Schedule Of Drug Delivery Research Articles

The progressive ratio and fixed ratio 1 schedules of cocaine self-administration in rats convey the same information

Progressive ratio (PR) schedules of drug delivery are used to determine the ‘motivational’ state of an animal and drug ‘reinforcing efficacy’. This widely held interpretation is supported mainly by the observation that the PR breakpoint (BP) is proportional to the unit dose of self-administered drug. The compulsion zone theory of cocaine self-administration was applied to determine whether it can explain the pattern of lever-pressing behavior and cocaine injections under the PR schedule in rats. This theory states that cocaine induces lever pressing when levels are below the satiety threshold and above the priming/remission threshold. Rats were trained to self-administer cocaine on a fixed ratio FR1 schedule over a range of cocaine unit doses. Then they were switched to a PR schedule. Typical for the self-administration under a PR schedule, long post-injection pauses occurred when calculated cocaine levels were in the satiety zone. The compulsion zone theory interprets BP simply as the maximal number of responses which rats can perform after an injection while cocaine levels remain within the compulsion zone. The thresholds delineating the compulsion zone were very stable and independent of the self-administration schedule. PR and fixed ratio schedules convey the same pharmacokinetic/pharmacodynamic information, i.e., these two schedules are invariant.

Role of preexisting inhibitory control deficits vs. drug use history in mediating insensitivity to aversive consequences in a rat model of polysubstance use.

RationaleThe nature and predictors of insensitivity to aversive consequences of heroin + cocaine polysubstance use are not well characterized.ObjectivesTranslational methods incorporating a tightly controlled animal model of drug self-administration and measures of inhibitory control and avoidance behavior might be helpful for clarifying this issue.MethodsThe key approach for distinguishing potential contributions of pre-existing inhibitory control deficits vs. drug use history in meditating insensitivity to aversive consequences was comparison of two rat strains: Wistar (WIS/Crl), an outbred strain, and the spontaneously hypertensive rat (SHR/NCrl), an inbred strain shown previously to exhibit heightened cocaine and heroin self-administration and poor inhibitory control relative to WIS/Crl.ResultsIn separate tasks, SHR/NCrl displayed greater impulsive action and compulsive-like behavior than WIS/Crl prior to drug exposure. Under two different schedules of drug delivery, SHR/NCrl self-administered more cocaine than WIS/Crl, but self-administered a similar amount of heroin + cocaine as WIS/Crl. When half the session cycles were punished by random foot shock, SHR/NCrl initially were less sensitive to punishment than WIS/Crl when self-administering cocaine, but were similarly insensitive to punishment when self-administering heroin + cocaine. Based on correlation analyses, only trait impulsivity predicted avoidance capacity in rats self-administering cocaine and receiving yoked-saline. In contrast, only amount of drug use predicted avoidance capacity in rats self-administering heroin + cocaine. Additionally, baseline drug seeking and taking predicted punishment insensitivity in rats self-administering cocaine or heroin + cocaine.ConclusionsBased on the findings revealed in this animal model, human laboratory research concerning the nature and predictors of insensitivity to aversive consequences in heroin and cocaine polysubstance vs. monosubstance users is warranted.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00213-022-06134-4.

Dramatic increase in lever-pressing activity in rats after training on the progressive ratio schedule of cocaine self-administration

Transition from the highest rate of lever-pressing activity during the unloading (extinction) phase of a cocaine self-administration session to an extremely low activity rate during the remission phase is in many cases gradual. This makes it difficult to assess the duration of the unloading phase after a fixed ratio 1 (FR1) or breakpoint after a progressive-ratio (PR) self-administration session. In addition, 3–5 days of training under the PR schedule results in a dramatic and persistent increase in the rate of presses during PR sessions and in the unloading phase following FR1 self-administration sessions. The goals of this study were to find the definition of the last press demarcating the border between the unloading and remission phases of the session and to determine if this border was also affected by PR training. Rats were trained to self-administer cocaine under the FR1 schedule and then under the PR schedule of drug delivery. Distributions of inter-press intervals (IPIs) during the unloading phase in sessions before and after PR training were compared. It was found that the distribution of cocaine-induced IPIs during the unloading phase was lognormal, bimodal, and independent of previously injected cocaine unit doses. The first mode represented intervals within the short bouts of stereotypic presses and the second mode represented intervals between bouts. The two modes were approximately 0.7 s and 21 s during unloading prior to and 0.6 s and 1.5 s after PR self-administration training. The total number of presses per unloading phase increased eightfold. When the FR1 schedule was restored, the intervals between bouts remained very short for at least 7–10 days and only then started a gradual increase towards baseline levels. The last unloading press was defined as the press followed by the IPI longer than the defined criterion. PR training resulted in a substantial and long-lasting increase in lever-pressing activity during unloading. The duration of the unloading phase did not depend on the rate of lever-pressing activity.

