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Vladimir Nigrovic

Publications and source records attributed to Vladimir Nigrovic.

11 recordsLinked to original sources
PubMed2006

Modeling of twitch fade based on slow interaction of nondepolarizing muscle relaxants with the presynaptic receptors.

Nondepolarizing muscle relaxants (MRs) diminish the indirectly evoked single twitch due to their binding to the postsynaptic receptors. Additionally, the MRs produce progressive diminution of successive twitches upon repetitive stimulation (fade). Our study addresses the generation of fade as observed under clinical situation. The study was conducted in two phases. In the clinical part, we have evaluated the time course of twitch depression and fade following the administration of several doses of three MRs (rocuronium, pancuronium, and cisatracurium). In the second part, we have modified our model of neuromuscular transmission to simulate the time course of twitch depression and fade. The MR was assumed to bind to a single site on the presynaptic receptor to produce fade. The rates of interaction with the presynaptic receptors were characterized in terms of the arbitrarily assigned equilibrium dissociation constant and the half-life for dissociation of the presynaptic complex. A method was developed to relate the release of acetylcholine to the occupancy of the presynaptic receptors. The strength of the first and the fourth twitch was calculated from the peak concentration of the activated postsynaptic receptors, i.e., of those receptors with both sites occupied by acetylcholine. Our results indicate that, while the affinity of the MR for the presynaptic receptor plays little role in the time course of fade, the rate of dissociation of the complex between the presynaptic receptors and the muscle relaxant may be critical in determining the time course of fade. Tentative estimates of this parameter are offered.

Acetylcholine↗
PubMed2005

Volume of the effect compartment in simulations of neuromuscular block.

BACKGROUND: The study examines the role of the volume of the effect compartment in simulations of neuromuscular block (NMB) produced by nondepolarizing muscle relaxants. METHODS: The molar amount of the postsynaptic receptors at the motor end plates in muscle was assumed constant; the apparent receptor concentration in the effect compartment is the ratio of this amount and the volume arbitrarily assigned to the effect compartment. The muscle relaxants were postulated to diffuse between the central and the effect compartment and to bind to the postsynaptic receptors. NMB was calculated from the free concentration of the muscle relaxant in the effect compartment. RESULTS: The simulations suggest that the time profiles of NMB and the derived pharmacokinetic and pharmacodynamic variables are dependent on the apparent receptor concentration in the effect compartment. For small, but not for large, volumes, times to peak submaximal NMB are projected to depend on the magnitude of NMB and on the binding affinities. CONCLUSION: An experimental design to estimate the volume of the effect compartment is suggested.

Animals↗
PubMed2005

Myasthenia gravis and myasthenic syndrome: simulation of twitch strength with or without therapy.

To examine the quantitative relationship between indirectly evoked twitch and decreases in the number of either postsynaptic receptors or acetylcholine molecules released by a single stimulus, we studied these variables in a computer-simulated model of neuromuscular transmission. Twitch strength decreased if the number of receptors decreased to below 30% of normal or the number of acetylcholine molecules released by a stimulus decreased to below 80%. Inhibition of acetylcholine hydrolysis to 50% restored twitch strength in the presence of a decreased number of receptors. However, twitch strength was more easily restored to normalcy by augmenting the release of acetylcholine, if the release was diminished by disease. The simulations mimic the clinically known therapeutic outcomes in certain disorders of neuromuscular transmission. These results provide useful quantitative insights into the relationship between acetylcholine receptors or the stimulus-induced release of acetylcholine and muscle function in myasthenia gravis or Lambert-Eaton myasthenic syndrome.

Acetylcholine↗
PubMed2004

Simulation of interaction between two non-depolarizing muscle relaxants: generation of an additive or a supra-additive neuromuscular block.

GOAL: To examine in a model of neuromuscular transmission the interaction between two non-depolarizing muscle relaxants. An additive or a supra-additive interaction was evaluated as a function of the affinities of acetylcholine and the muscle relaxants for the two binding sites at a single receptor. METHODS: Affinity of acetylcholine for site1 was postulated to be higher than for site2. Muscle relaxants may display a similar pattern of affinities, a higher affinity for site2, or the affinities may be identical. Receptors with both sites occupied by acetylcholine are activated and, if their concentration at an end plate surpasses the critical threshold, initiate contraction of the associated muscle fiber. The number of contracting muscle fibers determines twitch strength of the whole muscle. Neuromuscular block (NMB) = 1--twitch. NMB was simulated for muscle relaxants acting as single agents or in three types of combinations. (a) Complementary fractions of equieffective concentrations. (b) Variable combinations of equieffective concentrations producing NMB equal to NMB produced by the single muscle relaxant (isobolographic analysis), and (c) NMB-vs.-concentration relationship of single agents and of their combination in a fixed ratio. RESULTS: Additive interaction was simulated for pairs of muscle relaxants displaying identical ratios of affinities. All other pairs produce a supra-additive interaction, more prominent, the more divergent the patterns of affinities. The slopes of NMB-vs.-concentration curves were steeper for supra-additive combinations than for single agents. CONCLUSION: The simulations define conditions leading to additive or supra-additive interaction and suggest an experimental design suitable to test the results.

