Biomedical subjects

N B Modi

Publications and source records attributed to N B Modi.

35 records · Page 2Linked to original sources

PubMed1996

Pharmacokinetics and pharmacodynamics of TP-9201, a gpIIbIIIa antagonist, administered in combination with recombinant tissue-type plasminogen activator, heparin, and aspirin in beagles.

The effect of heparin, aspirin, and recombinat tissue-type plasminogen activator (rt-PA) on TP-9201 pharmacokinetics and pharmacodynamics was investigated in beagles. Animals received TP-9201, an Arginine-Glycine-Aspartic acid (RGD)-containing synthetic peptide glycoprotein (gp)IIbIIIa antagonist as a bolus of 0.31 mg/kg, followed by a 4-h infusion of 0.5 mg/kg/h. rt-PA was administered as a modification of the weight-adjusted standard regimen. Heparin was administered as a bolus followed by an infusion producing a 1.5- to 2-fold increase in the activated prothromboplastin time (aPTT) above baseline values. Aspirin was administered orally, approximately 24 and 2 h before TP-9201. TP-9201 had a plasma clearance of 9.9 +/- 2 ml/min/kg and a volume of distribution that was larger than plasma volume. Administration of heparin and aspirin with TP-9201 did not affect the clearance of TP-9201, whereas rt-PA resulted in a faster clearance (p = 0.05). Whether the faster clearance is physiologic or a result of rt-PA interference in the TP-9201 assay is unclear. TP-9201 completely inhibited ADP-mediated platelet aggregation. After discontinuation of TP-9201, recovery of platelet aggregation had a half life (t1/2) of 2-3 h and was complete < or = 24 h. Coadministration of heparin did not interfere with TP-9201 pharmacodynamics, whereas aspirin and rt-PA slowed the recovery of platelet aggregation. The template bleeding time profile for the TP-9201-treated animals was similar to that of the aspirin-treated animals.

Animals↗

PubMed1995

Pharmacokinetics and pharmacodynamics of TP-9201, a GPIIbIIIa antagonist, in rats and dogs.

Because activation of the glycoprotein IIbIIIa (GPIIbIIIa) on platelets represents the final common pathway of platelet aggregation, inhibition of fibrinogen binding to the GPIIbIIIa complex provides an excellent target for inhibiting platelet aggregation. Peptides containing the arginine-glycine-aspartic acid (RGD) sequence have been shown to inhibit the binding of fibrinogen to the GPIIbIIIa receptor on platelets competitively. We studied the pharmacokinetics of TP-9201, a synthetic cyclic peptide containing the RGD sequence, in rats and dogs after a 24-h intravenous (I.V.) infusion at three doses. The mean plasma clearance of TP-9201 after intravenous infusions of 30, 150, and 600 mg/kg/day in rats was 20.2, 18.7, and 18.5 ml/min/kg, respectively. In beagles, TP-9201 clearance was 9.0, 7.5, and 7.3 ml/min/kg, corresponding to infusions of 10, 75, and 600 mg/kg/day, respectively. The volume of distribution was larger than plasma volume, and the terminal half-life (t1/2) was short in both species studied ranging from 0.5 to 0.7 h in rats and from 2.5 to 2.6 h in dogs. The results suggest that TP-9201 follows linear pharmacokinetics over the dose range studied. Despite the multiple blood sampling procedure used in the study, there were no hemorrhagic complications. Pharmacodynamic assessment in beagles showed that TP-9201 produces a dose-dependent inhibition of ADP-mediated platelet aggregation. The estimated in vivo IC50 value and sigmoidicity were 124 and 3.5 ng/ml, respectively, suggesting that TP-9201 is a potent GPIIbIIIa antagonist with a steep concentration-effect relationship. TP-9201 is rapidly cleared from the circulation on termination of the intravenous infusion. There is a corresponding reversal of platelet inhibition as TP-9201 is cleared from the circulation.

Analysis of Variance↗

PubMed1994

Application of a variable direction hysteresis minimization approach in describing the central nervous system pharmacodynamic effects of alfentanil in rabbits.

