Log Dose-response Curves Research Articles

3D cell cultures exhibit increased drug resistance, particularly to taxanes.

e12599 Background: Cell culture platforms could be categorized into two main types: 2D and 3D. 3D cell cultures, known for mimicking the physiological cellular environment, are commonly preferred by researchers to assess drug responses as they accurately reproduce aspects of the in vivo cell behavior. We hypothesized that dose-response curves of 2D and 3D platforms may be drug dependent, with some being more sensitive or resistant depending on the platform. Methods: MCF-7 cancer cells were cultured and plated using a 2D flat bottom well plate platform or using a matrix-based and a matrix-free 3D platform. Cells were treated with chemotherapies and targeted therapies for four days and cellular sensitivity was assessed through a viability assay. Four-parameter logistic (4PL) dose response curves were generated and IC50 values (µM/Cmax) were quantified to understand the differences in dose response curves between the 2D and 3D cellular platforms. Results: While the dose-response curves generally correlate between 2D vs. 3D matrix-based (r2=0.82, p<0.001) and 2D vs. 3D matrix-free methods (r2=0.78, p<0.001), noteworthy variations were observed for certain drugs, particularly paclitaxel (2D IC50= 66; 3D matrix-based IC50 = ≥100; 3D matrix-free IC50 = ≥100) and docetaxel (2D IC50 = ≥34; 3D matrix-based IC50 = ≥100; 3D matrix-free IC50 = ≥100). Additionally, a general increase in resistance was evident when cells formed 3D structures compared to the 2D monolayer condition, as indicated by regression analysis (Y-intercept = 0.55, CI95% 0.32 to 0.78; slope = 0.47, CI95% 0.20 to 0.75). Conclusions: Our findings reveal that taxanes such as paclitaxel and docetaxel exhibit distinctive resistance patterns in 3D structures. In addition, a substantial increase in cellular resistance is observed in 3D cellular models when compared to the 2D assay for most drugs. Despite the overall correlation, these drug-specific differences should be considered. Thus, the next generation of an extreme drug resistance assay, aimed at enhancing the quality of life for patients by avoiding ineffective therapies, might preferentially employ a 3D platform to tailor patients’ cancer therapies.

Abstract 512: Cell-cycle inhibition may influence differences in 2D vs 3D tumor sensitivity profiles

Abstract Background: Traditional cell culture methods involve growing cells on flat surfaces, which do not fully replicate the human physiological conditions. In contrast, 3D cell cultures accurately reproduce aspects of the in-vitro malignant and non-malignant cell behavior. However, differences in tumor sensitivity platforms between 2D vs. 3D models might be relevant for some, but not for other drugs. Methods: The colorectal cancer cell line HCT-116 was cultured and plated in flat bottom well plates for the 2D condition and in Ultra Low Attachment round-bottom plates for the 3D condition. After plating, cells were treated with chemotherapies and targeted therapies for four days; cellular sensitivity was assessed through a viability assay. Four-parameter logistic (4PL) dose response curves were generated and IC50s were quantified to understand the differences in responses between 2D and 3D cellular environments. Results: HCT-116 exhibited similar responses to platinum drugs, taxanes, and several other tested drugs in both platforms, with the exception of gemcitabine (2D IC50 0.04 mcM; 3D IC50 12.8 mcM), lapatinib (2D IC50 23; 3D IC50 418), tucatinib (2D IC50 23.3; 3D IC50 79.3), and palbociclib (2D IC50 7.0; 3D IC50 24.0). Interestingly, these drugs share a common mechanism of action, which is the inhibition of cell cycle progression from G1 to S phase. Hence, we hypothesize that this shared mechanism may account for the observed differences in drug efficacy between the two environments. Conclusions: Similar dose responses have been observed with various drugs on both platforms, yet drugs that inhibit cell cycle progression from G1 to S phase, revealed higher sensitivity in 2D and more resistance in the 3D platform. Confirmatory cell-cycle results analyses are in progress. Further research is needed to understand if this applies to patient samples. Citation Format: Jahanvi Kumar, Chiara Maestri, Rajeshwar Nitiyanandan, Ivan Trus, Ricardo J. Parker, Brigitte Apfel, Christian Apfel. Cell-cycle inhibition may influence differences in 2D vs 3D tumor sensitivity profiles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 512.

