Pharmacokinetics,Mass Balance,and Induction Potential of a Novel GABA Uptake Inhibitor,CI-966 HC1, in Laboratory Animals

CI-966 exhibits anticonvulsant properties in various animal models. The drug acts by inhibiting synaptic uptake of -aminobutyric acid (GABA). Oral absorption of CI-966 in dogs given 1.39 mg/kg is rapid with a tmax of 0.7 hr. In rats given 5 mg/kg oral, a mean t _max of 4.0 hr was observed. Following iv administration of the same respective doses, elimination t _1/2 in dogs and rats averaged 1.2 and 4.5 hr. Absolute oral bioavailability of CI-966 was 100% in both species. Following oral dosing of [¹⁴C]CI-966 HC1 to dogs, fecal, and urinary excretion accounted for 89% and 2.3% of the ¹⁴C dose, respectively. In bile-duct cannulated rats, biliary excretion is the major elimination pathway of radioactivity (75%). Urinary and fecal excretion accounted for 4.1 and 12%, respectively. CI-966 does not induce or inhibit mouse hepatic mixed function oxidases, as determined by hexobarbital sleeping time.     

Preclinical Toxicological Evaluation of Fostriecin, a Novel Anticancer Antibiotic, in Rats

Preclinical Toxicological Evaluation of Fostriecin, a NovelAnticancer Antibiotic, in Rats. SUSICK, R. L., JR., HAWKINS,K. L., AND PEGG, D. G. (1990). Fundam Appl. Toxicol. 15,258–269.Fostriecin, a novel anticancer antibiotic produced by Steptomycespulveraecus,is believed to act via inhibition of topoisomerase II. Single-doseintravenous administration to rats at dose levels of 8.8 to48 mg/kg resulted in lethality at dose levels of 35 mg/kg andhigher. Major toxic effects were observed primarily at 17.5mg/kg and higher, were reversible, and consisted of bone marrowhypocellularity, leukopenia, neutropenia, thrombocytopenia,and diffuse necrosis of various lymphoid tissues. The kidneywas also identified as a target organ. Renal effects were observedprimarily at 20 mg/kg, were reversible, and included increasesin serum BUN, creati-nine, and 24-hr glucose excretion. Twenty-four-hourexcretion of Na⁺, K⁺ and urine osmolality were decreased postdosingat 10 and 20 mg/kg. Renal lesions, observed primarily at 20mg/kg, consisted of vacuolization and necrosis of proximal anddistal tubular epithelium at the corticomedullary junction extendinginto the medulla. Repeated daily intravenous administrationof fostriecin for 5 days to rats at dose levels of 2.5 to 26.5mg/kg resulted in death at 10 mg/ kg and above and similar hematologic,bone marrow, lymphoid tissue, and renal changes as observedin the single-dose study. Hematological, bone marrow, lymphoid,and renal changes observed in rats were consistent with thecytotoxic mechanism of action of the compound     

Kinetics of the Aspartyl Transpeptidation of Daptomycin,a Novel Lipopeptide Antibiotic

Two degradation products of the lipopeptide antibiotic, daptomycin, were identified and the reaction pathway and kinetics were delineated in aqueous solution at 60°C, pH range 3 to 8 and ionic strength 0.01. The degradation products were 1) a succinimido intermediate (anhydro-daptomycin) formed by attack of side-chain carbonyl on the peptide-bond nitrogen in the asp–gly sequence and 2) a -asp daptomycin isomer formed by rehydration of the anhydrodaptomycin succinimide. This aspartyl transpeptidation pathway was found to be reversible. Formation of the anhydrodaptomycin from either daptomycin or -asp daptomycin was pH dependent but the pH–rate profiles for anhydrodaptomycin formation were not mechanistically interpretable. The pH–rate profiles for the formation of daptomycin or -asp daptomycin from the anhydrodaptomycin were linear with slopes = 1, which is consistent with nucleophilic hydroxide ion attack of the succinimido intermediate at either the -carbonyl, giving rise to the -asp daptomycin, or the -carbonyl, giving rise to daptomycin.     

