Dose-activity Relationship Research Articles

Generalized Likelihood Ratios for Designing Dose Optimization Studies of Targeted Therapies

Dose optimization studies of new therapeutic agents aim to identify one or more promising doses for further evaluation in subsequent studies. Traditionally, dose optimization has focused on finding the maximum tolerated dose (MTD), assuming that drug activity and efficacy generally increase with increasing dose. For modern targeted agents, the dose-activity relationship is often non-monotone and such that activity starts to plateau or even decline before reaching the MTD. Finding the optimal biological dose (OBD) for a targeted agent requires considering both toxicity and activity in dose optimization. This article proposes a new design for finding the OBD that utilizes generalized likelihood ratios (GLRs) to measure statistical evidence regarding key scientific questions on toxicity and activity. This GLR-based design requires no parametric modeling assumptions and only assumes that the dose-toxicity relationship is monotone and that the dose-activity relationship follows a two-sided isotonic regression model. Compared with existing designs that operate under similar assumptions, the GLR-based design is more general and more flexible, and performs competitively in simulation experiments where drug activity starts to plateau or decline before reaching the MTD.

Change-point joint model for identification of plateau of activity in early phase trials.

This article presents a phase I/II trial design for targeted therapies and immunotherapies, with the objective of identifying the optimal dose (OD). We employ a joint modeling technique for discrete time-to-event toxicity data and repeated and continuous biomarker measurements. For the biomarker measurements, we implement a change point linear mixed effects skeleton model. This model can accommodate both plateauing and nonplateauing dose-activity relationships. For each new cohort of patients, we estimate the maximum tolerated dose (MTD) taking toxicity as a cumulative endpoint, over six treatment cycles. Then, we select the OD using two different criteria. The OD is a dose that is equally active to the MTD or a dose located on the beginning of the plateau of the dose-activity relationship. Joint modeling allows us to take into account informative censoring due to toxicities or lack of activity and we also consider consent withdrawal and intermittent missing responses. Model estimation relies on likelihood inference.

Pharmacological activities of myricetin and its glycosides

Myricetin and its glycosides are important flavonols commonly found in plants, and they are natural organic compounds with diverse pharmacological activities. Numerous studies have demonstrated that myricetin and its glycosides are strong antioxidants that have great potential in preventing, alleviating and assisting the treatment of chronic non-infectious diseases such as cancer, diabetes, and cardiovascular diseases. In addition, myricetin and its glycosides also have antiviral, antibacterial, anti-inflammatory, analgesic, liver protection and other pharmacological activities. Myricetin contains more hydroxyl groups in the parent ring structure than other flavonoids, so myricetin and its glycosides have stronger pharmacological activities than other flavonols or flavonoids such as quercetin and kaempferol. Therefore, myricetin and its glycosides have great development and application prospects. In this paper, the classification and distribution of myricetin and its glycosides, their pharmacological activity and mechanism, as well as comparison with other flavonoids were reviewed. In addition, limitations of the current research and application of myricetin and its glycosides were analyzed, and the further studies on pharmacological activities as well as their dose-activity relationship, structure-activity relationship, chemical modification, biosynthesis and application prospects of myricetin and its glycosides were discussed and proposed.