The relationship between the concentration of a drug and its pharmacologic effect is of central interest in pharmacodynamics. Various compartmental and noncompartmental methods have been proposed for elucidating this relationship when the plasma drug concentration and effects are both measured. Although the relationship between drug input and the pharmacologic effect is equally useful, it has not received as much attention. A system analysis hysteresis minimization pharmacodynamic method was developed to describe the central nervous system effects of alfentanil in rabbits. The spectral edge frequency (SEF) was used as the effect measure and the infusion rate as the pharmacokinetic variable. The sigmoid Emax and cubic polynomial representations of the transduction relationship were investigated in modeling the collapsed hysteresis loop. The results indicated that alfentanil has a relatively rapid biophase equilibration time (t50 = 6 min). Both the sigmoid Emax and cubic polynomial transduction relationships were equally effective in describing the observed effect data and gave similar predictions. The proposed approach has the advantage of not assuming a specific compartmental structure for the pharmacokinetic-pharmacodynamic link. A particular advantage of the method is that no functional relationship is assumed a priori for the transduction relationship, and errors in both regression variables are considered in the optimization. The system analysis pharmacodynamic approach assumes linear disposition pharmacokinetics, an instantaneous and time-invariant transduction, and that inductive effects like tolerance or sensitization do not develop significantly in the time frame studied.

Alfentanil↗

PubMed1994

Validation of a variable direction hysteresis minimization pharmacodynamic approach: cardiovascular effects of alfentanil.

An important goal in therapeutics is the quantitative prediction of drug effects. Although several comprehensive pharmacodynamic models have been proposed, relatively few of these have attempted to assess objectively the application of the models to predict pharmacologic responses. A variable-direction hysteresis minimization approach was proposed recently that allowed the pharmacodynamics of drugs to be modeled using information about drug input. The application and validation of this approach are demonstrated using the pharmacodynamic effect of alfentanil, a short-acting narcotic analgesic agent, in New Zealand White rabbits. A parameter is proposed to assess the ability of the pharmacodynamic model to predict responses.

Alfentanil↗

PubMed1994

Phenobarbital removal characteristics of three brands of activated charcoals: a system analysis approach.

The in vivo phenobarbital removal characteristics of three brands of activated charcoal (Actidose, Charcoaid, Superchar) were studied in normal volunteers using a system analysis approach. The subjects received a 200-mg dose of oral or intravenous phenobarbital followed by a single oral dose of 30 g of one of the three charcoals in a randomized crossover design. The relative merits of the three charcoals in enhancing the removal of oral and intravenous phenobarbital were assessed using a system analysis approach. The removal clearance, time to peak (tp), peak removal clearance (Rmax), percentage of dose removed (PCT infinity), and phenobarbital removal clearance (CLr) were calculated for the oral and intravenous treatments. Superchar had a pulse-like effect, with the shortest tp and the largest Rmax. Actidose and Charcoaid had similar effects, with Actidose inducing slightly greater phenobarbital removal. Superchar has the highest surface area and relative percentage of surface hydroxyl groups, whereas Actidose has the lowest surface area and relative percentage of surface hydroxyl groups of the three charcoals studied. Although correlations between the in vitro and the in vivo phenobarbital adsorption characteristics of the three charcoals may be difficult due to the presence of preservatives and palatibility enhancers in the commercial preparations, it appears that the in vivo effectiveness decreases as the surface area and the concentration of surface hydroxyl groups decrease. The proposed system analysis approach requires fewer assumptions than methods based on compartmental or physiologic approaches and has the advantage of describing the phenobarbital removal in a dynamic manner.

Absorption↗

PubMed1994

The pharmacokinetics, tissue localization, and metabolic processing of recombinant human hepatocyte growth factor after intravenous administration in rats.