Ocular Availability of Gentamicin in Small Animals After Topical Administration of a Conventional Eye Drop Solution and a Novel Long Acting Bioadhesive Ophthalmic Drug Insert

Purpose. Gentamicin eye drop solutions have a short precorneal residence time. The present study investigates the effect of gentamicin using a new long acting delivery Bioadhesive Ophthalmic Insert (BODI) in healthy dogs and rabbits and compares the results with a conventional regimen using an eye drop solution. Methods. In vivo assays were performed on animals after deposition of one BODI and instillations of an eye drop solution. Tear samples were collected over 72 hours and 60 minutes, in the case of inserts and eye drop solution respectively. The gentamicin concentration profiles in tear fluid (determined by a fluorescent polarization immunoassay technique) was individually analyzed, in each animal, in relation with the minimum inhibitory concentration observed in vitro against some bacteria. A non classical pharmacokinetic approach was used for the analysis of the topically applied drug substance, involving two parameters: the efficacy area under the curve (AUC_eff) and the efficacy time (t_eff). Results. In the case of the eye drop solution, the AUC_eff were higher in dogs (2.80 10³ – 3.64 10³ [µg ml^–1 h]) than in rabbits (0.64 · 10³ – 0.95 · 10³ [µg ml^–1h]); the t_eff had a similar behavior: 6-15 [h] in dogs and 2-6 [h] in rabbits. In the case of BODIs, the AUC_eff and the t_eff were quite similar between dogs and rabbits: 190 10³ – 205 10³ [µg ml^–1 h] and 70-76 [h], respectively. The AUC_eff and the t_effwere always much higher in the case of BODIs than for the eye drop solution both in dogs and rabbits. Conclusions. This study shows that topical administration of gentamicin using BODIs can improve treatment due to the decreasing number of applications while ensuring an effective level of antibiotic in tears controlled by the device.     

Preferential Binding of Polyethylene Glycol-Coated Liposomes Containing a Novel Cationic Lipid,TRX-20, to Human Subendthelial Cells via Chondroitin Sulfate

Purpose. To design novel cationic liposomes, polyethylene glycol (PEG)-coated cationic liposomes containing a newly synthesized cationic lipid, 3,5-dipentadecyloxybenzamidine hydrochloride (TRX-20) were formulated and their cellular binding and uptake investigated in vitro in the following cells: human subendothelial cells (aortic smooth muscle cells and mesangial cells) and human endothelial cells. Methods. Three different PEG-coated cationic liposomes were prepared by the extrusion method, and their mean particle size and zeta potential were determined. Rhodamine-labeled PEG-coated cationic liposomes were incubated with smooth muscle cells, mesangial cells, and endothelial cells at 37°C for 24 h. The amounts of cellular binding and uptake of liposomes were estimated by measuring the cell-associated fluorescence intensity of rhodamine. To investigate the binding property of the liposomes, the changes of the binding to the cells pretreated by various kinds of glycosaminoglycan lyases were examined. Fluorescence microscopy is used to seek localization of liposomes in the cells. Results. The cellular binding and uptake of PEG-coated cationic liposomes to smooth muscle cells was depended strongly on the chemical species of cationic lipids in these liposomes. Smooth muscle cells bound higher amount of PEG-coated TRX-20 liposomes than other cationic liposomes containing N-(1-(2,3-dioleoyloxy) propyl)-N, N, N-trimethylammonium salts or N-(-(trimethylammonio)acetyl)-D-glutamate chloride. Despite of the higher affinity of PEG-coated TRX-20 liposomes for subendothelial cells, their binding to endothelial cells was very small. The binding to subendothelial cells was inhibited when cells were pretreated by certain kinds of chondroitinase, but not by heparitinase. These results suggest that PEG-coated TRX-20 liposomes have strong and selective binding property to subendothelial cells by interacting with certain kinds of chondroitin sulfate proteoglycans (not with heparan sulfate proteoglycans) on the cell surface and in the extracellular matrix of the cells. This binding feature was different from that reported for other cationic liposomes. Conclusions. PEG-coated TRX-20 liposomes can strongly and selectively bind to subendothelial cells via certain kinds of chondroitin sulfate proteoglycans and would have an advantage to use as a specific drug delivery system.     