Phase I/II Platform Trial Design in pediatric cancer in relapse

Introduction In pediatric oncology, therapeutic strategies are limited for relapsed patients. Matching treatment to molecular abnormalities appears as a promising strategy. Due to the heterogeneity of the detected molecular abnormalities and the low number of pediatric patients, Gustave Roussy with the ITCC network has launched a platform trial of 10 phase I/II parallel arms. In each arm, the design integrates a Continual Reassessment Method (CRM) to identify the recommended phase 2 dose (RP2D) defined as the dose associated with 25 % of severe toxicity and an Ensign three-stage design to test whether preliminary estimate of the response rate is below 10 % versus higher than 30 % at the 10 % level with a 90 % power. The two stages are intricated as patients treated at the identified MTD will contribute to the activity assessment and vice versa. The objective of this presentation is to report on the operating characteristics of the chosen design, to illustrate the limits of the phase II cohorts plugged in phase I and the risk of missing an active dose due to erroneous dose selection. Methods Each arm is run independently. We performed a series of simulations to assess the performance of the design of the study. We investigated the probability to identify an active drug for various dose-toxicity and dose-activity relationship. In particular, we considered the case of narrow therapeutic index (doses below the MTD are not active), the case of plateau in activity and the case of active doses deemed too toxic. In each case, after identifying the MTD and applying the Ensign design, we performed the test and evaluated the power. We also re-estimated the risk of toxicity after completion of both the phase I and the phase II parts. Finally, the expected number of patient to be enrolled in this design, the percentage of correct dose recommendation and the percentage of arms declared positive will be provided for selected scenarios. Results For one arm, the percentage of correct MTD selection was 57 %, regardless of the dose-activity relation. If the MTD is active and associated with a 40 % response rate, a mean number of 32 patients were enrolled and the percentage of arm declared active was 86 %. Conversely, if the MTD is not active and associated with a 10 % response rate, a mean number of 26 patients were enrolled and the percentage of arms declared active reached 12 %. Moreover, if 50 % of arms were declared active, the total number of patients to be enrolled was 290. Finally, if all arms were stopped for lack of activity, the overall type error I was 28 %. So far, 77 patients have been enrolled and the key aspects of the statistical implementation will be provided. Conclusion This is the largest phase I/II pediatric program based on tumor biology running worldwide. This design enables to propose multiple personalized therapeutic options to improve comprehension and treatment of pediatric cancers. However, integration of phase I and II is appealing but raises practical difficulties due to variation in analysis populations for toxicity and activity or observation of responses at doses higher or lower than the RP2D. We showed that finding the correct MTD is key to select active treatments and more patients should be dedicated to dose finding.

Hypoglycemic and hypolipidemic effects of quercetin and its glycosides

Quercetin and its glycosides are important flavonols in traditional herbal drugs and plant-derived food, and they have diverse hiological activities such as antioxidant, anticarcinogenic, anti-inflammatory, hypoglycemic and hypolipidemic activities. Numerous studies have demonstrated that quercetin and its glycosides were effective in the prevention and treatment of non-infectious chronic disease such as diabetes, obesity, and hyperlipidemia. They can regulate glucose and lipid metaholism through different mechanisms. They can decrease blood glucose via protecting pancreatic/p cells or/and improving insulin sensitivity. Also, they have lipid-lowering effects, which may be the result of regulation of lipid catabolism or/and anabolism. Their distributions, as well as the hypoglycemic and hypolipidemic effects are reviewed in this paper. In addition, further bioactivities as well as their dose-activity relationship, structure-activity relationship, bioavailability, and future clinical application of quercetin and its glycosides are discussed and proposed.

Cytotoxic Effects of Methanolic Extract and Essential Oil of Artemisia kopetdaghensis

In this study, a methanolic extract and an essential oil of Artemisia kopetdaghensis were tested for possible Cytotoxic activity using potato disk assay. Seven concentration of methanolic extract and four concentration of the essential oil were applied on potato discs. The methanolic extract and essential oil of A. kopetdaghensis exhibited tumor growth induction at different concentrations but at concentration equal to 0.01 % (v/v) the essential oil of A. kopetdaghensis exhibited tumor growth inhibition (52 %). A dose activity relationship between methanolic extract and essential oil concentration with tumor growth on potato discs was observed.

In Vitro Binding of Heavy Metals by an Edible Biopolymer Poly(γ-glutamic acid)

An edible biopolymer poly(gamma-glutamic acid) (gamma-PGA) was evaluated for possible use as an chelating/binding agent in the treatment of metal intoxication in humans. In vitro binding of the toxic heavy metals lead and cadmium as affected by pH, contact time, metal concentration, gamma-PGA dose, and essential metals was carried out in a batch mode. A maximum binding occurred in the pH range 5-7, corresponding to the gastrointestinal pH values except for the stomach. Binding isotherms at pH 5.5 were well described by the heterogeneous models (Freundlich and Toth), while the lead isotherm at pH 2.5 showed a S-type curve, which was fitted as multiple curves with the Langmuir model and a shifted-squared Langmuir model. However, no adsorption occurred for cadmium at pH 2.5. The maximum binding capacities of lead and cadmium at pH 5.5 were 213.58 and 41.85 mg/g, respectively. A curvilinear biphasic Scatchard plot signified a multisite interaction of metals. Binding was extremely rapid with 70-100% of total adsorption being attained in 2 min. Kinetics at low and high metal concentrations obeyed pseudo-first-order and pseudo-second-order models, respectively. The gamma-PGA dose-activity relationship revealed a low dose of gamma-PGA to be more efficient in binding a large amount of metals. Incorporation of Cu, Zn, Fe, Mg, Ca, and K showed only a minor influence on lead binding but significantly reduced the binding of cadmium.