Methodological and analytical issues of progressive ratio schedules: Definition and scaling of breakpoint

BackgroundThe break point (BP) of the progressive ratio (PR) schedule of drug delivery is a well-recognized parameter in self-administration studies. Nonetheless, two problems remain unresolved: there is no rationally justified criterion for the last response at BP; the both commonly used definitions of BP as the number of deliveries or the last complete progressive ratio requirement are not the best assuming that BP is a measure of motivation. New MethodA criterion for the last lever press is proposed in this study using intravenous cocaine self-administration in rats. The rationale is based on the finding that long inter-press intervals have initially very low probability to occur during the self-administration phase of the session under the PR schedule. But this probability dramatically increases when inter-injection intervals increase due to high ratio requirements. ResultsFor cocaine these critical inter-press intervals were 7.5 min and longer. This novel criterion was applied to measure BP according to all four theoretically plausible definitions of BP including the new one: the higher of the two numbers of presses before or after the last delivery of the reinforcer. Comparison with Existing MethodThe conventionally defined BP is significantly lower (by 12 %) than BP defined according to the new proposed definition. The new definition of BP provides not only a more accurate value of BP but now the variance of BP at different cocaine doses is homogeneous as required by many statistical tests. ConclusionThese new definitions of the last press and BP provide more accurate and statistically homogenous measure of BP.

Oxidation-Responsive, Tunable Growth Factor Delivery from Polyelectrolyte-Coated Implants.

Polyelectrolyte multilayer (PEM) coatings, constructed on the surfaces of tissue engineering scaffolds using layer-by-layer assembly (LbL), promote sustained release of therapeutic molecules and have enabled regeneration of large-scale, pre-clinical bone defects. However, these systems primarily rely on non-specific hydrolysis of PEM components to foster drug release, and their pre-determined drug delivery schedules potentially limit future translation into innately heterogeneous patient populations. To trigger therapeutic delivery directly in response to local environmental stimuli, an LbL-compatible polycation solely degraded by cell-generated reactive oxygen species (ROS) was synthesized. These thioketal-based polymers were selectively cleaved by physiologic doses of ROS, stably incorporated into PEM films alongside growth factors, and facilitated tunable release of therapeutic bone morphogenetic protein-2 (BMP-2) upon oxidation. These coatings' sensitivity to oxidation was also dependent on the polyanions used in film construction, providing a simple method for enhancing ROS-mediated protein delivery in vitro. Correspondingly, when implanted in critically-sized rat calvarial defects, the most sensitive ROS-responsive coatings generated a 50% increase in bone regeneration compared with less sensitive formulations and demonstrated a nearly threefold extension in BMP-2 delivery half-life over conventional hydrolytically-sensitive coatings. These combined results highlight the potential of environmentally-responsive PEM coatings as tunable drug delivery systems for regenerative medicine.

Abstract 1385: In vitro evaluation of platinum chemotherapy combinations with the ATR inhibitor, ceralasertib (AZD6738)

