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Current Opinion in Investigational... Jul 2003Lerisetron is a 5-hydroxytryptamine3 receptor antagonist under development by FAES Farma for the potential treatment of emesis resulting from chemotherapy. Phase I... (Review)
Review
Lerisetron is a 5-hydroxytryptamine3 receptor antagonist under development by FAES Farma for the potential treatment of emesis resulting from chemotherapy. Phase I trials of lerisetron were underway in Spain by 1994, and as of June 2000, the compound was in phase II trials in the UK. By the end of 2001, phase II trials had been completed and phase III trials had commenced.
Topics: Animals; Antineoplastic Agents; Benzimidazoles; Clinical Trials as Topic; Drugs, Investigational; Humans; Piperidines; Technology, Pharmaceutical; Vomiting
PubMed: 14619411
DOI: No ID Found -
ACS Omega Mar 2020A phenotypic whole cell high-throughput screen against the asexual blood and liver stages of the malaria parasite identified a benzimidazole chemical series. Among the...
A phenotypic whole cell high-throughput screen against the asexual blood and liver stages of the malaria parasite identified a benzimidazole chemical series. Among the hits were the antiemetic benzimidazole drug Lerisetron (IC NF54 = 0.81 μM) and its methyl-substituted analogue (IC NF54 = 0.098 μM). A medicinal chemistry hit to lead effort led to the identification of chloro-substituted analogue with high potency against the drug-sensitive NF54 (IC NF54 = 0.062 μM) and multidrug-resistant K1 (IC K1 = 0.054 μM) strains of the human malaria parasite . Compounds and gratifyingly showed in vivo efficacy in both and mouse models of malaria. Cardiotoxicity risk as expressed in strong inhibition of the human ether-a-go-go-related gene (hERG) potassium channel was identified as a major liability to address. This led to the synthesis and biological assessment of around 60 analogues from which several compounds with improved antiplasmodial potency, relative to the lead compound , were identified.
PubMed: 32258933
DOI: 10.1021/acsomega.0c00327 -
Cancer Chemotherapy and Pharmacology 1998The aim of this study was, (1) to characterize the serum protein binding of lerisetron, a new 5-hydroxytryptamine (5-HT3) receptor antagonist under investigation as an... (Comparative Study)
Comparative Study
The aim of this study was, (1) to characterize the serum protein binding of lerisetron, a new 5-hydroxytryptamine (5-HT3) receptor antagonist under investigation as an antiemetic agent, and (2) to measure the percentage of unbound lerisetron in cancer patients. The binding parameters were determined in human serum albumin (HSA), alpha1-acid glycoprotein (AAG) and in pooled serum from six healthy volunteers. Concentrations of lerisetron ranging from 50 ng/ml to 2 microg/ml were used. The serum protein binding of 14C-lerisetron (2 microg/ml) was determined by ultrafiltration in three groups of individuals. Group I comprised healthy subjects (n = 11), group II comprised cancer patients undergoing radiotherapy (n = 9), and group III comprised cancer patients receiving chemotherapy (n = 18). The unbound concentration of lerisetron was measured in all samples by liquid scintillation counting. Concentrations of both AAG and HSA were also measured in all serum samples. The drug was extensively bound in pooled serum, involving a nonsaturated process. In HSA, lerisetron was also highly bound (4.04+/-0.8% unbound) and the protein binding was essentially unchanged within the studied concentration range of lerisetron. The extent of binding to AAG was high but significantly lower than in serum and in HSA and was also independent of lerisetron concentration. The unbound lerisetron was significantly decreased in group II cancer patients when compared with group I subjects (2.38+/-0.64% vs 3.70+/-0.70%; P < 0.001). No significant changes in lerisetron binding were observed in group III patients. HSA was diminished in both groups of patients and AAG was only significantly increased in group II. Unbound lerisetron was correlated with AAG in group II and with HSA in group III.