Antiviral activity of nano carbon fullerene lipidosome against influenza virus in vitro

The activity of nano carbon fullerene lipidosome (NCFL) against influenza virus H1N1 in vitro was studied by observing the cytotoxicities and its activity rendered by different intensities of lighting with various periods of time. Rimantadine hydrochloride was used as the positive control drug. By using microcultural technique, the morphological changes of cells were observed and by using the gentian violet staining, antiviral activity of the NCFL against influenza virus was assayed. The results showed that: (1) The maximal concentration of the NCFL was 7 microg/mL and the 50% toxic concentration (TC(50)) was 13.54 microg/mL respectively; (2) NCFL had a significant activity of directly killing the influenza virus, while the activities in antiadsorption and antireplication were not obvious; (3) There was a dose-activity relationship between the dosages of NCFL and the direct killing effect against the influenza virus, and the periods of lighting-time could influence the activity partly. It was concluded that NCFL had a significant activity of directly killing the influenza virus.

Hair Dosimetry Following Neutron Irradiation

Use of hair as a biological dosimeter of neutron exposure was proposed a few years ago. To date, the (32)S(n,p)(32)P reaction in hair with a threshold of 2.5 MeV is the best choice to determine the fast neutron dose using body activation. This information is essential with regards to the heterogeneity of the neutron transfer to the organism. This is a very important parameter for individual dose reconstruction from the surface to the deeper tissues. This evaluation is essential to the adapted management of irradiated victims by specialized medical staff. Comparison exercises between clinical biochemistry laboratories from French sites (the CEA and COGEMA) and from the IRSN were carried out to validate the measurement of (32)P activity in hair and to improve the techniques used to perform this examination. Hair was placed on a phantom and was irradiated at different doses in the SILENE reactor (Valduc, France). Different parameters were tested: variation of hair type, minimum weight of hair sample, hair wash before measurement, delivery period of results, and different irradiation configurations. The results obtained in these comparison exercises by the different laboratories showed an excellent correlation. This allowed the assessment of a dose-activity relationship and confirmed the feasibility and the interest of (32)P measurement in hair following fast neutron irradiation.

Cytotoxic and Antimycotic Activities of Essential Oil of Artemisia turanica Krasch from Iran

The cytotoxic and anti-fungal activities of Artemisia turanica essential oil were investigated. Also the composition of the essential oil of the plant was determined. For cytotoxic activity tests, a potato disc tumor inhibition method was exploited. For antifungal activity tests, a poisoned food technique against standard strains of Trichophyton rubrum, Trichoderma reesei, Microsporum gypseum and Aspergillus niger was adopted. The essential oils of A. turanica exhibited tumor growth inhibition (100 % ) inhibition at concentrations equal to 0.02 % (w/v) and higher. Thirteen components were identified in the essential oil of Artemisia turania. The main compounds consisted of 1,8-cineol (40.9 %), cis-verbenyl actate (19.0 %) and camphor (11.0 %). A dose activity relationship between the essential oil concentrations with inhibition of tumor growth on potato discs, and between the essential oil concentrations with antifungal activities was observed.

A rapid and simple assay method for UDP-glucose: ceramide glucosyltransferase

We have developed a simple rapid method for measuring UDP-glucose: ceramide glucsoyltransferase; the method utilizes ceramide immobilized on the surface of silica gell and [ 14C]UDP-glucose as substrate. The reaction product, [ 14C]glucosylceramide formed on the surface of the silica gel was easily separated from free [ 14C]UDP-glucose, either by centrifugation or by filtration. The reliability of this solid phase method was evaluated by using rat brain membrane fraction as an enzyme source. This enzyme had an optimal pH of 6.4–6.5 and required Mn 2+, Mg 2+ in the presence of 3-[(3-cholamidopropyl)dimethylammonio]-1- propanesulfonate (CHAPS). Apparent K m values of 8.7 μM for UDP-glucose and 292 μM for ceramide were determined using the new method. Under the optimal conditions, the solid phase method yielded 2–5 times more product than did the method using micellar system. Moreover, the reaction was highly quantitative in its enzyme dose-activity relationship.