Volumetric changes of the parotid gland during IMRT based on mid-treatment imaging: implications for parotid stem cell sparing strategies in head and neck cancer

Background To evaluate the change in parotid glands at mid-treatment during IMRT and the association between radiation dose to the parotid gland stem cell (PGSC) region and patient-reported xerostomia for patients with head and neck cancer (HNC). Material and Methods Patients who were treated from 2006–2012 at our institution with patient-reported xerostomia outcomes available at least 9 months following RT were included. PG and PGSC regions were delineated and the dose was estimated from the treatment plan dose distribution, using contours from pre- and mid-treatment CT scans. The association between radiation dose and volumetric changes was assessed using linear regression. Univariable logistic regression, logistic dose-response curves, and receiver operating characteristics (ROC) were used to examine the relationship between radiation dose and patient-reported xerostomia. Results Sixty-three patients were included, most treated with 70 Gy in 33 fractions; 34 patients had mid-treatment CT scans. Both contralateral and ipsilateral PGs had considerable volume reduction from baseline to mid-treatment (25% and 27%, respectively, both p < .001), significantly associated with mean PG dose (−0.44%/Gy, p = .008 and −0.54%/Gy, p < .001, respectively). There was a > 5 Gy difference in mean PG and PGSC dose for 8/34 patients at mid-treatment, with 6/8 (75%) reporting severe xerostomia. Xerostomia prediction based on whole PG or PGSC region dose showed similar performance (ROC AUC 0.754 and 0.749, respectively). The corresponding dose-response models also predicted similar risk of patient-reported xerostomia with mean dose to the contralateral PG (32.5%) or PGSC region (31.4%) at the 20 Gy QUANTEC-recommended sparing level. Conclusions The radiation dose to the PGSC region did not show stronger association with patient-reported xerostomia compared to that of whole PG, possibly due to considerable anatomical changes identified at mid-treatment. This shift in the size and position of the PG warrants adaptive planning strategies to evaluate the true benefit of parotid stem cell sparing.

Antimicrobial Effects of L-Chg10-Teixobactin against Enterococcus faecalis In Vitro.

Objective: Teixobactin and its analogues are a new class of antibiotics that have no detectable bacterial resistance. This study was designed to determine the antibacterial and antibiofilm activities of a novel teixobactin analogue, L-Chg10-teixobactin, against two strains of Enterococcus faecalis (E. faecalis). Materials and Methods: The efficacy of L-Chg10-teixobactin against two strains of E. faecalis (ATCC 29212 and 47077) was determined using Clinical and Laboratory Standards Institute methods. L-Chg10-teixobactin was prepared at a stock concentration of 1 mg/mL in 5% DMSO. The minimum inhibitory concentration (MIC) was calculated using a two-fold serial broth dilution method, utilizing a 96-well plate. The minimum bactericidal concentration (MBC) was determined by plating the bacteria onto agar to define the concentration that resulted in 99.9% of bacterial death. Ampicillin was used as the control. The effect of L-Chg10-teixobactin on the inhibition of ATCC 47077 strain biofilm formation was determined by measuring the minimum biofilm inhibitory concentration (MBIC) using the safranin assay, while the eradication of the preformed biofilm was determined by measuring the minimum biofilm eradication concentration (MBEC) using the XTT assay. For nonlinear data, the log dose–response curve was plotted to calculate the optimum concentration using Excel (version 16.51, Microsoft® excel. 2021, Microsoft Corporation, Reymond, WA, USA). The data are presented as mean ± standard deviation (SD). Results: The MIC and MBC values of L-Chg10-teixobactin against both strains of E. faecalis were 0.8 μg/mL. The MIC of ampicillin was 1.25 μg/mL for ATCC 29212 and ranged from 1.25 to 5 μg/mL for ATCC 47077. The MBC of ampicillin for ATCC 29212 and ATCC 47077 was 10 and 20 μg/mL, respectively. The MIC and MBC of ampicillin were much higher compared with those of L-Chg10-teixobactin. The MBEC80 of L-Chg10-teixobactin was 4.60 μg/mL for ATCC 47077, which was much lower than that of ampicillin (20 μg/mL). Conclusions: L-Chg10-teixobactin demonstrated potent antibacterial and antibiofilm effects against E. faecalis, suggesting its potential role an effective antibacterial and antibiofilm agent in endodontic treatment.

