plasma samples from the t-PA-treated dogs. The sustained recanalization and improved blood flow in the bat-PA group relative to the t-PA group and the avoidance of fibrinogenolysis by bat-PA, despite its prolonged mean residence time, suggest that bat-PA may be superior to t-PA as a thrombolytic agent.

Animals↗
PubMed1991

Effect of intraperitoneal injection volume and antibody protein dose on the pharmacokinetics of intraperitoneally administered IgG2a kappa murine monoclonal antibody in the rat.

The i.p. route of antibody administration offers a regional delivery advantage to the peritoneal cavity. In an effort to optimize this method of delivery, the volume of i.p. injection and total protein dose were examined for their effect on the absorption and disposition of an IgG2a kappa murine monoclonal antibody. 5G6.4, administered i.p. Normal rats (Sprague-Dawley) were given one of two protein doses (1-2 or 100 micrograms) of 125I-5G6.4 in a 2.0-ml i.p. injection volume. In both cases the same radiation dose (approximately 20 mu Ci/rat) was administered since only the tracer level (1-2 micrograms) was labeled. Hence, the 100-micrograms dose consisted of approximately 2 micrograms of labeled antibody with 98 micrograms of unlabeled antibody. In a separate experiment, two i.p. injection volumes (2.0 or 20.0 ml) of 125I-5G6.4 (approximately 20 mu Ci/rat) were administered to normal Sprague-Dawley rats. Pharmacokinetic modeling of the whole blood radioactivity levels was undertaken for both groups. The liver, kidney, muscle, lung, diaphragm, and anterior mediastinal lymph nodes were excised upon sacrifice and tissue levels at sacrifice were recorded. The volume of i.p. injection is shown to be a significant factor with respect to i.p. transport. Maximum concentration in the blood, Cmax, was reduced (P less than 0.1) and time of maximum concentration, tCmax was prolonged (P less than 0.05) from 8.4 h (in the 2-ml group) to 14.5 h (in the 20-ml group). Both contribute to a modest reduction in AUC(0----infinity) (P less than 0.15) in which AUC is the area under the concentration-time curve. The increase in blood clearance, Clb, at the higher injection volume (0.287 ml/h for the 20-ml volume and 0.194 ml/h for the 2-ml volume) is presumably due to increased diuresis resulting from autoregulation of fluid removal via lymphatic drainage. Volume of distribution, Vd, is increased since Vd and Clb are functionally proportionate and elimination is assumed constant. Tissue levels at sacrifice, except for the thyroid and anterior mediastinal lymph nodes, were the same. Mean thyroid levels were reduced in the 20-ml group (P less than 0.05) by 22.5%, likely as a result of increased diuresis. Increased nodal uptake (P less than 0.01) can be attributed to the dilution effect of the bolus injection. The rate of mass transfer is greater for the 2-ml group up to 4 h postinjection. Subsequently, the mass transfer rate is greater for the 20-ml group.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Investigations into the route of uptake and pharmacokinetics of intraperitoneally-administered monoclonal antibodies: I. Transdiaphragmatic blockade of the terminal lymphatics in the rat.

Recent studies on the intraperitoneal administration of radiolabeled monoclonal antibodies indicate that the diaphragm and, in particular, the lymphatics associated with the diaphragm are more involved in the transport of such high-molecular-mass moieties than was earlier suspected. The current study examines the role of the diaphragm in the i.p. transport of an IgG2a murine monoclonal antibody, 5G6.4, by observing the effect on the absorption of the antibody produced when the diaphragm has been scarred. Normal, sham-operated, and diaphragmatically scarred (abrasions made with 600-grade sandpaper) female Sprague Dawley rats (150-250 g) were administered intraperitoneal injections of 125labeled 5G6.4 in a volume of 2.0 cm3. Approximately 5 micrograms antibody protein was administered in the individual 19-microCi injections per rat. Scarring was effective in partially blocking the amount of labeled antibody that crossed the diaphragm. Mean diaphragm levels (% injected dose/g) of 125I-labeled 5G6.4 from the scarred group were 16.8% lower than values from the sham-operated rats and 37.2% lower than those from the control rats. The blockade was effective in slowing the appearance of the labeled antibody in the systemic circulation. The half-time to absorption was significantly prolonged in the scarred group; mean t1/2 absorption values of 2.5 h for the control group, 5.3 h for the sham-operated group, and 9.6 h for the diaphragmatically blocked group were recorded. Scarring the diaphragm reduced the mean maximum blood concentration by 27.6% over the control group and 23.9% over the sham-operated group. The mean time to maximum blood concentration was lengthened by 93..0% over the control group and 35.3% over the sham-operated group due as a result of scarification. Presumably this impedence to absorption would increase the time that the radiolabeled antibody bathed the peritoneal space. The scarred group also had the largest "system mean residence time" (162.5 h) compared to the sham-operated (147.9 h) and control (118.7 h) groups. These values further verify the effect of surgery on the kinetics of the i.p. administered radiolabeled monoclonals. This work demonstrates that scarifying the diaphragm does alter the kinetics of the i.p. administered monoclonal antibodies and supports the concept that transdiaphragmatic lymphatic absorption is an important route of antibody clearance from the peritoneal cavity.

Absorption↗
PubMed1978

Magnetic property of the nerve.

An electromagnet of inhomogeneous magneticfield has been used to measure the magnetic susceptibility of the frog's nerve. Specimen of frog sciatic nerve were attached to a thin tungsten wire hanging into the inhomogeneous magnetic field, and from the deviation of this pendulum from the perpendicular position the magnetic susceptibility of the nerve has been determined to be -0.8 . 10(-6) cm3g-1 in a good agreement with the known magnetic property of the constituents of the nerve.

Animals↗