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T Iga

Publications and source records attributed to T Iga.

At least 19 recordsLinked to original sources
PubMed1997

Determination of erythromycin concentrations in rat plasma and liver by high-performance liquid chromatography with amperometric detection.

A simple method for the quantitative determination of erythromycin (EM) concentrations in rat plasma and liver by high-performance liquid chromatography with amperometric detection was developed. EM was extracted from 200 microl of plasma or liver homogenate sample under sodium hydroxide alkaline conditions with tert.-butyl methyl ether. Oleandomycin was used as an internal standard. The recovery rate of EM was up to 100%. The detector cell potential for the oxidation of EM was +1100 mV. The calibration curves were linear over the concentration ranges 0.1-20.0 microg/ml for plasma and 0.5-100.0 microg/g for liver. The method was applied to the determination of the plasma and liver concentrations of EM in rats after intravenous administration (50 mg/kg dose). The method presented here has proved to be of great use for the investigation of the pharmacokinetic characteristics of EM in small animals such as rats.

Animals↗
PubMed1997

Prediction of the therapeutic dose for benzodiazepine anxiolytics based on receptor occupancy theory.

Many benzodiazepines (BZPs) are now used as anxiolytics with nearly 200-fold variety of therapeutic doses. The variation of the doses of BZPs is due to differences both in their pharmacokinetics and in their receptor binding characteristics. The purpose of this study is to clarify the mechanism of the differences in therapeutic dose by retrospective analyses and to develop a system for the quantitative estimation of optimal doses of BZPs. The values of receptor dissociation constant (Kd), which indicates the binding affinity of each BZP at the receptor site, were obtained from a number of works based on in vitro binding experiments. The plasma unbound concentrations of the BZPs and their active metabolites were calculated using the reported values of their total plasma concentrations after average oral doses of the BZPs and the values of their plasma unbound fractions, which were also taken from the literature. There were log-linear relationships between the Kd values of BZPs and their average therapeutic doses or maximum plasma concentrations, but the correlation coefficients were relatively small (r < 0.77). In contrast, a good log-linearity (r = 0.96) was observed in the correlation between their Kd values and the effective plasma unbound concentrations considering the active metabolites. This finding indicates that the receptor occupancy after administration of therapeutic dose of BZPs is consistent (52.3 +/- 3.2%) among the BZPs. In this study, we also develop a possible system for estimating the appropriate doses of BZPs based on receptor occupancy theory.

Administration, Oral↗
PubMed1997

The pharmacokinetics of glycyrrhizin and its restorative effect on hepatic function in patients with chronic hepatitis and in chronically carbon-tetrachloride-intoxicated rats.

The relationships between the pharmacokinetic behaviour of glycyrrhizin and its restorative effect for hepatic function were investigated in patients with chronic hepatitis and in rats chronically treated with carbon tetrachloride (CCl4-treated rats). In patients, the restorative effects in plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were 62.2 +/- 7.4 and 64.4 +/- 7.5%, respectively, after daily 80 mg intravenous (i.v.) doses of glycyrrhizin for 2 weeks, and 63.1 +/- 19.1 and 68.7 +/- 15.2% after 120 mg doses. The present work suggests that the threshold plasma glycyrrhizin concentration for sufficient effect is near 5 micrograms mL-1. In rats, the total body clearance (Cltot) for glycrrhizin in the CCl4-treated rats after i.v. administration of glycyrrhizin (5 mg kg-1 dose) was three-tenths of that of the control, and the t1/2 for glycyrrhizin was 3.4-fold longer than that of the control. A good correlation was observed between Cltot and AST (r = -0.838) or ALT (r = -0.873) activity in both rats. When glycyrrhizin was administered intraperitoneally (i.p.) three times a week for 2 weeks, both the AST and ALT activities in the CCl4-treated rats showed a greater improvement than for a 10 mg kg-1 dose. Furthermore, the finding on the threshold plasma concentration in patients as above was also supported from the results of the experiments in rats.

Alanine Transaminase↗
PubMed1997

Inhibitory effect of new quinolones on GABA(A) receptor-mediated response and its potentiation with felbinac in Xenopus oocytes injected with mouse-brain mRNA: correlation with convulsive potency in vivo.