Pressure drops and mixture friction factor for gas–liquid two-phase transitional flows in a horizontal pipe at low gas flow rates

In this work, we investigate the behaviors of gas–liquid two-phase flow in a horizontal pipe under the transition from laminar flow to turbulence at low gas flow rates. The variations of frictional pressure drop gradient with different liquid flow rates and volumetric gas quality are obtained experimentally and verified theoretically by two separated models. Then, the critical Reynolds number is found for different volumetric gas quality. The composite correlations between the friction factor and Reynolds number are proposed for two-phase transitional flows, and the dependence of friction factor on volumetric gas quality is determined. Finally, the flow field inside the pipe are analyzed by numerical simulation. The results reveal that the influence of gas flow rates on the pressure drop is more significant for higher liquid flow rate, the composite correlations for the mixture friction factor fit well with experimental data and can be described by the logistic dose–response curves.

Clinical Pharmacology of CTL019 in Patients with Relapsed/Refractory (r/r) Diffuse Large B-Cell Lymphoma (DLBCL)

Clinical Pharmacology of CTL019 in Patients with Relapsed/Refractory (r/r) Diffuse Large B-Cell Lymphoma (DLBCL)

Synergism between oral paracetamol and nefopam in a murine model of postoperative pain.

The use of paracetamol or nefopam for postoperative pain control is limited by the need of high doses associated with unwanted effects. Previous works suggest positive interactions between both compounds that may be exploited to obtain potentiation of antinociception. Mechanical and heat antinociception induced by oral doses of paracetamol, nefopam or their combination was studied by isobolographic analysis in a murine model of postsurgical pain. The effective doses that produced 50% antinociception (ED50 ) were calculated from the log dose-response curves for each compound. Subsequently, the effects of ED8.7 s, ED12.5 s, ED17.5 s and ED35 s of nefopam and paracetamol combined were assessed. Oral paracetamol induced dose-dependent relief of postoperative sensitivity and showed higher efficacy reducing mechanical hypersensitivity (ED50 177.3±15.4mg/kg) than heat hyperalgesia (ED50 278.6±43mg/kg). Oral nefopam induced dose-dependent antinociception with similar efficacy for mechanical and heat hypersensitivity (ED50 s 5.42±0.81 vs. 5.83±0.72). Combinations of increasing isoeffective doses revealed that combined ED17.5 s (85.76mg/kg paracetamol and 1.9mg/kg nefopam) and ED35 s (132.67mg/kg and 3.73mg/kg) showed synergistic effects leading to 75% and 90% mechanical antinociception, respectively. These mixtures were defined by interaction indexes of 0.43 and 0.41 and ratios 45:1 and 35:1 paracetamol:nefopam, respectively. The same combinations showed additive effects for the inhibition of incisional thermal hyperalgesia. This work describes a synergistic antinociceptive interaction between low doses of nefopam and paracetamol for the treatment of postoperative hypersensitivity to peripheral stimuli. The promising results obtained on reflexive nociceptive responses of young male mice subjected to plantar surgery highlight the interest of further research evaluating the effects of this mixture on the affective-motivational component of pain and in females and additional age groups. Confirmation of pain-relieving efficacy and safety of this oral combination clinically available in European and Asian countries could provide a useful tool for postsurgical pain management. Early postoperative pain is currently undertreated and has been recognized as a relevant source of chronic postsurgical pain. Oral efficient treatments could facilitate fast-track surgeries and patient recovery at home. Here, we identify in a mouse model of postoperative pain a potent synergistic oral combination consisting of low paracetamol and nefopam doses that provides relief of postsurgical hypersensitivity to mechanical and thermal stimuli. Oral multimodal paracetamol-nefopam mixtures represent a potential clinically available pharmacological strategy for the relief of incisional sensitivity and the promotion of patient recovery.

Effect of Fluoxetine and Paroxetine on Intestinal Motility in Presence of Ondansetron in ex-vivo Model

&#x0D; &#x0D; &#x0D; Objective: To understand the effects of fluoxetine and paroxetine with ondansetron on the intestinal motility of rabbit ileum. Study Design: Observational study. Place and Duration of Study: The study was conducted from March to April 2018 in a multidisciplinary lab of Army Medical College, Rawalpindi.Materials and Methods: The contractile effect of intestinal motility was recorded in the power lab. Subjects were twenty four healthy rabbits (Oryctolagus Cuniculus). Semi log dose-response curve was constructed for increasing concentrations of serotonin, ondansetron, fluoxetine, and paroxetine (10-9 to 10-6 M) alone and then in the presence of a fixed concentration of ondansetron (10-6 M) to observe the modulatory role of ondansetron. The serotonin mediated contractions were taken as control.Results: Ondansetron and serotonin caused an increase in the contractile response of rabbits ileum. A depressive response was observed when the contractions were recorded with increased concentration of fluoxetine and paroxetine in the presence of ondansetron. Conclusion: Ondansetron when used concomitantly with selective serotonin reuptake inhibitors(SSRIs), abolishes their antidepressant effects by causing a decrease in the intestinal motility of rabbit ileum.&#x0D; &#x0D; &#x0D;