Abstract Introduction: The combination of platinum-based chemotherapy with inhibitors of the DNA damage response (DDR) is therapeutically challenging due to overlapping toxicities, such as myelosuppression. The optimal sequence and schedule of drug delivery to mitigate toxicity and maximise efficacy has not been determined for many combinations. Ceralasertib is an oral inhibitor of ATR, a key constituent of the DDR. Ceralasertib has entered early phase clinical trials in combination with carboplatin (NCT02264678). The aim of the current study was to investigate the mechanism of interaction of ceralasertib with platinum (Pt) chemotherapy, characterising the formation and removal of Pt-induced DNA adducts, in order to provide insight into the repair and recovery of DNA following combination treatment. Methods: The growth inhibitory effects of ceralasertib alone and in combination with cisplatin were tested using sulphorhodamine B (SRB) colorimetric assays in a panel of non-small cell lung (H460 and H23) and breast (MCF7, T47D, HCC1806, MDA-MB-436 and MDA-MB-468) cancer cell lines. Median effect analysis using CalcuSyn software (Biosoft, Cambridge, UK) was used to evaluate synergistic combinations. Time- and schedule-dependent analyses of Pt-DNA adduct formation in cells treated with the combination were carried out using inductively-coupled mass spectrometry (ICP-MS). Cell cycle analysis and DNA replication combing assays were performed to explore alternative mechanisms of synergy between ceralasertib and cisplatin. Results: Ceralasertib was synergistic with cisplatin, inhibiting growth across the cell line panel. However, neither pre-exposure with either agent or co-exposure of cisplatin treated cells to ceralasertib affected the total number, nor longevity, of Pt-DNA adducts compared with cisplatin treatment alone. Continued exposure to ceralasertib for up to 48 hours following wash out of cisplatin (after 4, 8 or 24 hours treatment) did not maintain Pt-induced adducts within the DNA. Peak Pt-DNA adduct formation did not consistently correlate with cell line sensitivity to either drug, combination synergy score, or the effects of ceralasertib or cisplatin on cell cycle progression. Combination treatment did result in a reduction in replication fork speed, but this effect was no greater than that seen with ceralasertib monotherapy. Conclusion: Synergy was observed between cisplatin and ceralasertib in the cell lines tested. However, our in vitro data suggests that this is not associated with an interaction at the level of Pt-DNA adduct formation. Citation Format: Sally E. Hall, Alan Lau, Emma Dean, Elizabeth Martin, Christopher Ottley, Yvette Drew, Gareth Veal. In vitro evaluation of platinum chemotherapy combinations with the ATR inhibitor, ceralasertib (AZD6738) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1385.

A PROGNOSTIC IMMUNOTHERAPY MODEL FOR 4T1 BREAST CANCER WITH COMBINED CYCLOPHOSPHAMIDE AND TLR AGONIST

Based on experimental results of a mouse model provided in the literature, we develop a mathematical model by using system biology approach, aiming to investigate immunotherapy for 4T1 breast cancer. It is worth to mention that only 4 types of cells (tumor cells, CD8[Formula: see text] T cells, regular T cells (Tregs), and tumoricidal myeloid CD11b[Formula: see text]Gr1dim cells) are quantitatively measured in experiments, which make the immunotherapy modelling more difficult since only limited system knowledge is available. To overcome the difficulty, the mathematical model is proposed by employing Evolutionary Computation to optimize the system parameters. Furthermore, with the mathematical model, analysis can be conducted to capture the inherent properties of the model, such as the number and stability of equilibria, and parameter sensitivity analysis, which disclose the nature of 4T1 breast cancer from a system biological perspective. Not limited to replication of experimental results, we further show that the mathematical model is in fact a prognostic immunotherapy model that can predict treatment outcomes of various cases; for instance, different combinations of drug delivery schedules. By virtue of computational convenience, it is relatively easy to intensively investigate most of the treatments that are impossible for animal models or clinical trials. In other words, a mathematical model based on system biology can provide meaningful reference when exploiting more effective treatment protocols.

Bioresorbable photonic devices for the spectroscopic characterization of physiological status and neural activity.

Capabilities in real-time monitoring of internal physiological processes could inform pharmacological drug-delivery schedules, surgical intervention procedures and the management of recovery and rehabilitation. Current methods rely on external imaging techniques or implantable sensors, without the ability to provide continuous information over clinically relevant timescales, and/or with requirements in surgical procedures with associated costs and risks. Here, we describe injectable classes of photonic devices, made entirely of materials that naturally resorb and undergo clearance from the body after a controlled operational lifetime, for the spectroscopic characterization of targeted tissues and biofluids. As an example application, we show that the devices can be used for the continuous monitoring of cerebral temperature, oxygenation and neural activity in freely moving mice. These types of devices should prove useful in fundamental studies of disease pathology, in neuroscience research, in surgical procedures and in monitoring of recovery from injury or illness.