Hepatocyte growth factor (HGF) is a pluripotent mitogen thought to be involved in liver regeneration. It is synthesized as a single chain promitogen and requires proteolytic processing to a two-chain heterodimeric form for biological activity. The pharmacokinetics and tissue distribution of radioiodinated single chain recombinant human HGF ([125I]rhuHGF) were studied in male Sprague-Dawley rats after an iv bolus dose. Pharmacokinetic parameters were determined from trichloroacetic acid-precipitable radioactivity in serum samples. There was a rapid distribution phase (t1/2 alpha = 3.1 min) and a slower elimination phase (t1/2 beta = 114 min). Tissue distribution was assessed by whole body autoradiography 5, 60, and 1440 min after an iv bolus dose. rhuHGF rapidly distributed to the liver, kidney, adrenal gland, and spleen. The importance of the liver in the rapid clearance and subsequent conversion of single chain pro-rhuHGF to the mitogenically active two-chain form was demonstrated using an isolated rat liver perfusion system. TCA-precipitable radioactivity excreted into the bile (1.0 +/- 0.1%) and released into the venous effluent (38.9 +/- 6.1%) was monitored for 60 min after a portal vein injection. The appearance of radioactivity in both the bile and venous effluent was maximal between 20-35 min. Further characterization of the reduced samples by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography revealed that the two-chain form of [125I]rhuHGF was the predominant form after hepatic perfusion. These studies suggest that the liver plays a major role in the rapid clearance and subsequent activation of pro-rhuHGF in vivo.

Animals↗

PubMed1993

A system approach to pharmacodynamics. Input-effect control system analysis of central nervous system effect of alfentanil.

Virtually all biological variables, including those affected by drugs, are subject to adaptive self regulation. In the description of the pharmacodynamics (PD) of drugs, it may be necessary to consider the endogenous control system (ECS) as an integral part of the PD. A PDECS model based on system analysis principles is presented and tested on PD data for alfentanil considering the central nervous system activity quantified by a power spectrum analysis of the electroencephalogram. The model was tested in terms of a proposed relative prediction performance criterion that measures the accuracy of future predictions relative to how well the model describes (fits) the past effect data. A mean value of 80% (standard deviation, 28) for relative prediction performance indicates that the model performs well when challenged by the complex multiple infusion scheme used in the test. The overshoot phenomenon observed in the data is considered by the PDECS model as a ECS-based tolerance phenomenon. The proposed development of tolerance is modeled as a variable gain in the ECS processing that influences the effect. Although the development and loss of tolerance is determined by a single rate constant in the tolerance model, the rates of increase and decrease of tolerance may be substantially different. Contrary to other PD tolerance models, the proposed PDECS approach models the tolerance in terms of an effect deviation from an ECS set point. The intrinsic (no tolerance) effect of the drug is isolated in terms of an open loop (no feedback) effect.

Alfentanil↗

PubMed1993

Application of a system analysis approach to population pharmacokinetics and pharmacodynamics of nicardipine hydrochloride in healthy males.

Nicardipine hydrochloride, a dihydropyridine calcium channel blocker, possesses antihypertensive and arterial vasodilator properties. A system analysis approach, which makes fewer structural assumptions than compartmental methods, is presented for determining the pharmacokinetics and pharmacodynamics of nicardipine hydrochloride in healthy males following a discontinuous infusion at four dose levels. The results indicate that the average total body clearance of nicardipine is 0.920 L/h/kg and the volume of distribution is 0.275 L/kg. Nicardipine hydrochloride has a mean residence time in the body of 1.27 h, of which 0.324 h were spent in the systemic circulation and the remainder in the periphery. The determined pharmacokinetic model was linked to a pharmacodynamic model that allowed the change in the mean arterial blood pressure and heart rate to be described and predicted. A population pharmacokinetic-pharmacodynamic model was derived and the predictive power of the proposed model was assessed with a cross-validation technique that employs a relative predictive quotient for comparing the predictions to the fitted model. The results indicate that the proposed model describes the pharmacodynamics of nicardipine in healthy males and has good predictive ability when tested with a cross-validation procedure.

Adult↗

PubMed1993

A system approach to pharmacodynamics. Plasma iron mobilization by endogenous erythropoietin in the sheep fetus; evidence of threshold response in spontaneous hypoxemia.