Effects of Positive Inotropic Drugs on the Frequency of Contraction of the Isolated Atria: Influence of Dose Regimen and Age

The dose-activity relationship of various positive inotropic drugs has been investigated in the spontaneously beating right atria of the rat. The influence of dose regimen and age has been evaluated. There is a significant difference between the maximal response of single and cumulative dose experiments with amrinone (P less than 0.05) and dobutamine (P less than 0.001) in animals aged 2 months and in dopamine (P less than 0.001) in animals aged 4 months. The maximum response is lowered significantly with age for isoprenaline with single (P less than 0.05) and for dopamine and dobutamine with cumulative dosing (P less than 0.001). In the single dose study the response is achieved within 4 min. for isoprenaline, noradrenaline, dobutamine, xamoterol and amrinone, but not until after 14 min. for prenalterol. It is concluded that both age and methods used in the study of pharmacodynamics are important. Thus when comparing effects the use of the same method and tissue from rats of the same age is necessary.

Antibacterial activity of cefpodoxime proxetil in a pharmacokinetic in-vitro model

The antibacterial activity of cefpodoxime proxetil was studied in an in-vitro model simulating doses of 100, 200 and 400 mg. Strains of Klebsiella spp. Proteus mirabilis, Escherichia coli, Streptococcus pyogenes, and Haemophilus influenzae were effectively reduced by a dose of 200 mg. While for Esch. coli no dose-activity relationship was observed--the maximal effect was achieved with a simulated dose of 100 mg--Staphylococcus aureus could be reduced effectively only by a simulated dose of 400 mg. The lower doses showed stepwise lower activities. Apart from broad spectrum beta-lactamases like SHV 2 or TEM 5 the presence of plasmid coded beta-lactamases in Esch. coli and H. influenzae did not affect the antibacterial activity of cefpodoxime proxetil. The results show that cefpodoxime was more active against Gram-negative bacteria than amoxycillin, and comparable activity to intramuscular cefotiam in the in-vitro model.

Antitumor properties of organometallic metallocene complexes of tin and germanium.

The antitumor activity of the four metallocene compounds decaphenylstannocene [eta 5-(C6H5)5C5]2Sn(II), decabenzylstannocene [eta 5-(C6H5CH2)5C5]2Sn(II), decaphenylgermanocene [eta 5-(C6H5)5C5]2Ge(II), and decabenzylgermanocene [eta 5-(C6H5CH2)5C5]2Ge(II), containing the main group IV elements tin or germanium as the central metal atom and two pentasubstituted cyclopentadienyl ring ligands in sandwich arrangement, were tested against Ehrlich ascites tumor in female CF1 mice. The complexes caused cure rates of 40% to 90% of the animals treated over rather broad dose ranges. With both germanocene complexes, no strong dose-activity relationship was manifest. The toxicity of all four metallocenes was low, the LD10 values of both stannocenes being 460 and 500 mg/kg, and those of both germanocenes higher than 700 mg/kg. Regarding the isolated pentasubstituted cyclopentadiene ligands (C6H5)5C5H and (C6H5CH2)5C5H, these also exhibited antitumor activity which was less pronounced than that of the metal-containing sandwich complexes. Decasubstituted stannocene and germanocene compounds represent a new type of non-platinum group metal antitumor agents structurally differing from known inorganic and organometallic cytostatics.

Generation of Cytotoxic T Lymphocytes in Vitro

Abstract Subcellular particulate membrane fragments prepared from murine lymphoid or tumor cells were used as a cell-free antigen source in order to stimulate the generation of cytolytic thymus-derived effector cells (CTL) in vitro. When cultivated with normal spleen cells as a source of responding lymphocytes, particulate antigen preparations induced only low CTL activities; in contrast, virtually normal responses were observed when immune spleens were used as a source of responding cells. In both cases, results were compared to those responses obtained with intact irradiated (1000 rads) normal spleen cells as stimulating antigen. The effector cells generated with particulate antigen preparations (obtained either by hypotonic shock or by sonication) were shown to be T cells and were characterized with regard to the kinetics of their response and their dose-activity relationship. It was also shown that the responses observed were specific, both at the level of initiation and at the effector level. The results obtained suggest that there exists a fundamental difference between normal and alloimmune spleen cells in their ability to respond in vitro to stimulation by subcellular antigen preparations.