Relative Effects of Multiple Stressors on Reef Food Webs in the Northern Gulf of Mexico Revealed via Ecosystem Modeling

Since 2010, the northern Gulf of Mexico (NGoM) has experienced two unique environmental stressors. First, the 2010 Deepwater Horizon oil spill (DWH) impacted a broad range of taxa and habitats and resulted in declines of small demersal reef fish over the study area (88.5°-85.5° W, 29°-30.5° N). Then, from 2011-2014 the invasive Indo-Pacific lionfish (Pterois volitans) underwent exponential population growth, leading to some of the highest densities in their invaded range. The primary objective of this study was to evaluate the effect of these stressors on reef ecosystems, and specifically how invasive lionfish and fishing may have impacted recovery following DWH. Site-specific datasets on fish density and diet composition were synthesized into an Ecopath with Ecosim food web model of a NGoM reef ecosystem. The model consisted of 63 biomass groups and was calibrated to time series of abundance from 2009-2016. The model accounted for mortality from the DWH using forcing functions derived from logistic dose-response curves and oil concentrations. Eight stressor scenarios were simulated, representing all combinations of DWH, lionfish, and fishing. Simulated biomass differed across model groups due to singular and cumulative impacts of stressors and direct and indirect effects arising through food web interactions. Species with high exploitation rates were influenced by fishing more than lionfish following DWH. Several small demersal fish groups were predicted to be strongly influenced by either the cumulative effects of lionfish and DWH or by lionfish alone. A second group of small demersal fish benefited in the stressor scenarios due to reduced top-down predation and competition in the combined stressor scenarios. We conclude that lionfish had a major impact on this ecosystem, leading to slower recoveries following DWH and lower fish biomass and diversity. Additionally, the lack of recovery for some groups in the absence of lionfish suggests system reorganization may be preventing return to a pre-DWH state. We intended for this work to improve our understanding of how temperate reef ecosystems, like those in the NGoM, respond to broad scale stressors and advance the state of applied ecosystem modeling for resource damage assessment and restoration planning.

Involvement of NO in Antinociception of NSAIDS in Murine Formalin Hind Paw Assay.

There are different animal models to evaluate pain among them the formalin hind paw assay which is widely used since some of its events appear to be similar to the clinical pain of humans. The assay in which a dilute solution of formalin is injected into the dorsal hindpaw of a murine produces two 'phases' of pain behavior separated by a inactive period. The early phase (Phase I) is probably due to direct activation of nociceptors and the second phase (Phase II) is due to ongoing inflammatory input and central sensitization. Mice were used to determine the potency antinociceptive of piroxicam (1,3,10,and 30 mg/kg), parecoxib (0.3, 1,3,10 and 30 mg/kg), dexketoprofen (3,10,30 and 100 mg/kg) and ketoprofen (3,10,30 and 100 mg/kg). Dose-response for each NSAIDs were created before and after 5 mg/kg of L-NAME i.p. or 5 mg/kg i.p. of 7-nitroindazole. A least-squares linear regression analysis of the log dose-response curves allowed the calculation of the dose that produced 50% of antinociception (ED50) for each drug. The ED50 demonstrated the following rank order of potency, in the phase I: piroxicam > dexketoprofen > ketoprofen > parecoxib and in the phase II: piroxicam > ketoprofen > parecoxib > dexketoprofen. Pretreatment of the mice with L-NAME or 7-nitroindazol induced a significant increase of the analgesic power of the NSAIDs, with a significant reduction of the ED50. It is suggested that NO may be involved in both phases of the trial, which means that nitric oxide regulates the bioactivity of NSAIDs.

Hypothyroidism (HT) after Radiotherapy (RT) in Children: Initial Results of Thyroid Gland Dose-Response Relationship from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) Initiative