Evolution of cancer cell populations under cytotoxic therapy and treatment optimisation: insight from a phenotype-structured model

We consider a phenotype-structured model of evolutionary dynamics in a population of cancer cells exposed to the action of a cytotoxic drug. The model consists of a nonlocal parabolic equation governing the evolution of the cell population density function. We develop a novel method for constructing exact solutions to the model equation, which allows for a systematic investigation of the way in which the size and the phenotypic composition of the cell population change in response to variations of the drug dose and other evolutionary parameters. Moreover, we address numerical optimal control for a calibrated version of the model based on biological data from the existing literature, in order to identify the drug delivery schedule that makes it possible to minimise either the population size at the end of the treatment or the average population size during the course of treatment. The results obtained challenge the notion that traditional high-dose therapy represents a “one-fits-all solution” in anticancer therapy by showing that the continuous administration of a relatively low dose of the cytotoxic drug performs more closely to i.e. the optimal dosing regimen to minimise the average size of the cancer cell population during the course of treatment.

Mathematical Approach to Differentiate Spontaneous and Induced Evolution to Drug Resistance During Cancer Treatment.

PurposeDrug resistance is a major impediment to the success of cancer treatment. Resistance is typically thought to arise from random genetic mutations, after which mutated cells expand via Darwinian selection. However, recent experimental evidence suggests that progression to drug resistance need not occur randomly, but instead may be induced by the treatment itself via either genetic changes or epigenetic alterations. This relatively novel notion of resistance complicates the already challenging task of designing effective treatment protocols.Materials and MethodsTo better understand resistance, we have developed a mathematical modeling framework that incorporates both spontaneous and drug-induced resistance.ResultsOur model demonstrates that the ability of a drug to induce resistance can result in qualitatively different responses to the same drug dose and delivery schedule. We have also proven that the induction parameter in our model is theoretically identifiable and propose an in vitro protocol that could be used to determine a treatment’s propensity to induce resistance.

Demand for Methamphetamine and Methcathinone Under Fixed Ratio and Second‐Order Schedules of Reinforcement

Behavioral economic procedures, e.g., demand curve analysis, provide powerful quantitative metrics for scaling the strength of drugs of abuse. Most studies that have utilized such procedures employ simple fixed ratio (FR) schedules of reinforcement to generate demand curves. However, second‐order schedules, in which a subject responds under one schedule of conditioned reinforcement (e.g., for presentation of a brief light stimulus) that is nested within a second schedule of primary reinforcement, have been suggested to more accurately reflect the complex patterns of behavior that accompany human drug taking. Further, the conditioned stimulus presented during second order schedules may develop conditioned reinforcer properties that serve to maintain drug‐taking behavior in their own right. The objective of the present study was to begin to compare self‐administration and demand for intravenous methamphetamine and methcathinone under both simple FR and second‐order schedules of reinforcement in nonhuman primates. Adult male squirrel monkeys (N=4) with histories of stimulant self‐administration responded for intravenous methamphetamine and methcathinone injections under FR10 and FR10(FR5:S) schedules of reinforcement. After self‐administration of vehicle and a range of methamphetamine (0.001–0.1 mg/kg) and methcathinone (0.001–0.1 mg/kg) doses were evaluated under each schedule, two doses of each drug (0.01 and 0.03 mg/kg/inj) were studied using a demand procedure; for the FR condition, the response requirement for drug delivery increased across multiple sessions in an ascending order, i.e. FR 10, 30, 56, 100, etc. For the second‐order condition, the response requirement for the drug delivery schedule increased according to a similar progression (i.e., FR10(FR5:S), FR30(FR5:S), FR56(FR5:S), etc.). Each condition was presented in a random order that was counterbalanced across subjects. Results indicate that methamphetamine and methcathinone self‐administration followed an inverted‐U shaped pattern with similar total intake (mg/kg) under the two schedules of reinforcement. During demand procedures, both methamphetamine and methcathinone self‐administration gradually decreased as the response requirement was increased. Application of the exponential model of demand shows that the higher dose of methamphetamine (0.03 mg/kg) produced slightly greater breakpoints than the lower dose (0.01 mg/kg) under both schedule conditions whereas demand for methcathinone was generally higher under FR than second‐order schedules regardless of dose. Interestingly, demand for the high doses of the two drugs was less elastic under the FR condition, whereas demand for the lower doses was more elastic under the second‐order schedule. These results suggest that the demand for self‐administered drugs may be influenced by schedule of reinforcement in a manner that varies across drugs. Further, the present results do not support a facilitative influence of conditioned reinforcement on the reinforcing strength of self‐administered drugs.Support or Funding InformationThis work was funded by National Institutes of Health grants DA002519 and DA039306This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The toxicity profile of TAS-102. Practical considerations about neutropenia.