Convulsions induced by the interaction of new quinolone antimicrobial agents (NQs) and nonsteroidal anti-inflammatory drugs (NSAIDs) were previously reported, and blockade of GABA(A) receptor by NQs and its potentiation with NSAIDs were considered as one of its possible mechanisms. However, useful methodology for prediction of convulsive potencies of NQs with or without NSAIDs in vivo based on in vitro screening was not established. Therefore, we applied the Xenopus oocytes translation system of exogenous messenger RNA (mRNA) to examine the mechanism of convulsion induced by interaction of NQs and NSAIDs, and the relationship between convulsive potencies in vivo and inhibitory effect on GABA-induced current response in vitro was investigated. This system also has alternative possibility for the in vivo toxicological studies sacrificing innumerous animals. Glutamic acid, kainic acid, quisqualic acid, NMDA, and serotonin-induced currents were not modified by ENX of NQs and/or FLB of NSAIDs, while glycine- and ACh-induced currents were slightly inhibited. GABA (10 microM)-induced current was inhibited by norfloxacin (NFLX), ciprofloxacin, ENX, and ofloxacin (OFLX) with IC50 of 17, 33, 58, and 280 microM, respectively. IC50 of NQs decreased to 1/3 (OFLX)-1/165 (NFLX) in the presence of 10 microM FLB, while FLB did not modulate the GABA response in the absence of NQs. CSF concentration of ENX at the time of convulsion in clinical situation approximated the IC50 of ENX for the GABA response. The increase of incidence for NQs-induced convulsion by concomitant NSAIDs in vivo could also be explained by the potentiation of inhibitory effects of NQs with FLB in the normal range of CSF concentration of these drugs. We also examined convulsive potency (threshold dose for convulsion) in CNS by intracerebral infusion of NQs to mice with or without FLB pretreatment, and significant correlations between the convulsive potencies and IC50 of NQs for the GABA response were observed. These findings suggested that the blockade of GABA-ersic neurotransmission in CNS is a dominant mechanism of convulsion induced by NQs and that the convulsant-adverse reaction of NQs in vivo may be predicted from the inhibitory effect on the GABA(A) receptor in vitro using the Xenopus oocytes translation system of exogenous mRNA.

Animals↗
PubMed1997

Pharmacokinetic analysis of benzodiazepine receptor binding of [123I]iomazenil in human brain.

PURPOSE: The purpose of this study is to evaluate the central benzodiazepine (BZP) receptor binding of iomazenil (IMZ) by pharmacokinetic analysis and to establish a methodology for the diagnosis of CNS disorders with abnormalities in BZP receptor binding. METHODS: BZP receptor binding of IMZ was analyzed kinetically using plasma concentration-time profiles and dynamic single photon emission computed tomography (SPECT) data obtained after the intravenous administration of IMZ to patients with neuropsychiatric disease. The analysis was based on a 3-compartmental model including the processes of both blood-brain barrier (BBB) transport and BZP receptor binding. RESULTS: Hydrolized metabolite of IMZ was detected in plasma, indicating the need for separation by HPLC. The BBB influx clearance and the receptor binding potential of IMZ in the medial temporal region was reduced in the epileptic patient. CONCLUSIONS: Our findings suggest the possibility of detecting the epileptic focus by using our method.

Blood-Brain Barrier↗
PubMed1997

A comparative pharmacokinetic-pharmacodynamic study of the electrocardiographic effects of epinastine and terfenadine in rats.

The effects of epinastine hydrochloride and terfenadine on electrocardiographic (ECG) parameters in rats were investigated from a pharmacokinetic and pharmacodynamic perspective. Epinastine hydrochloride (1 or 3 mg kg-1 h-1) or terfenadine (5, 10 or 15 mg kg-1 h-1) was intravenously infused into rats anaesthetized with urethane and alpha-chloralose. The changes in the QT interval derived from limb lead II and the chest lead, heart rate and PR interval were analysed. The time-course of the plasma drug-concentration of each drug was also investigated. Terfenadine prolonged the QT interval in an infusion-rate-dependent manner, its EC50 value was 792-1039 ng mL-1. An obvious QT prolongation was, moreover, observed even at a plasma terfenadine concentration of 100-200 ng mL-1, which is clinically quite high, but might be achieved under a definite condition such as a restrained terfenadine metabolism. Terfenadine also induced PR prolongation and bradycardia in an infusion-rate dependent manner. Epinastine slightly increased the heart rate, but did not affect any of the other ECG parameters even at a plasma concentration of 400 ng mL-1, which is more than 10 times the maximum concentration attained after an ordinary dosage regimen in man. We conclude that epinastine might have an advantage over terfenadine in avoiding adverse electrocardiographic reactions.