At present, nearly all infants with birth weights of < 1 kg receive blood transfusions for treatment of clinical signs of tissue hypoxia resulting from anemia of prematurity. In contrast to the successful use of recombinant human erythropoietin (rhEp) in adults, treatment of anemic neonates with rhEp to stimulate red cell production and reduce the need for transfusions that pose serious infectious and immunologic risk has not been effective. The present study investigates the pharmacodynamics (PD) of endogenous erythropoietin (Ep) in sheep fetuses to determine possible causes for the poor rhEp response in early development. The dynamic relationship between plasma Ep and plasma iron resulting from spontaneous hypoxemic episodes is investigated by PD system analysis. The erythropoietic effect of Ep is measured in terms of the mobilization of plasma iron needed in the production on new erythrocytes. A hysteresis minimization approach is employed to determine the intrinsic PD dose-response relationship (transduction) of Ep. The dose-response relationship shows a well-defined threshold level that has to be exceeded before Ep begins to show a significant effect on plasma iron. It is postulated that the threshold mechanism may serve a useful purpose during early development by reducing the risk of the fetus developing a pathological degree of polycythemia and hyperviscosity in the relatively hypoxemic fetal environment. At the same time, the threshold serves the purpose of providing a needed response to more severe pathologic hypoxemic episodes. The occurrence of anemia during subsequent postnatal life when PaO2 levels increase markedly may be the inevitable, but unfortunate corollary of a continuation of this mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Application of neural networks to pharmacodynamics.

Neural networks (NN) are computational systems implemented in software or hardware that attempt to simulate the neurological processing abilities of biological systems. A synopsis is presented of the operational characteristics, structures, and applications of NN. The NN technology has primarily been aimed at recognition science (e.g., handwriting, voice, signal, picture, image, pattern, etc.). It is pointed out that NN may also be particularly suitable to deal with pharmacokinetic (PK) and pharmacodynamic (PD) systems, especially in cases such as multivariate PK/PD population kinetics when the systems are so complex that modeling by a conventional structured model building technique is very troublesome. The main practical advantage of NN is the intrinsic ability to closely emulate virtually any multivariate system, including nonlinear systems, independently of structural/physiologic relevance. Thus, NN are most suitable to model the behavior of complex kinetic systems and unsuitable to model the structure. In a practical sense, this structure limitation may be inconsequential because NN in its multivariate formulation may consider any physiologic, clinical, or population variable that may influence the kinetic behavior. The application of NN in PD is demonstrated in terms of the ability of an NN to predict, by extrapolation, the central nervous system (CNS) activity of alfentanil. The drug was infused by a complex computer-controlled infusion scheme over 180 min with simultaneous recording of the CNS effect quantified by a fast Fourier transform power spectrum analysis. The NN was trained to recognize (emulate) the drug input-drug effect behavior of the PD system with the input-effect data for the 180 min as a training set.(ABSTRACT TRUNCATED AT 250 WORDS)

Alfentanil↗

PubMed1992

An algorithm for constrained deconvolution based on reparameterization.

The method of deconvolution is the most general method of evaluating drug absorption. Deconvolution does not normally subscribe to a particular structured model for the input function that would ensure non-negativity of the calculated input rate. Unfortunately, the increased flexibility gained by this "model independence" sometimes results in a calculated input rate that becomes negative in the late absorption phase. A method for constrained deconvolution is proposed to overcome this deficiency. The method is based on a reparameterization of the input function in a "model-free" context. The reparameterization schemes proposed are optimal in the sense that they give the input function its maximum flexibility possible while at the same time ensuring non-negativity. The method makes use of "deconvolution through convolution." The basic procedure of this technique is, during the curve fitting, to iteratively adjust the input function so that when it is convolved with the unit impulse response function it results in a curve that best fits the data from the extravascular administration. Cimetidine data from oral and iv administrations are deconvolved by the proposed method to demonstrate the basic procedures involved. The proposed method is easy to implement since it relies on simple curve-fitting procedures as routinely performed in pharmacokinetics. The procedure can be carried out using any of the many curve-fitting programs available that allow the user to supply the function to be fitted and allow simple bounds to be specified for the fitted parameters. The convolution required by the method can be done analytically using a previously published computer program.

Algorithms↗

PubMed1992

Pharmacodynamic system analysis of the biophase level predictor and the transduction function.