Topics: Adult; Antiemetics; Benzimidazoles; Carbon Radioisotopes; Female; Humans; Male; Middle Aged; Neoplasms; Orosomucoid; Piperidines; Protein Binding; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Serum Albumin
PubMed: 9771958
DOI: 10.1007/s002800050839 -
Arzneimittel-Forschung 2002The purpose of these studies was to evaluate the effect of lerisetron (1-phenyl-methyl-2-piperazinyl-1H-benzimidazole hydrochloride, CAS 143257-98-1, F-0930-RS2), a new... (Comparative Study)
Comparative Study
The purpose of these studies was to evaluate the effect of lerisetron (1-phenyl-methyl-2-piperazinyl-1H-benzimidazole hydrochloride, CAS 143257-98-1, F-0930-RS2), a new 5-HT3 receptor antagonist, on ipecacuanha-induced nausea and vomiting. The ipecacuanha model of emesis has been used to test the anti-emetic activity of several different 5-HT3 antagonists and the anti-emetic doses that were effective in the ipecacuanha model have been found to correlate well with the clinically effective doses. Study 1 investigated oral doses of lerisetron from 4 mg to 40 mg. Study 2 evaluated the duration of effect of a single dose of 20 mg oral lerisetron. Study 3 evaluated intravenous doses of 18 mg and 12 mg lerisetron. In Study 1, the 40 mg dose of oral lerisetron inhibited emesis in all test subjects. The percentage of subjects who experienced an emetic episode increased as the dose of lerisetron decreased. At the lowest dose level tested five of six subjects had an emetic episode compared with four out of five in the placebo group. In Study 2, 20 mg oral lerisetron was effective up to 12 h after administration. When ipecacuanha was administered at 18 h post-dose three of seven subjects had an emetic episode and at 24 h post-dose the incidence of emesis was similar to the placebo treatment groups in the previous study. Study 3 demonstrated the effectiveness of intravenous doses of lerisetron. The 18 mg intravenous dose reduced the number of patients experiencing emetic episodes by 75% compared with placebo, doses below 12 mg i.v. were not evaluated because of the reduced efficacy of the compound at this dose level. In conclusion, lerisetron has been shown to be effective in the treatment of ipecacuanha-induced nausea and vomiting at intravenous doses of 18 mg and at oral doses of 20 mg for up to 12 hours.
Topics: Administration, Oral; Adolescent; Adult; Antiemetics; Benzimidazoles; Dose-Response Relationship, Drug; Emetics; Granisetron; Humans; Injections, Intravenous; Ipecac; Male; Nausea; Piperidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Time Factors; Vomiting
PubMed: 12404884
DOI: 10.1055/s-0031-1299952 -
Altered disposition and effect of lerisetron in rats with elevated alpha 1-acid glycoprotein levels.Pharmaceutical Research Jun 2001To examine the effect of changes in plasma alpha1-acid glycoprotein (AAG) levels on the pharmacokinetics (PK) and pharmacodynamics (PD) of lerisetron, a novel serotonin...
PURPOSE
To examine the effect of changes in plasma alpha1-acid glycoprotein (AAG) levels on the pharmacokinetics (PK) and pharmacodynamics (PD) of lerisetron, a novel serotonin 5-HT3 receptor antagonist, in the rat.
METHODS
After subcutaneous administration of turpentine oil, AAG was significantly elevated compared with controls. The PK of unchanged lerisetron (UL; high-performance liquid chromatography with radioactivity monitoring) and total lerisetron (TL; unchanged + changed, scintillation counting) was characterized post intravenous (i.v.) 14C lerisetron (50 microg/kg) in control and turpentine oil pretreated rats. The PK (0-180 min) was described by a two-compartmental model. Protein binding of lerisetron in vitro was measured using an ultrafiltration technique. The effect of lerisetron (5 microg/kg, i.v.) over 180 min was measured in anesthetized rats (control and pretreated) with the Bezold-Jarisch reflex (inhibition of bradycardia after 16 microg/kg serotonin i.v.) as the endpoint. PD parameters were estimated by sigmoid Emax models.
RESULTS
The unbound fraction was significantly diminished in pretreated rats (mean +/- SEM) (6.60 +/- 1.23% vs. control 14.4 +/- 1.40%, P < 0.05). Volume of distribution (V) and clearance for UL and TL were significantly decreased when compared to the controls (P < 0.0001 for UL and P < 0.05 for TL). Plasma clearance based on unbound concentration for UL did not differ between groups but the unbound V and steady-state unbound V remained decreased (P < 0.05 and P < 0.0001). Pretreated rats showed a significantly diminished drug effect: the area under the E-t curve over 180 min was (mean +/- SEM) 5,189 +/- 657.7 in control animals vs. 3,486 +/- 464.4 in the pretreated group (P < 0.05). The EC50 (concentration at half maximum effect) for UL and TL were increased in pretreated rats and were not compensated when the unbound concentration was used.
CONCLUSIONS
An increase in AAG causes alterations in the PK and PD of lerisetron, and because this is not compensated with the unbound concentration, we suggest that mechanisms not linked to protein binding may be involved.
Topics: Animals; Benzimidazoles; Bradycardia; Female; Orosomucoid; Piperidines; Protein Binding; Rats; Rats, Sprague-Dawley; Serotonin Antagonists
PubMed: 11474789
DOI: 10.1023/a:1011096714860 -
Pharmaceutical Research Nov 2005The twofold aim of this study was to characterize in vivo in rats the pharmacokinetics (PK) and pharmacodynamics (PD) of L6-OH, a metabolite of lerisetron with in vitro...