Animals↗
PubMed1997

Neurotoxic study of H2 antagonists using Xenopus oocytes injected with mouse-brain mRNA.

To clarify the dominant mechanism for the convulsant activity of H2 antagonists, the effects of an H2 antagonist, cimetidine, on membrane currents induced by various agonists were investigated. In Xenopus oocytes injected with mouse-brain mRNA, acetylcholine (ACh), serotonin (5-HT), gamma-aminobutyric acid (GABA), glycine (Gly), glutamic acid (Glu), kainic acid (KA), quisqualic acid (QA) and N-methyl-D-aspartic acid (NMDA)-induced current responses were recorded under a voltage-clamp condition. Cimetidine inhibited GABA-induced currents in a concentration-dependent manner; however, the current responses induced by the other agonists were not modified. The IC50 of various H2 antagonists, famotidine, nizatidine, cimetidine and ranitidine, for GABA (10 microM)-induced current response were 66, 260, 450 and 980 microM, respectively. However, these values of cimetidine and ranitidine were 40-400 times higher than the reported brain and cerebrospinal fluid (CSF) concentration of H2 antagonists at the occurrence of a clonic convulsion in vivo. In conclusion, we observed an inhibitory effect of H2 antagonists on the GABA response; however, this inhibition of GABA-mediated neurotransmission may not be the dominant mechanism for H2 antagonist-induced clonic convulsion in vivo.

Animals↗
PubMed1997

Pharmacokinetic/pharmacodynamic analysis of neutrophil proliferation induced by recombinant granulocyte colony-stimulating factor (rhG-CSF): comparison between intravenous and subcutaneous administration.

Pharmacological effect after intravenous (i.v.) or subcutaneous (s.c.) administration of human recombinant granulocyte colony stimulating factor (rhG-CSF) was evaluated by using a physiologically based pharmacokinetic/pharmacodynamic model. The increase of neutrophil counts in blood after s.c. administration of rhG-CSF (0.5-1.0 microgram/kg) was larger than that after i.v. administration of the same dose, while area under the curves of plasma concentration of rhG-CSF after s.c. administration was smaller than that after i.v. administration (Azuma et al., J. Clin. Therap. Med., 5, 1579-1603, 1989). Based on the pharmacokinetic/pharmacodynamic model considering metabolic turnover of neutrophil in vivo, time course of absolute neutrophil counts in blood after either type of rhG-CSF administration to normal healthy volunteers was analyzed. The nonlinear relationship between the concentration of rhG-CSF and in vitro activity for proliferation of neutrophil could be explained by the drug-receptor-effector ternary complex model. These in vivo and in vitro models made it possible to understand the above-mentioned discrepancy of pharmacokinetic/pharmacodynamic behavior between i.v. and s.c. administration of rhG-CSF. Simulation of the neutrophil count-time profiles after repeated i.v. and s.c. dosing of rhG-CSF according to these models showed good agreement with the observed data. In order to obtain the rational dosage regimen of rhG-CSF from pharmacological and economical points of view, a slow constant infusion method may be more useful than rapid infusion.

Administration, Cutaneous↗
PubMed1997

Effect of acute renal failure on neurotoxicity of enoxacin in rats.

We investigated the effect of acute renal failure on the neurotoxicity of enoxacin (ENX) in rats. Experimental acute renal failure was produced by bilateral ureteral ligation. ENX was intravenously infused to ureter ligated (UL) and control rats, and its concentration in plasma, brain and cerebrospinal fluid (CSF) was compared. Plasma concentration of ENX increased rapidly in UL rats as compared with control rats. Brain/plasma concentration ratio (Kp)-time profile of ENX was similar in UL and control rats. Brain concentration of ENX at the occurrence of convulsion did not depend on the infusion rate, suggesting that in the brain tissue it equilibrates rapidly with the site of action for clonic convulsion. Brain concentration of ENX in UL rats at the occurrence of clonic convulsion was lower than that in control rats. A similar tendency was also observed with CSF concentration. In conclusion, the potentiation of neurotoxicity of ENX with acute renal failure may be caused by not only decreased capability for renal elimination of ENX but also increased sensitivity to convulsant activity of ENX in the central nervous system.