This work deals with the pharmacodynamic problem of relating a drug effect E(t) to an observable pharmacokinetic (PK) predictor variable r(t), which may be a venous and/or arterial drug level, some other PK variable, or a drug infusion scheme. It is proposed that the relationship between E(t) and r(t) may, in many cases, be appropriately modeled as E(t) = N(F(r(t))) [for practical analysis reasons, F(r(t)) is denoted the biophase level, cb(t), the operator F() is accordingly denoted the biophase level predictor (BLP), and N() is denoted the transduction function (TF)]. This work proposes a method for determining the two fundamental components, BLP and TF, that define the E(t)-r(t) relationship. The BLP is determined by a hysteresis minimization (HM) technique with the following features: (1) the method considers errors in both HM variables; (2) the method is suitable for dealing with the important case in which the predictor variable is a drug infusion scheme; (3) the approach is noncompartmental in contrast to the effect-compartment approaches and it does not require a specific structured modeling of the cb(t)-r(t) relationship when dealing with drugs with linear PKs in a general operational sense; and (4) the method makes use of a dimensionless transformation of the hysteresis variable that eliminates numerical scaling problems so that a complex penalty function optimization approach can be avoided. The TF is determined by a cross validation procedure in conjunction with the BLP determined by HM. The method is demonstrated using pharmacodynamic data for several drugs, considering both concentration-based and drug input-based r(t) values. The significance of the information obtained from the determined BLP and TF is discussed, including the concepts of equilibration dynamics and overloading. The limitations and potential problems of the methodology are discussed.

Alfentanil↗

PubMed1992

Neural networks in pharmacodynamic modeling. Is current modeling practice of complex kinetic systems at a dead end?

Neural networks (NN) are computational systems implemented in software or hardware that attempt to simulate the neurological processing abilities of biological systems, in particular the brain. Computational NN are classified as parallel distributed processing systems that for many tasks are recognized to have superior processing capability to the classical sequential Von Neuman computer model. NN are recognized mainly in terms of their adaptive learning and self-organization features and their nonlinear processing capability and are considered most suitable to deal with complex multivariate systems that are poorly understood and difficult to model by classical inductive, logically structured modeling techniques. A NN is applied to demonstrate one of the potentially many applications of NN for modeling complex kinetic systems. The NN was used to predict the effect of alfentanil on the heart rate resulting from a complex infusion scheme applied to six rabbits. Drug input-drug effect data resulting from a repeated, triple infusion rate scheme lasting from 30 to 180 min was used to train the NN to recognize and emulate the input-effect behavior of the system. With the NN memory fixed from the 30- to 180-min learning phase the NN was then tested for its ability to predict the effect resulting from a multiple infusion rate scheme applied in the subsequent 180 to 300 min of the experiment. The NN's ability to emulate the system (30-180 min) was excellent and its predictive extrapolation capability (180-300 min) was very good (mean relative prediction accuracy of 78%). The NN was best in predicting the higher intensity effect and was able to identify and predict an overshoot phenomenon likely caused by a withdrawal effect from acute tolerance. Current modeling philosophy and practice is discussed on the basis of the alternative offered by NN in the modeling of complex kinetic systems. In modeling such systems it is questioned whether traditional modeling practice that insists on structure relevance and conceptually pleasing structures has any practical advantages over the empirical NN approach that largely ignores structure relevance but concentrates on the emulation of the behavior of the kinetic system. The traditional searching for appropriate models of complex kinetic systems is a painstakingly slow process. In contrast, the search for empirical models using NN will continue to improve, limited only by technological advances supporting the very promising NN developments.

Alfentanil↗

PubMed1992

A sensitive and specific erythropoietin immunoprecipitation assay: application to pharmacokinetic studies.