Comparison of Hepatic Drug-Oxidizing Activity after Simultaneous Administration of Two Probe Drugs,Caffeine and Trimethadione,to Human Subjects

Abstract: Pharmacokinetic interactions between caffeine 2 mg/kg and trimethadione 4 mg/kg were evaluated in 10 healthy volunteers. Whether administered alone or together, the total body clearance (CL), the apparent volume of distribution (Vd) and half-life (t_1/2) of caffeine and trimethadione were the same, however, there was a weak correlation between the CL of caffeine and trimethadione [alone: r = 0.51 (P<0.05); coadministered: r = 0.56 (P<0.05)]. There were also weak correlations between the CL of trimethadione and the area under the serum concentration-time curves (AUC) of theobromine (r= —0.61, P<0.05), paraxanthine (r = ?0.69, P<0.05) and theophylline (r = ?0.60. P<0.05), when the two drugs were administered alone. After combined administration, the correlation between the CL of trimethadione and the AUCs of the metabolites of caffeine were as follows: theobromine r = ?0.63 (P<0.05); paraxanthine r = ?0.68 (P<0.05); theophylline r = ?0.65 (P<0.05). These findings suggest that caffeine and trimethadione metabolism in healthy subjects is mediated by only in part by a form(s) of P450 enzymes involved.     

新抗病毒抗生素17997在大鼠体内药代动力学和组织分布研究

目的:建立大鼠血浆、胆汁和组织中17997的高效液相色谱测定法,研究大鼠静脉注射17997后药代动力学、组织分布和胆汁排泄,以及血浆蛋白结合率。方法:SD大鼠以 4或1 mg·kg~(-1)剂量尾静脉注射给药,按实验设计采集血样、组织、胆汁,用HPLC法测定药物浓度;血浆蛋白结合率用平衡透析法测定。结果:17997保留时间为约7.0min;大鼠静脉推注4mg·kg~(-1)17997后药代动力学参数如下:消除半衰期为75.71 min,C_0为4.51μg·mL~(-1),清除率为52.5mL·min~(-1)·kg~(-1),药时曲线下面积AUC为76.16 min·μg·mL~(-1);给药后15 min 17997在大鼠体内组织分布依次为肺16.55 μg·g~(-1)、十二指肠7.34 μg·g~(-1)、肝6.51 μg·g~(-1)、心4.18 μg·g~(-1)、肾3.31 μg·g~(-1)、脾3.12 μg·g~(-1)、胸腺1.83 μg·g~(-1)和淋巴结0.74 μg·g~(-1)。大鼠静脉推注4、1mg·kg~(-1)17997后24 h胆汁排泄率分别为(55.4±9.4)％和(58.8±11.8)％;大鼠血浆蛋白结合率为(92.27±2.91)％。结论:本实验建立了测定大鼠血浆、胆汁和组织中17997的高效液相色谱紫外检测法,操作便捷,高效灵敏,样品用量少。大鼠静脉推注17997后体内分布排泄速度较快,肺组织浓度最高,蛋白结合率高,主要通过胆汁排泄。应用于临床时,需综合考虑各种因素对     

The Metabolism and Disposition of 14C-Indolidan,a Potent and Orally Active Cardiotonic Agent,in Four Species of Laboratory Animals

1. The metabolism and disposition of ¹⁴C-indolidan, a potent, orally-active positive inotrope with vasodilator properties, has been studied after single dose oral administration to rats, mice, dogs and monkeys.