Acute Kidney Injury↗
PubMed1997

Effect of acute renal failure on the distribution of iomeprol, a nonionic contrast agent, to cerebrospinal fluid in rats.

The effect of acute renal failure on the pharmacokinetics concerning the cerebrospinal fluid (CSF) distribution of iomeprol, a nonionic contrast agent, was studied. The concentrations of iomeprol in the plasma and CSF were measured after intravenous (i.v.) administration at the dose of 50 or 500 mg/kg body weight. The time courses of plasma and CSF concentration were linear within the dose studied. Influx and efflux clearances estimated by simultaneous fitting were 4.6 x 10(-5) ml/min and 8.8 x 10(-4) ml/min, respectively, which suggested that the distribution of iomeprol to CSF low and linear. The distribution volume at steady state was 300-500 ml/kg, suggesting that iomeprol was readily distributed to the extracellular space but hardly distributed to the intercellular space. Total body clearance (9-13 ml/min/kg) indicated that iomeprol was mainly excreted by glomerular filtration. In the rat with acute renal failure induced by ligating the binary ureters, the concentration of iomeprol in CSF after i.v. administration of 500 mg/kg dose was much higher than that in the intact rat according to the delay of elimination from plasma (CLtot = 0.07 ml/min/kg). However, the time course of iomeprol concentration in CSF was predictable using the values of the influx clearance to CSF and the efflux clearance from CSF determined by intact rats. In conclusion, renal failure is one risk factor for central nervous system toxicity because of decreased total body clearance, while acute renal failure may not affect the transport of iomeprol to CSF.

Acute Kidney Injury↗
PubMed1997

[Quantitative evaluation of pharmacological effects and adverse effects based on receptor occupancy theory].

For the quantitative assessment of therapeutic/pharmacologic effects and adverse/toxic effects of drugs which interact with several specific receptors, we developed an integrated pharmacokinetic analysis system by considering a receptor occupancy theory and a ternary complex model. The developed system has made it possible to predict the optimal dosage for the investigation of drugs using pre-clinical and clinical data (phase I study) under development, and to assess quantitatively the intensity of adverse/toxic effects of drugs which are not observed in the stage of clinical study. As for commercially available drugs, the developed system may be useful for planning the rational drug dosage regimen to obtain desired therapeutic effects with minimum adverse/toxic effects. Our new methodology for the rational dosage regimen of a new drug will be established based on the results of this study.

Animals↗
PubMed1997

Kinetics of respiratory depression in rats induced by buprenorphine and its metabolite, norbuprenorphine.

The respiratory depression induced by buprenorphine and its active metabolite, norbuprenorphine (NBN), was evaluated in rats by measurement of changes in respiratory rate and arterial pCO2 levels. After i.v. bolus administration of buprenorphine no effects were noted over the dose range 0.008 to 3 mg/kg; by contrast, the respiratory rate after rapid i.v. administration of NBN decreased in a dose-dependent fashion within the dose range of 1 to 3 mg/kg, and the arterial pCO2 levels also varied in relation to the change in respiratory rate. The minimum respiratory rate was observed 15 min after NBN administration. Judging by the respiratory depressive effect after i.v. infusion, NBN was approximately 10 times more potent than the parent drug. In spite of the similarity of NBN concentrations in the brain after i.a. and after i.v. administration of NBN (3 mg/kg), neither the respiratory rate nor the arterial pCO2 levels after i.a. administration changed compared with the control levels. Moreover, the NBN concentration in the lungs after i.v. administration was approximately 4-fold higher than that after i.a. administration. NBN-induced depression was rapidly reduced after i.v. administration of naloxone and beta-funaltrexamine, but ICI 174864 was without effect. These results suggest that the respiratory depression induced by NBN may be mediated by opioid mu receptors in the lung rather than in the brain.

Analgesics, Opioid↗
PubMed1997

Prediction of drug-induced catalepsy based on dopamine D1, D2, and muscarinic acetylcholine receptor occupancies.