PURPOSE
The twofold aim of this study was to characterize in vivo in rats the pharmacokinetics (PK) and pharmacodynamics (PD) of L6-OH, a metabolite of lerisetron with in vitro pharmacological activity, and evaluate the extent to which L6-OH contributes to the overall effect.
METHODS
The PK of L6-OH was determined directly postmetabolite i.v. dose (PK-1), and also simultaneously for L (lerisetron concentration) and for generated L6-OH after lerisetron dose (200 microg kg(-1), i.v.), using Nonlinear Mixed Effects Modeling with an integrated parent-metabolite PK model (PK-2). Surrogate effect was measured by inhibition of serotonin-induced bradycardia. Protein binding was assayed via ultrafiltration and all quantification was performed via liquid chromatography-electrospray ionization-mass spectrometry.
RESULTS
L6-OH showed elevated plasma and renal clearances, and volume of distribution (PK-1). The in vivo potency (PD) of L6-OH was high (EC(50) = 0.098 ng mL(-1) and EC(50unbound) = 0.040 ng mL(-1)). Total clearance for L (PK-2) in the presence of generated L6-OH (CL(L) = CL(-->L6-OH) + CL(n)) was 0.0139 L min(-1). Most of this clearance was L6-OH formation (F(c) = 99.6%), but only an 8.6% fraction of L6-OH was released into the bloodstream. The remainder undergoes biliar and fecal elimination. The parameters estimated from PK-2 were used to predict concentrations of L6-OH (Cp(L6)) generated after a lerisetron therapeutic dose (10 microg kg(-1)) in the rat. These concentrations are needed for the PD model and are below the quantification limit. Cp(L6max) was less than the EC(50) of L6-OH.
CONCLUSIONS
We conclude that after lerisetron administration, L6-OH is extensively formed in the rat but it is quickly eliminated; therefore, besides being equipotent with the parent drug, the L6-OH metabolite does not influence the effect of lerisetron.
Topics: Animals; Benzimidazoles; Dose-Response Relationship, Drug; Heart Rate; Hydroxylation; Male; Models, Biological; Piperidines; Rats; Rats, Sprague-Dawley; Serotonin Antagonists
PubMed: 16158214
DOI: 10.1007/s11095-005-7750-6 -
Journal of Pharmaceutical Sciences Jan 2002The pharmacokinetics of lerisetron, a novel 5HT(3) antagonist, are studied together with its efficacy in inhibiting the serotonin (5-HT)-evoked transient bradycardia... (Comparative Study)
Comparative Study
The pharmacokinetics of lerisetron, a novel 5HT(3) antagonist, are studied together with its efficacy in inhibiting the serotonin (5-HT)-evoked transient bradycardia reflex (von Bezold-Jarisch reflex) in Sprague Dawley rats. [(14)C]Lerisetron (50, 100, and 200 microg/kg) was given to rats by intravenous (iv) injection and plasma levels of unchanged (UL) and total (unchanged + changed, TL) drug were measured by liquid chromatography with radioactivity monitoring and scintillation counting, respectively. Linearity of UL and TL pharmacokinetics over the dose range was established by noncompartmental analysis. Protein binding of lerisetron was measured in vitro by ultrafiltration. The unbound fraction was 14.4 +/- 1.4%. A nonlinear mixed effects ("population") bicompartmental pharmacokinetic analysis showed that volume of distribution and clearance (CL) were high for both forms of the drug, but CL was significantly smaller for TL [(mean +/- SEM) 0.014 +/- 0.03 L/min for UL versus 0.006 +/- 0.03 L/min for TL, p < 0.05)]. Large interindividual variabilities were observed for both forms. The response to lerisetron administration (inhibition of bradycardia) was evaluated at different doses (2, 3, 5, 6, and 10 microg/kg, iv) at times 2-180 min after dose administration and related to simulated concentrations. Inhibition was 100% 5 min after the 10-microg/kg dose and, 3 h later, it was still > 10%. Response to lerisetron was dose related in the range studied. Pharmacodynamic parameters were estimated by a sigmoid E(max) naive-pooled model. The parameters were also different between the two forms: EC(50) was 0.44 ng/mL (CV = 5.9%) for UL and 0.88 ng/mL (CV = 4.9%) for TL. We conclude that UL and TL pharmacokinetics were linear and that the differences in the kinetics and dynamics between the two forms suggest the presence of at least one metabolite.