2. Excretion of ¹⁴C in all 4 species was mostly via the urine, largely as parent drug together with two other major metabolites.

3. The two metabolites have been isolated and identified, by mass spectroscopy and ¹H-n.m.r., as a dehydro-compound, with a double bond in the pyridazanone ring, and a hydroxylated derivative of the parent drug.

4. Plasma t_1/2 values, based on ¹⁴C, were 14 h in dog, 5 h in mouse and 8 h in monkey. Plasma t_1/2 of parent drug, by h.p.l.c. was 10 h in dog, approx. 5h in rodents, and 8h in monkeys.

5. Tissue distribution in rats showed no accumulation in any tissue; ¹⁴C concn. in all tissues were indistinguishable from background 48 h after dosage. ¹⁴C peaked at 6–8 h for most tissues but in blood and plasma, ¹⁴C was maximal 1 h after dosing.     

Glucagon Produced by Recombinant DNA Technology: Repeated Dose Toxicity Studies,Intravenous Administration to CD Rats and Beagle Dogs for Four Weeks

The toxicity of glucagon produced by recombinant DNA technology (Glucagon (ge)^®) was studied by daily intravenous administration to rats and dogs for 4 weeks. Pancreatic glucagon of bovine or porcine origin (Glucagon Novo^®) was used as a reference control in the dogs. Glucagon (ge)^® has the same sequence of the 29 animo acids as pancreatic glucagon of humans, cows, pigs, rats and dogs. The dosages were 0 (control), 0.2, 1.0 and 5.0 mg Glucagon (ge)^®/kg/day in the rats, and 0 (control), 1.0 and 5.0 mg Glucagon (ge)^® and 5.0 mg Glucagon (Novo)^®/kg/day in the dogs. The studies complied with current EEC, US and Japanese guidelines for 4 week toxicity studies of drugs. All dose levels were well tolerated. The plasma glucose and cardiovascular responses to dosing were monitored in the dogs and found to be in agreement with well-known effects of pancreatic glucagon. The most consistent finding in both species was an increase in liver weight. This change was without concomitant pathological deviations in the other parameters examined. There were no differences in the reaction of dogs following treatment with Glucagon (ge)^® or Glucagon (Novo)^®. A dose of 1 mg Glucagon (ge)^®/kg/day was regarded as a clear no-toxic-effect-level in both species.     

四氯化碳、黄磷、三硝基甲苯引起肝纤维化及某些生化指标变化规律的研究

本研究分别给四组大鼠注射CCl_4、P_4、TNT及纯生油,进行亚慢性实验,在不同的时间处死动物,测定血清及肝组织NAG、CP、MAO、羟脯氨酸和肝组织病理观察。CCl_4染毒3周后就发生肝纤维化;P_4和TNT染毒12周后才发生肝纤维化。血清中NAG、CP及肝组织中NAG、羟辅氨酸含量在肝纤维化早期即有明显升高,其中血清NAG、CP与肝组织中羟脯氨酸含量有明显正相关关系。血清NAG、CP似可以用作了解肝纤维化情况的指标。     

Effect of Chronic Administration of Mestranol, Tamoxifen, and Toremifene on Hepatic Ploidy in Rats