TAS-102 represents an important therapeutic resource for patients with metastatic refractory colorectal cancer. Albeit generally well tolerated, clinically relevant neutropenia may interfere with the regular delivery of full-dose cycles with a possible detrimental effect on the dose-intensity. Judicious and personalized use of colony-stimulating growth factors as well as alterative schedules of drug delivery could mitigate neutropenia, so contributing to an even better therapeutic index of the drug.

Chronic Administration of Pimozide Fails to Attenuate Motor and Pathological Deficits in Two Mouse Models of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which presently does not have any efficient therapeutic approach. Pimozide, a Food and Drug Administration (FDA)-approved neuroepileptic drug, has been recently proposed as a promising treatment for ALS patients based on apparent stabilization of right hand muscles after a short-time administration. A new clinical trial started at the end of 2017 to recruit patients with a prolonged drug delivery schedule. Here, our aim was to investigate the effects of chronic administration of pimozide on disease progression and pathological events in two mouse models of ALS. Pimozide was administered every 2 days to transgenic mice bearing the ALS-linked A315T mutation on the human TAR DNA-binding protein 43 (TDP-43) gene and to mice carrying the human superoxide dismutase 1 (SOD1) gene with the ALS-linked G93A mutation. Chronic administration of pimozide exacerbated motor performances in both animal models and reduced survival in SOD1G93A mice. In TDP-43A315T, it decreased the percentage of innervated neuromuscular junctions (NMJs) and increased the accumulation of insoluble TDP-43. In SOD1G93A mice, pimozide had no effects on NMJ innervation or motoneuron loss, but it increased the levels of misfolded SOD1. We conclude that a chronic administration of pimozide did not confer beneficial effects on disease progression in two mouse models of ALS. In light of a new clinical trial on ALS patients with a chronic regime of pimozide, these results with mouse models suggest prudence and careful monitoring of ALS patients subjected to pimozide treatment.

Immune response to infection by Leishmania: A mathematical model

Leishmaniasis is a disease caused by the Leishmania parasites. The injection of the parasites into the host occurs when a sand fly, which is the vector, bites the skin of the host. The parasites, which are obligate, take advantage of the immune system response and invade both the classically activated macrophages (M1) and the alternatively activated macrophages (M2). In this paper, we develop a mathematical model to explain the evolution of the disease. Simulations of the model show that, M2 macrophages steadily increase and M1 macrophages steadily decrease, while M1+M2 reach a steady state which is approximately the same as at healthy state of the host. Furthermore, the ratio of Leishmania parasites to macrophages depends homogeneously on their ratio at the time of the initial infection, in agreement with in vitro experimental data. The model is used to simulate treatment by existing or potential new drugs, and to compare the efficacy of different schedules of drug delivery.

Novel agents and treatment techniques to enhance radiotherapeutic outcomes in carcinoma of the uterine cervix.

Survival of patients with locally advanced carcinoma cervix (LACC) using the current standard of concurrent chemo-radiotherapy (CCRT) has reached a plateau over the last two decades. Loco-regional failure in first two years of treatment completion and distant metastasis in the subsequent years has put the survival curves at a halt. Strategies of induction and adjuvant chemotherapy have yielded little as has any advancement in techniques of delivery of radiation therapy. This article aims at discussing the current existing literature as well as promising novel strategies to enhance radiotherapeutic outcomes in carcinoma of the uterine cervix. The review of English literature included phase I-III trials evaluating either a novel agent, novel application/modifications of an existing treatment regimen or an innovative treatment technique. The studies have been divided in to subsections with summary of most important findings at the end of each section. Despite CCRT being the 'gold standard' treatment, several issues like optimum drug combination, schedule of drug delivery, combination with molecular targeted agents etc. remain undefined. Taxane, topoisomerase and gemcitabine based regimen needs to be further explored and compared with cisplatin based CCRT regimen. Several approaches like local delivery of cytotoxic agents, use of nano-medicine with CCRT are appearing on horizon with promises for the future. Therapies need to be designed based on the human papillomavirus titers of the patients and incorporation of radiosensitizers as an effective way of palliation with short course of radiotherapy may further enhance the radiotherapeutic outcomes. The results of the studies with novel agents and treatment techniques appear promising. Further research in this arena including incorporation of cost-effectiveness analysis and quality of life issues in future trial designs are warranted.