Topics: Animals; Benzimidazoles; Bradycardia; Dose-Response Relationship, Drug; Female; Male; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists
PubMed: 11782896
DOI: 10.1002/jps.1169 -
Gerontology 2003The importance of studying the effects of age on the pharmacokinetics and pharmacodynamics of lerisetron - a new 5-hydroxytryptamine-3 (serotonin) receptor antagonist -...
BACKGROUND
The importance of studying the effects of age on the pharmacokinetics and pharmacodynamics of lerisetron - a new 5-hydroxytryptamine-3 (serotonin) receptor antagonist - comes from the facts that lerisetron will be administered to patients that are being treated with cytotoxic drugs and that the elderly frequently suffer from neoplastic diseases.
OBJECTIVE
The present study was designed to explore the effects of age on the pharmacokinetics and pharmacodynamics of lerisetron by using an aged rat model. A mixed-effects population study was carried out in order to analyze the sparse data and to create covariate models which could be used to derive dosage recommendations.
METHODS
Fischer 344 rats (n = 44) were divided into three groups, depending on their age: 5, 13, and 25 months. Blood samples were collected before administration of 200 micro g/kg of lerisetron for measurements of albumin, alpha(1)-acid glycoprotein, and unbound fraction of lerisetron. The lerisetron plasma concentrations were measured by high-performance liquid chromatography. A two-compartment model was fitted to the data using the nonlinear mixed-effects computer program WinNonMix. The population analysis was performed with the complete set of the collected data, and the potential sources of variability in the population parameters were investigated. Additionally, a pharmacodynamic study was performed. The effect of lerisetron (inhibition of the von Bezold-Jarisch reflex) was evaluated in young, adult, and senescent Fischer 344 rats.
RESULTS
The mean values of the individual Bayes estimates of the parameters showed a decrease in total clearance and distribution volume of the central compartment in old rats. The lerisetron free (unbound) fraction remained unchanged among the groups, and there were no significant differences in alpha(1)-acid glycoprotein levels. The concentration-effect relationship was best described by a sigmoid E(max) model. Since the drug concentration in plasma at half-maximal effect (EC(50)) decreased in old rats, an increased sensitivity to the effect of lerisetron in old animals could be expected.
CONCLUSION
Both pharmacokinetic changes (decreased volume of distribution and clearance and increased elimination half-life) and pharmacodynamic alterations (decrease in total and unbound EC(50)) may be responsible for the different responses to lerisetron observed in old rats.
Topics: Aging; Animals; Bayes Theorem; Benzimidazoles; Female; Half-Life; Models, Biological; Osmolar Concentration; Piperidines; Rats; Rats, Inbred F344; Tissue Distribution
PubMed: 12792155
DOI: 10.1159/000070400 -
Acta Oncologica (Stockholm, Sweden) 1998The 5-HT3 receptor antagonists are the most potent antiemetics known at present. Lerisetron is a new 5-HT3 receptor antagonist chemically unrelated to other antagonists...
The 5-HT3 receptor antagonists are the most potent antiemetics known at present. Lerisetron is a new 5-HT3 receptor antagonist chemically unrelated to other antagonists like Ondansetron. An emesis model in the dog induced by irradiation with 60Co was used, and 8 Gy were administered over the total body surface. An irradiated control group was established and received no medication, and two irradiated groups received treatment with either Ondansetron or Lerisetron. The 'up-down' technique was employed to determine the effective dose (ED50). A logarithmic-scale was used to increase or decrease the doses in each case. The initial doses were 300 microg/kg for Ondansetron and 100 microg/kg for Lerisetron. All animals in the control group vomited. The ED50 of Ondansetron was 178+/-151 microg/kg body wt and that of Lerisetron was 63+/-18 microg/kg. Lerisetron is more potent and presented less individual variability than Ondansetron, but its antiemetic effects were equally effective.
Topics: Animals; Antiemetics; Benzimidazoles; Cobalt Radioisotopes; Dogs; Drug Administration Schedule; Ondansetron; Piperidines; Radiotherapy; Serotonin Antagonists; Vomiting
PubMed: 10050999
DOI: 10.1080/028418698430160 -
Bioorganic & Medicinal Chemistry Letters Aug 2001The design, synthesis, and use of lerisetron-based molecular probes to investigate the 5-HT(3)R binding site are described. A SAR study, which involved distance and...
The design, synthesis, and use of lerisetron-based molecular probes to investigate the 5-HT(3)R binding site are described. A SAR study, which involved distance and electronic parameter modifications of lerisetron's N-benzyl group, resulted in the discovery of a partial agonist.
Topics: Benzimidazoles; Drug Design; Piperidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Structure-Activity Relationship
PubMed: 11514154
DOI: 10.1016/s0960-894x(01)00417-6