The nonsteroidal antiestrogen tamoxifen increases the incidenceof rat liver cancer through a variety of mechanisms. To comparethe effects of tamoxifen (TAM) and a structurally similar analogtoremifene (TOR) on rat liver, we determined the ploidy distributionfor hepatocytes isolated from rats treated for 18 months withthese antiestrogens or the estrogenic compound mestranol (MS).Female Sprague-Dawley rats were subjected to a 70% partial hepatectomyand administered the solvent, trioctanoin, or diethyhiitrosamine(10 mg DEN/kg). After a 2-week recovery from the surgery, therats were administered a basal diet or one containing TAM (250or 500 ppm), TOR (250, 500, or 750 ppm), or MS (0.2 ppm) for18 months. Pathologic changes in the liver were examined inthe 15–22 rats per treatment group at the 18-month timepoint. An increased incidence of hepatocellular carcinomas (HCC)was detected in the 500 ppm TAM group, but not with the othertreatments that did not include DEN. Both TOR and TAM promotedformation of DEN-initiated HCCs. At sacrifice, four to fiverats per group were perfused and the hepatocytes isolated andcultured. Karyotypic analysis was performed on colcemid-blockedcells after 2 days in culture. The hepatic ploidy distributionwas characterized in Giemsa-stained metaphase spreads. Thesestudies indicated that chronic treatment with TAM alone resultedin a shift from tetraploid to diploid, as was also observedfor rats treated once with DEN. TOR and MS alone did not causethis change in hepatic ploidy at the doses examined. A shifttoward an increased content of diploid hepatocytes occurredin all rats treated once with DEN followed by TAM, TOR, or MS.These results indicate that tamoxifen administration resultsin a shift toward growth of diploid hepatocytes, thus contributingto its carcinogenic action in the rat liver.     

Neuroendocrine Response to Exogenous Ghrelin Administration,Combined With Alcohol,in Heavy-Drinking Individuals: Findings From a Randomized,Double-Blind,Placebo-Controlled Human Laboratory Study

BackgroundAccumulating evidence has established a role for the orexigenic hormone ghrelin in alcohol-seeking behaviors. Accordingly, the ghrelin system may represent a potential pharmacotherapeutic target for alcohol use disorder. Ghrelin modulates several neuroendocrine pathways, such as appetitive, metabolic, and stress-related hormones, which are particularly relevant in the context of alcohol use. The goal of the present study was to provide a comprehensive assessment of neuroendocrine response to exogenous ghrelin administration, combined with alcohol, in heavy-drinking individuals.MethodsThis was a randomized, crossover, double-blind, placebo-controlled human laboratory study, which included 2 experimental alcohol administration paradigms: i.v. alcohol self-administration and i.v. alcohol clamp. Each paradigm consisted of 2 counterbalanced sessions of i.v. ghrelin or placebo administration. Repeated blood samples were collected during each session, and peripheral concentrations of the following hormones were measured: leptin, glucagon-like peptide-1, pancreatic polypeptide, gastric inhibitory peptide, insulin, insulin-like growth factor-1, cortisol, prolactin, and aldosterone.ResultsDespite some statistical differences, findings were consistent across the 2 alcohol administration paradigms: i.v. ghrelin, compared to placebo, increased blood concentrations of glucagon-like peptide-1, pancreatic polypeptide, cortisol, and prolactin, both acutely and during the whole session. Lower levels of leptin and higher levels of aldosterone were also found during the ghrelin vs placebo session.ConclusionThese findings, gathered from a clinically relevant sample of heavy-drinking individuals with alcohol use disorder, provide a deeper insight into the complex interplay between ghrelin and appetitive, metabolic, and stress-related neuroendocrine pathways in the context of alcohol use.     

A Novel Pharmacokinetic Bridging Strategy to Support a Change in the Route of Administration for Biologics

Determination of appropriate pharmacokinetic end point to bridge different dosing regimens is often a challenge when developing a new route of administration. Trough concentrations (C_trough) are often considered the most relevant PK end point to predict efficacy (ACR20/DAS28) in the treatment of rheumatoid arthritis for biologics. However, no systematic research has been conducted to evaluate this approach. We developed a novel strategy to predict the most relevant PK variables that may be used to support a change in the route of administration for biological products. Our analysis indicated that matching only C_trough when switching from intravenous dosing to subcutaneous dosing with decreasing dosing interval may result in a lower treatment response. If only average concentration (C_ave) is considered as the relevant variable, our analysis showed that treatment response may be worsened when switching from subcutaneous dosing to intravenous dosing with increasing dosing interval. The study results demonstrated that matching a single pharmacokinetic end point (C_trough or C_ave) may not be sufficient to ensure efficacy when switching between intravenous dosing and subcutaneous dosing. A practical novel pharmacokinetic bridging approach is provided to support a change in the route of administration for biological products.     