It is known that catalepsy serves as an experimental animal model of parkinsonism. In this study, the relationship between in vivo dopamine D1 and D2 receptor occupancies and catalepsy was investigated to predict the intensity of catalepsy induced by drugs that bind to D1 and D2 receptors nonselectively. 3H-SCH23390 and 3H-raclopride were used for the labeling of D1 and D2 receptors, respectively. The ternary complex model consisting of agonist or antagonist, receptor, and transducer was developed, and the dynamic parameters were determined. After coadministration of SCH23390 and nemonapride, catalepsy was stronger than sum of the values predicted by single administration of each drug, and it was intensified synergistically. This finding suggested the existence of interaction between D1 and D2 receptors, and the necessity for constructing the model including this interaction. To examine the validity of this model, catalepsy and in vivo dopamine receptor occupancy were measured after administration of drugs that induce or have a possibility to induce parkinsonism (haloperidol, flunarizine, manidipine, oxatomide, hydroxyzine, meclizine, and homochlorcycilzine). All of the tested drugs blocked both dopamine D1 and D2 receptors. Intensity of catalepsy was predicted with this dynamic model and was compared with the observed values. In contrast with haloperidol, flunarizine, manidipine, and oxatomide (which induced catalepsy), hydroxyzine, meclizine, and homochlorcyclizine failed to induce catalepsy. Intensities of catalepsy predicted with this dynamic model considering the interaction between D1 and D2 receptors overestimated the observed values, suggesting that these drugs have catalepsy-reducing properties as well. Because muscarinic acetylcholine (mACh) receptor antagonists inhibit the induction of catalepsy, the anticholinergic activities of the drugs were investigated. After SCH23390, nemonapride and scopolamine were administered simultaneously; catalepsy and in vivo mACh receptor occupancy were measured to evaluate quantitatively the anticholinergic activity. Relationship between mACh receptor occupancy and change in catalepsy was used as the measure of catalepsy-reducing effects of the drugs. Measurement of in vivo mACh receptor occupancy revealed a significant blockade of mACh receptor by all of the tested drugs except for haloperidol. The predicted values of catalepsy, when corrected for the mACh receptor-related reduction, approached the observed values. This finding indicates the possibility that mACh receptor antagonism of drugs may contribute to the reduction of catalepsy. In conclusion, the dynamic model considering D1, D2, and mACh receptor occupancies and synergism between D1 and D2 receptors may be useful for quantitative prediction of drug-induced catalepsy.

Animals↗
PubMed1997

Tissue distribution kinetics of a new nonsteroidal 5 alpha-reductase [correction of 5 A-reductase] inhibitor, 4-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]-1H-indol-1-YL ]-butyric acid, in rats.

The disposition of a new nonsteroidal 5alpha-reductase inhibitor, 4-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]-1H-indol-1-yl]-butyric acid (FK143), was investigated in rats. After intravenous administration of FK143 at 1 and 5 mg/kg, total body clearance, elimination half-life, and volume of distribution at steady-state were, respectively, 6.96 and 8.76 ml/min/kg, 10.31 and 9.83 hr, and 4.11 and 3.33 liters/kg. There were no essential differences between the two doses in any parameters. The serum protein binding in vitro was very high (>99%). The unidirectional uptake clearance (CL1) to 13 tissues was determined by integration plot until 10 min after intravenous administration of 1 mg/kg. CL1 values were much smaller than blood flow rate in all tissues, including the prostate, the target organ, indicating that FK143 was transported from blood to tissues by a membrane-limited process. Since the elimination rates of FK143 from the liver, kidney, lung, epididymis, seminal vesicle, and prostate were slower than from the blood, the efflux rate constant (k2) and rate constants at a binding compartment (k3 and k4) were assumed in the pharmacokinetic model. A correlation was found between the binding potential of binding compartment (k3/k4) and V(max) of steroid 5alpha-reductase, the target enzyme, suggesting that the levels of 5alpha-reductase activity or that of associated substances are a primary determinant of the specific binding of FK143 in these tissues.

5-alpha Reductase Inhibitors↗
PubMed1996

Quantitative determination of epinastine in plasma by high-performance liquid chromatography.