Random-ratio schedules produce greater demand for i.v. drug administration than fixed-ratio schedules in rhesus monkeys

Organisms emit more responses when food is provided according to random as compared with fixed schedules of reinforcement. Similarly, many human behaviors deemed compulsive are maintained on variable schedules (e.g., gambling). If greater amounts of behavior are maintained by drugs of abuse when earned according to variably reinforced schedules, this would suggest that excessive drug-taking behavior may be due in part to the nature of drug availability. The aim was to determine whether random schedules of contingent intravenous drug delivery would produce more responding than similarly priced fixed schedules. Six rhesus macaque subjects responded to produce cocaine (0.003-0.03mg/kg/inj), remifentanil (0.01-1.0μg/kg/inj), or ketamine (0.01-0.1mg/kg/inj) according to either fixed or random ratio requirements that increased systematically across sessions. Demand curves were generated with the most effective dose of each drug and compared across drug and schedule type. Cocaine and remifentanil maintained higher levels and rates of responding when earned according to random-ratio schedules as compared with fixed-ratio schedules. This difference was most pronounced when drugs were available at high unit prices. Differences in responding across the schedule types generated by ketamine-a lesser-valued reinforcer-were qualitatively similar but smaller in magnitude. The current study provides a systematic replication across reinforcer type demonstrating that drugs delivered after a random number of responses generate more behavior than those delivered according to a fixed schedule. The variable nature of the availability of drugs of abuse-particularly those that are scarce or expensive-may be a contributing factor to excessive drug intake by humans. This effect is most likely to be observed when more highly demanded (reinforcing) drugs are being consumed.

Exploiting the Synergy between Carboplatin and ABT-737 in the Treatment of Ovarian Carcinomas

Platinum drug-resistance in ovarian cancers mediated by anti-apoptotic proteins such as Bcl-xL is a major factor contributing to the chemotherapeutic resistance of recurrent disease. Consequently, concurrent inhibition of Bcl-xL in combination with chemotherapy may improve treatment outcomes for patients. Here, we develop a mathematical model to investigate the potential of combination therapy with ABT-737, a small molecule inhibitor of Bcl-xL, and carboplatin, a platinum-based drug, on a simulated tumor xenograft. The model is calibrated against in vivo experimental data, wherein xenografts established in mice were treated with ABT-737 and/or carboplatin on a fixed periodic schedule. The validated model is used to predict the minimum drug load that will achieve a predetermined level of tumor growth inhibition, thereby maximizing the synergy between the two drugs. Our simulations suggest that the infusion-duration of each carboplatin dose is a critical parameter, with an 8-hour infusion of carboplatin given weekly combined with a daily bolus dose of ABT-737 predicted to minimize residual disease. The potential of combination therapy to prevent or delay the onset of carboplatin-resistance is also investigated. When resistance is acquired as a result of aberrant DNA-damage repair in cells treated with carboplatin, drug delivery schedules that induce tumor remission with even low doses of combination therapy can be identified. Intrinsic resistance due to pre-existing cohorts of resistant cells precludes tumor regression, but dosing strategies that extend disease-free survival periods can still be identified. These results highlight the potential of our model to accelerate the development of novel therapeutics such as BH3 mimetics.

Administering the Optimum Dose of l-Arginine in Regional Tumor Therapy.