Role of Dopamine Receptors on Electroencephalographic Changes Produced by Repetitive Apomorphine Treatments in Rats

Repeated psychostimulants induce electroencephalographic (EEG) changes, which reflect adaptation of the neural substrate related to dopaminergic pathways. To study the role of dopamine receptors in EEG changes, we examined the effect of apomorphine, the dopamine D1 receptor antagonist, SCH-23390, and the D2 receptor antagonist, haloperidol, on EEG in rats. For single and repeated apomorphine treatment groups, the rats received saline or apomorphine for 4 days followed by a 3-day withdrawal period and then apomorphine (2.5 mg/kg, i.p.) challenge after pretreatment with saline, SCH-23390, or haloperidol on the day of the experiment. EEGs from the frontal and parietal cortices were recorded. On the frontal cortex, apomorphine decreased the power of all the frequency bands in the single treatment group, and increased the theta (4.5~8 Hz) and alpha (8~13 Hz) powers in the repeated treatment group. Changes in both groups were reversed to the control values by SCH-23390. On the parietal cortex, single apomorphine treatment decreased the power of some frequency bands, which were reversed by haloperidol but not by SCH-23390. Repeated apomorphine treatment did not produce significant changes in the power profile. These results show that adaptation of dopamine pathways by repeated apomorphine treatment could be identified with EEG changes such as increases in theta and alpha power of the frontal cortex, and this adaptation may occur through changes in the D1 receptor and/or the D2 receptor.     

Hepatic Clearance of ONO-5046, a Novel Neutrophil Elastase Inhibitor,in Rats and in the Rat Perfused Liver

The hepatic clearance of ONO-5046 (N-[2-[4-(2,2-dimethylpropionyloxy)phenylsulphonyl-amino]benzoyl]aminoacetic acid), a low-molecular-weight neutrophil elastase inhibitor, has been investigated in rats and in the rat perfused liver. This ester was easily hydrolysed to its inactive metabolite EI-601 (N-[2-[(4-hydroxy-phenyl)sulphonylamino]benzoyl]aminoacetic acid) in liver homogenate and in erythrocytes suspension in-vitro. On the other hand, it was stable in biological media such as plasma and whole blood, which contain plasma proteins. Scatchard plot analysis of ONO-5046 binding to bovine serum albumin (BSA) in-vitro indicated that the association constant (K) and number of binding sites (n) were 6.91 times 10⁴ (M^?1) and 4.33, respectively. Thus, ONO-5046 (100 μM) would bind to plasma proteins to an extent >99% at physiological plasma-protein concentrations. The total plasma clearance of ONO-5046 in rats was constant (approximately 9 mL min^?1 kg^?1) under different steady-state plasma concentrations (5–50 μM) a value equivalent to the hepatic clearance. In the rat perfused liver, the hepatic extraction ratio of ONO-5046 was significantly reduced by adding BSA to the dosing solution. Thus, the relatively low hepatic clearance of ONO-5046, which has an ester linkage in its structure and is naturally susceptible to enzymatic hydrolysis, was found to be because of the extremely high protein-binding of the compound.     

Novel use of 308-nm excimer laser to treat a primary cutaneous CD30+ lymphoproliferative nodule

CD30+ cutaneous lymphoproliferative disorders, the second most common cutaneous T cell lymphoma after mycosis fungoides, represent a spectrum of conditions ranging from lymphomatoid papulosis to borderline CD30+ lesions to anaplastic large-cell lymphoma. We report the case of a solitary cutaneous CD30+ lymphoproliferative nodule that was successfully treated with a 308-nm excimer laser. Our findings suggest that the 308-nm excimer laser may be a safe, effective, and well-tolerated therapy for primary localized CD30+ cutaneous lymphoproliferative lesions.     