A high-performance liquid chromatographic (HPLC) method for the quantitative determination of epinastine, a non-sedating histamine H1 receptor antagonist, in rat plasma, was developed. A 100-microliters volume of plasma sample was spiked with a solution of internal standard (diphenidol) and extracted with dichloromethane under alkaline conditions. The extract was applied onto the HPLC system and detected by ultraviolet absorption at a wavelength of 220 nm. The linearity of the calibration curve was preserved over the concentration range of 20-1000 ng/ml. Both intra-assay variation and relative error were less than 5% for the plasma containing 50 ng/ml or 1000 ng/ml of epinastine hydrochloride. The analytical method presented here should be useful for the investigation of the pharmacokinetic properties of epinastine, which is of clinical significance.

Animals↗
PubMed1996

Neurotoxic convulsions induced by histamine H2 receptor antagonists in mice.

Convulsive potency was evaluated to investigate the mechanism of neurotoxic convulsion induced by histamine H2 receptor antagonists (H2 blockers). Four H2 blockers, cimetidine (721-1236 nmol), ranitidine (477-954 nmol), famotidine (7.4-44 nmol), and nizatidine (226-603 nmol) were administered intracerebrally (i.c.) to mice. Dose dependency of clonic and/or tonic convulsion was observed, and the ED50 values of convulsive occurrence for cimetidine, ranitidine, famotidine, and nizatidine were 997, 662, 23.4, and 404 nmol, respectively. Intraperitoneal pretreatment of muscimol, aminooxy acetic acid, diazepam, (+/-)2-amino-7-phosphonoheptanoic acid (APH), or (+)MK801 suppressed the tonic convulsion after i.c. administration of ranitidine, but had no effect on clonic convulsion. Furthermore, the convulsive threshold concentration in the brain determined by constant rate infusion of ranitidine was not affected by the pretreatment of muscimol, diazepam, APH, and MK801. Ed50 values for convulsive occurrence after i.c. administration of four H2 blockers correlated well with the EC50 values for gastric acid secretion inhibition. The convulsive threshold concentrations of cimetidine and ranitidine in the brain were 11 and 2.5 microM, respectively, which were similar to the dissociation constants determined from the inhibition of gastric acid output in mice. From these results, tonic convulsion induced by H2 blockers can be suppressed by GABAergic or glutamatergic anticonvulsants, while clonic convulsion induced by H2 blockers may be associated with the blockade of H2 receptor in the brain and not be directly associated with the GABA and glutamate-mediated neurotransmission.

Animals↗
PubMed1996

Pharmacodynamic analysis of contractile potentiation by cholinesterase inhibitors in rats.

Pharmacological profiles of four cholinesterase (ChE) inhibitors: edrophonium, pyridostigmine, neostigmine, and ambenonium after to administration to rats were analyzed. A pharmacodynamic model was developed by considering acetylcholinesterase (AChE) inhibition, direct antagonism to the nicotinic receptor, and desensitization of the nicotinic receptor. Pharmacokinetics of these drugs are dose-independent and have similar volumes of distribution at steady state (0.4-0.6 L/kg various doses). The t1/2 increases in the order of neostigmine, edrophonium, pyridostigmine, and ambenonium. Inhibitory constants of ChE inhibitors to bovine erythrocyte AChE determined in vitro were 2019, 276, 26, and 3.7 nM for edrophonium, pyridostigmine, neostigmine, and ambenonium, respectively. The effect of ChE inhibitor was monitored as the increase of developed tension of triceps muscle induced by sciatic nerve stimulation. The maximum value of contractile tension after i.v. administration decreased at high doses of each drug and the dose-response curves were biphasic. Time courses of plasma concentration and contractile muscle tension were modeled to estimate the association/dissociation rate constants to AChE and the nicotinic receptor, desensitization rate constant of receptor and the dissociation constant of acetylcholine (ACh) to nicotinic receptor/basal acetylcholine level ratio (Kd/ACh0). The estimated Kd/ACh0 values were not dependent on the drug. A significant correlation between inhibitory constants of ChE inhibitors to AChE estimated by in vivo pharmacodynamic analysis and those determined by an in vitro enzyme kinetic study was shown, while the relationship between dissociation constants to nicotinic receptor estimated by in vivo pharmacodynamic analysis and those measured by an in vitro binding study was not clear. Other process such as desensitisization induced by endogenous ACh diffusion rate of drugs into the synaptic cleft, action of presynaptic receptors, etc., might contribute to the dose-effect relationship of ChE inhibitors.

Ambenonium Chloride↗