Previous pharmacokinetic studies with radiolabeled erythropoietin have relied on results of nonspecific methods to derive pharmacokinetic parameters. Dependence on nonspecific protein precipitation or total radioactivity may result in falsely high determinations of plasma radiolabeled erythropoietin and erroneous determinations of pharmacokinetic elimination and distribution parameters. In the present study pharmacokinetic parameters were derived by using a specific, sensitive, and reproducible immunoprecipitation assay for biologically active iodine 125-labeled recombinant human erythropoietin (125I-rhEp) and compared with those obtained by using nonspecific protein precipitation with trichloroacetic acid (TCA). Tracer amounts of 125I-rhEp were administered by bolus injection to six newborn lambs. Plasma-precipitable radioactivity assayed by the immunoprecipitation method became progressively lower with time relative to those observed with the TCA method. Pharmacokinetic parameters derived from the immunoprecipitation assay demonstrated significantly more rapid plasma and elimination clearances, shorter terminal half-life, shorter mean body residence time, and shorter distribution time when compared with the TCA assay (p less than 0.01). Volume of distribution was not different. Comparison of immunoprecipitation and TCA assay results from gel permeation fractions of iodinated erythropoietin demonstrated that immunoprecipitation assay results provide a better evaluation of biologically active hormone as determined by comparisons with SDS-PAGE and erythropoietin radioreceptor data. We conclude that 125I-rhEp pharmacokinetic parameters derived by using the immunoprecipitation assay more accurately reflect physiologic conditions than do those derived by using TCA precipitation.

Animals↗

PubMed1992

Developmental differences in erythropoietin pharmacokinetics: increased clearance and distribution in fetal and neonatal sheep.

Although erythropoietin (Ep) is considered the primary hormone responsible for erythrocyte production throughout development, the administration of recombinant human Ep (rhEp) to premature human neonates has, thus far, been ineffective in the prevention and treatment of their anemia. To determine if developmental pharmacokinetic differences might in part be responsible for this lack of efficacy, Ep pharmacokinetic studies were carried out in four groups of sheep: late gestation fetal, neonatal, adult and pregnant. After i.v. bolus injection of tracer amounts of the biologically active [125I]rhEp, plasma [125I]rhEp was measured using a sensitive and specific Ep immunoprecipitation assay. Pharmacokinetic parameters were derived using noncompartmental system analysis. Significantly greater clearances, shorter half-lives, shorter residence times, greater distribution volumes and greater Ep production rates were found in the fetal and neonatal groups compared to pregnant and nonpregnant adults (P less than .01). These developmental differences likely reflect more rapid metabolism and greater distribution of Ep in less mature individuals. As such, they could result in a reduction in Ep's erythropoietic effect similar to that reported in premature infants. We speculate that treatment of anemic premature neonates using rhEp doses shown to be effective in adults may be inadequate.

Animals↗

PubMed1991

Optimal extravascular dosing intervals.

An explicit formula is presented for simple calculations of the dosing time, tau, that results in a steady-state peak-to-trough ratio of 2 in extravascular dosings. Contrary to other formulae presented, the calculations are guaranteed to be well bound in the percentage error (less than 1%) for any parameter value combination. It is shown that the biexponential dosing interval problem can be transformed into a general, dimensionless problem enabling a global error analysis in the approximation. The proposed formula is demonstrated in the calculation of an "optimal" dosing interval for quinidine. An algorithm and FORTRAN computer program OPTAU for exact calculation of tau and dosing simulations is also demonstrated in the quinidine example.

Algorithms↗

PubMedDate not supplied

Dapoxetine, a novel treatment for premature ejaculation, does not have pharmacokinetic interactions with phosphodiesterase-5 inhibitors.

Potential pharmacokinetic interactions between dapoxetine, a serotonin transporter inhibitor developed for the treatment of premature ejaculation (PE), and the phosphodiesterase-5 inhibitors tadalafil and sildenafil, agents used in the treatment of erectile dysfunction (ED), were investigated in an open-label, randomized, crossover study (n=24 men) comparing dapoxetine 60 mg, dapoxetine 60 mg+tadalafil 20 mg, and dapoxetine 60 mg+sildenafil 100 mg. Plasma concentrations of dapoxetine, tadalafil, and sildenafil were determined by liquid chromatography-tandem mass spectrometry. Tadalafil did not affect the pharmacokinetics of dapoxetine, whereas sildenafil increased the dapoxetine AUCinf by 22%; these effects were deemed not clinically important. Dapoxetine did not appear to affect the pharmacokinetics of tadalafil or sildenafil. Most adverse events were mild in nature. Thus, dapoxetine has no clinically important pharmacokinetic interactions with tadalafil or sildenafil, and the combinations are well tolerated.

Adolescent↗