Combined toxicity to HeLa cells of 30 drug pairs,studied by a two-dimensional microtitre method

The complete pattern of the cytotoxic interaction of two drugs may be obtained in a single test, by incubation of the drugs, diluted at a right angle to each other in the same area of a microtitration plate, with HeLa cells, grown at a density of 5.10⁴ cells/ml in Parker's medium 199 plus 5% calf serum at 37°C for 7 days, and the recording of cyto-inhibition in all cups of the plate by microscopy after 24 h, supplemented by the study of pH-change of the medium after 7 days. Thirty drug combinations were tested by this method; most developed an additive pattern, while minor groups developed patterns of no interference, potentiative antagonism or supra-additive synergism.     

Continuous Administration of Low Dose Rates of Physostigmine and Hyoscine to Guinea-pigs Prevents the Toxicity and Reduces the Incapacitation Produced by Soman Poisoning

Abstract— A regime was developed, using mini-osmotic pumps, for the continuous subcutaneous administration of low doses of physostigmine (12.1, 9.7, 4.85 and 2.43 μgh^?1), in combination with hyoscine (1.94 or 0.39 μg h^?1), to guinea-pigs for up to 13 days. Physostigmine, in combination with hyoscine, inhibited plasma Cholinesterase, and red blood cell and brain acetylcholinesterase, in a concentration-dependent manner, did not affect the normal growth rate of guinea-pigs, and produced no obvious signs of poisoning. A dose rate of 4.85 μg h^?1 physostigmine and 1.94 μg h^?1 hyoscine was required to inhibit red cell acetylcholinesterase by 30% and brain acetylcholinesterase by 5–15%, with an accompanying plasma hyoscine concentration of 700–850 pg mL^?1. There was an apparent decline in red cell acetylcholinesterase activity during the 13 days. Hyoscine levels were higher in the cholinergic-rich areas of the brain than in the plasma. Continuous pretreatment (1 or 6 days) with physostigmine (4.84 μg h^?1) and hyoscine (1.94 μg h^?1) provided complete protection against the lethal effects, and minimized the incapacitation and weight loss produced by soman at a dose equivalent to the LD99 value. Following soman challenge, guinea-pigs exhibited early signs of soman poisoning, but generally these signs of poisoning were minimal by 1–2 h. Extending the pretreatment time to 13 days protected 75% of the guinea-pigs against the lethal effects of soman poisoning. Red cell acetylcholinesterase activity, 24 h after soman poisoning, was higher following continuous pretreatment with physostigmine and hyoscine than after acute treatment with atropine.     

Improvement of Parameter Estimations in Tumor Growth Inhibition Models on Xenografted Animals: a Novel Method to Handle the Interval Censoring Caused by Measurement of Smaller Tumors

The purpose of this study was to explore the interval censoring induced by caliper measurements on smaller tumors during tumor growth experiments in preclinical studies and to show its impact on parameter estimations. A new approach, the so-called interval-M3 method, is proposed to specifically handle this type of data. Thereby, the interval-M3 method was challenged with different methods (including classical methods for handling below quantification limit values) using Stochastic Simulation and Estimation process to take into account the censoring. In this way, 1000 datasets were simulated under the design of a typical of tumor growth study in xenografted mice, and then, each method was used for parameter estimation on the simulated datasets. Relative bias and relative root mean square error (relative RMSE) were consequently computed for comparison purpose. By not considering the censoring, parameter estimations appeared to be biased and particularly the cytotoxic effect parameter, k ₂ , which is the parameter of interest to characterize the efficacy of a compound in oncology. The best performance was noted with the interval-M3 method which properly takes into account the interval censoring induced by caliper measurement, giving overall unbiased estimations for all parameters and especially for the antitumor effect parameter (relative bias?= 0.49%, and relative RMSE?=?4.06%).