The purpose of this study is optimizing the l-arginine (l-Arg) doses on the basis of chemical structure in regional accessible tumor therapy to settle down a new protocol for the treatment of cancer. (3)H-thymidine-based cell proliferation assay was performed in vitro on tumor cell lines of fibrosarcoma (FS), lymphosarcoma-ascitic and on normal cell line of NIH 3T3 after treatment with different concentrations of l-Arg in phosphate buffered saline (PBS). The cultures were harvested after 22h and the incorporated radioactivity was counted to identify their histologic grades as described in earlier studies. In vivo therapy of murine tumors was conducted where FS cells injected subcutaneously at ventro-lateral position of mice. Various drug delivery schedules were injected into the centre of tumor base, once a day for 4 days. Tumor diameter and survivals were monitored where the day of sacrifice was considered for monitoring the survival period. By identifying the histologic grades of the treated cultures in vitro and in vivo by different concentrations of l-Arg, the corresponding energy of such concentrations were determined. An efficient model with a good fit (R(2)=0.98) was established to describe the energy yield by l-Arg dose. The equivalence between the tumor histologic grade and energy of the l-Arg dose delivered in saline (PBS) environment is the optimum condition for regional tumor therapy achieves higher survival rate. The selective cytotoxicity to tumor cells with minimal damage to normal cells by l-Arg due to its chemical structure suggests to be considered the most promising drug for regional therapy of the accessible tumors like breast cancers of early stage with no distant metastasis.

The Serotonin 2C Receptor Antagonist SB 242084 Exhibits Abuse-Related Effects Typical of Stimulants in Squirrel Monkeys

Antagonists of the serotonin (5-hydroxytryptamine; 5-HT) type 2C receptor (5-HT(2C)R) are being considered as potential pharmacotherapeutics for various affective disorders, but evidence suggests that these compounds enhance the effects of cocaine and related psychostimulants in rodents. However, the effects of selective 5-HT(2C)R antagonists have not been evaluated in nonhuman primates. The present studies used operant-behavioral and in vivo microdialysis techniques to assess the impact of 5-HT(2C)R antagonism on the behavioral and neurochemical effects of cocaine in squirrel monkeys. In subjects trained to lever-press on a fixed-interval schedule of stimulus termination, pretreatment with the highly selective 5-HT(2C)R antagonist 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride (SB 242084) (vehicle, 0.01-0.1 mg/kg) produced behavioral-stimulant effects alone and interacted with cocaine in an apparently additive manner. In monkeys trained to self-administer intravenous cocaine according to a second-order schedule of drug delivery, SB 242084 (vehicle, 0.03-0.1 mg/kg) modulated cocaine-induced reinstatement of previously extinguished responding and maintained self-administration behavior when substituted for cocaine availability. These studies are the first to assess the direct reinforcing effects of a 5-HT(2C)R-selective antagonist in any species. Finally, in vivo microdialysis studies revealed that pretreatment with SB 242084 (0.1 mg/kg) modulated cocaine-induced dopamine increases within the nucleus accumbens, but not the caudate nucleus, of awake subjects. Taken together, the results suggest that SB 242084 exhibits a behavioral profile that is qualitatively similar to other psychostimulants, although its efficacy is modest compared with cocaine. The observed interactions with cocaine and the substitution for cocaine self-administration may be indicative of some degree of abuse potential in humans.

Skin surface temperature rhythms as potential circadian biomarkers for personalized chronotherapeutics in cancer patients

Chronotherapeutics involve the administration of treatments according to circadian rhythms. Circadian timing of anti-cancer medications has been shown to improve treatment tolerability up to fivefold and double efficacy in experimental and clinical studies. However, the physiological and the molecular components of the circadian timing system (CTS), as well as gender, critically affect the success of a standardized chronotherapeutic schedule. In addition, a wrongly timed therapy or an excessive drug dose disrupts the CTS. Therefore, a non-invasive approach to accurately detect and monitor circadian rhythms is needed for a dynamic assessment of the CTS in order to personalize chronomodulated drug delivery schedule in cancer patients. Since core body temperature is a robust circadian biomarker, we recorded temperature at multiple locations on the skin of the upper chest and back of controls and cancer patients continuously. Variability in the circadian phase existed among patch locations in individual subjects over the course of 2-6 days, demonstrating the need to monitor multiple skin temperature locations to determine the precise circadian phase. Additionally, we observed that locations identified by infrared imaging as relatively cool had the largest 24 h temperature variations. Disruptions in skin temperature rhythms during treatment were found, pointing to the need to continually assess circadian timing and personalize chronotherapeutic schedules.