Acetylcholine↗
PubMed2004

Analysis of the pharmacodynamic parameters in a model for neuromuscular block.

BACKGROUND: The study examines the roles of the pharmacodynamic parameters and of the assumptions underlying the pharmacokinetic-pharmacodynamic model proposed by Sheiner and coworkers to interpret the time course of neuromuscular block (NMB) produced by nondepolarizing muscle relaxants. MATERIAL/METHODS: The model of Sheiner et al. was modified by considering (a) a multiexponential equation for the time course of the relaxant's concentrations in plasma, (b) the transport of a hypothetical muscle relaxant from plasma to the site of action via diffusion, and (c) NMB as a function of the relaxant's concentration at the site of action, of gamma and IC50. The feasibility of obtaining reliable estimates of the PD parameters was evaluated for either a complete or an incomplete NMB. RESULTS: The results confirmed that reliable estimates of the PD parameters, i.e., of the transport rate constant, gamma, and IC50, may be obtained simultaneously if NMB is incomplete. Estimates of the same parameters obtained from a complete NMB are interdependent and, hence, unreliable. The assumptions in the original model of (i) a negligibly small amount of the relaxant in the effect compartment, (ii) steady state plasma concentration at half-maximal NMB, Cp(ss)(50), and (iii) transport of the muscle relaxant from the effect compartment to "Outside", are neither needed nor are justified. CONCLUSIONS: The model proposed by Sheiner et al. interprets well the time course of an incomplete NMB even without the three assumptions. The simulations suggest methods to verify independently the estimates for the transport rate constant and gamma.

Animals↗
PubMed2003

Competition between acetylcholine and a nondepolarizing muscle relaxant for binding to the postsynaptic receptors at the motor end plate: simulation of twitch strength and neuromuscular block.

UNLABELLED: The goal of the study was to simulate twitch strength and neuromuscular block produced by nondepolarizing muscle relaxants. METHODS: In the proposed model, affinities of the two binding sites at a single postsynaptic receptor for acetylcholine (A) and the muscle relaxant (D) define the formation of three complexes with A only, three complexes with D only, and two complexes with both A and D. Twitch strength was postulated to be a function of the receptors with both binding sites occupied by A, and two constants. Neuromuscular block (NMB) was calculated from NMB = 1-twitch. RESULTS: Stimulus-induced release of A results in rapid, but transient, changes in the concentrations of free A, the eight complexes, and the unoccupied receptors. Muscle relaxants that display either a congruous or an inverse pattern of affinities for the binding sites relative to those of A produce NMB vs. [D] curves with slightly different slopes but markedly different estimates for IC50. Depending on the number of activated receptors at the end plates of muscle fibers, the simulations represent the distributions of contracting fibers in a whole muscle. CONCLUSION: Simulations of competition between A and D for binding to two sites at a receptor reveal that the potencies of muscle relaxants, defined by IC50, and the slopes of the NMB vs. [D] curves depend on (1) the affinities of D for the two binding sites, (2) the orientation of the affinities relative to those of A, and (3) the affinities of A for the same two sites.

Acetylcholine↗
PubMed2002

Physiologic-pharmacologic interpretation of the constants in the Hill equation for neuromuscular block: a hypothesis.

Neuromuscular block (NMB) is simulated in pharmacodynamic models using the concentration of a muscle relaxant (MR) in the effect compartment and two constants, gamma and IC50. No physiologic or pharmacologic interpretation is offered for either constant. We desired to explore whether the constants are properties of the muscle or the MR and to simulate NMB when the MR binds to two sites at a single receptor. Based on steady state conditions, we defined receptor occupancy using the equilibrium dissociation constants. Two concepts are introduced: threshold occupancy and occupancy at half-maximal NMB, Occ(NMB50). Threshold occupancy is defined as receptor occupancy at the motor end plate of a muscle fiber when the fiber fails to contract and Occ(NMB50) as the median threshold occupancy. NMB may be simulated as a function of either the concentration of the muscle relaxant or receptor occupancy. We suggest: (1) The distribution of threshold occupancies is an intrinsic property of a muscle and is characterized by two constants (gamma(o) and Occ(NMB50)); (2) gamma(o) is numerically equal to the slope of the NMB vs. concentration curves and is independent of the equilibrium dissociation constants. IC50 is code termined by Occ(NMB50) and by the equilibrium dissociation constants. (3) Binding of a muscle relaxant to the second binding site influences only the estimate of IC50 but not gamma.

Binding Sites↗