HT is a common long-term complication in children who received neck RT. Peer-reviewed reports were analyzed to quantify the relationship between elevated levels of thyroid stimulating hormone and RT dose; the putative factors of sex and age were also assessed. From PubMed, Medline and Cochrane Library databases, studies published from 1970-2017 were identified using search criteria developed by the PENTEC thyroid task force. Among 1,709 studies, 20 were selected that described thyroid or neck RT exposure in pediatric patients, and risks of HT. Data were extracted as cumulative incidence at extended follow-up (10-20 years) where available and otherwise as crude rates. A sensitivity analysis was performed between the two methods. Data relating to age and sex were extracted as relative risks or odds ratios where modeled in the original publications or as crude rates in the absence of such modeling. Extracted data were combined using inverse variance weighting in the review manager software. Dose-response modeling was performed by assuming a logistic dose response curve. The steepness parameter (gamma50) was meta-analyzed by inverse variance weighting according to individual study fits. To this end, individual study fits were performed in a computer algorithm with data weights according to inverse variance. The tolerance dose was assumed different between studies according to sensitivity of assay but the median D50 is reported for completeness. Individual study dose levels were taken as the mean of reported doses where available, and midpoint in dose bin if not. Main results are provided in the table. Two studies allowed analysis of age at exposure (cutpoint of 14-15 years old) on HT risk. Four studies allowed analysis of sex on HT risk; female sex was associated with greater risk. In both analyses we observed moderate heterogeneity between studies. Eight studies reported data amenable for dose-response assessment; one study was excluded due to systematically longer follow-up in the low dose group and a negative dose response that did not fit the model. 2,582 patients were included in dose-response analysis. The risk ratio of subclinical vs. clinical (i.e., need for thyroid hormone replacement) was 3.5 (95% CI: 2.5-5.0). From studies of pediatric patients, we demonstrate age and sex dependence on the risks of RT-induced HT and highly significant thyroid gland dose response.Abstract 166; Table 1RISK FACTORS:Risk ratio (95% CI), p-value# of patients- age (younger vs. older)1.4 (1.1 - 1.7), p=0.0022,252- sex (female vs. male)1.7 (1.4 - 2.0), p<0.00012,426DOSE-RESPONSE:Mean dose 10, 20 and 30 Gy2,582- subclinical HT risk20%, 30% and 41%- clinical HT risk (based on risk ratio of 3.5)6%, 9% and 12% Open table in a new tab

Susceptibility to adverse drug reactions.

The pharmacological effects of a drug depend on its concentration at the site of action, and therefore on the concentration in blood and on the dose. The relationship between the concentration or dose and the corresponding effect can usually be represented mathematically as a rectangular hyperbola; when effect is plotted against log concentration or log dose, the curve is sigmoidal. Inevitably, the effect size and the doses causing benefit and harm will differ among individuals, since they are biological phenomena: some individuals are more likely than others to suffer harm at any given dose. Some harmful effects can occur at much lower doses than those used in therapeutics; that is, the log dose-response curve for harm lies far to the left of the log dose-response curve for benefit. Those who suffer such reactions are hypersusceptible. When the dose-response curves for harm and therapeutic effect are in the same range, dose cannot separate the harmful effects from the therapeutic effects, and adverse reactions are collateral. Toxic effects occur when harmful doses are above the doses needed for benefit. In this review we consider factors that influence a subject's susceptibility to adverse drug reactions. Determinants of susceptibility include Immunological, Genetic, demographic (Age and Sex), Physiological and Exogenous factors (drug-drug interactions, for example), and Diseases and disorders such as renal failure, giving the mnemonic I GASPED. Some susceptibility factors are discrete (for example, all-or-none) and some are continuous; susceptibility can therefore be discrete or continuous; and the factors can interact to determine a person's overall susceptibility to harm.

Regression of Survivability Variance on the Cohort Age in Drosophila melanogaster. I. Survivability: Reaction Norm and Its Inheritance

We analyze the regression of survivability variance by cohort age in several generations of Drosophila melanogaster Canton-S stock. This estimation reflects survivability reaction norm. Three phases were detected. First and second was approximated by exponential equation and the third - by logistic dose-response curve. Parameters of the equations remains stable for decades and thus must have high heritability.

THE ADDITIVITY ANTINOCICEPTIVE INTERACTIONS BETWEEN DICLOFENAC AND THE DERRIS SCANDENS EXTRACT DRUG IN MICE.

Objective: Combination therapy is a valid approach in pain treatment, in which a reduction of doses could reduce side effects and still achieve optimal analgesia. The objective was to determine the effects of coadministered diclofenac and the Derris scandens extract drug.Methods: Acetic acid-induced abdominal constriction test in mice was used to determine the type of interaction between components. The effective dose that produced 50% antinociception (ED50) was calculated from the log dose-response curves of fixed ratio combinations of diclofenac with the D. scandens extract drug. The ED50 was compared to the theoretical additive ED50 calculated from the ED50 of diclofenac and of the D. scandens extract drug alone.Results: Diclofenac and the D. scandens extract drug dose‐dependently and significantly reduced the abdominal writhing. The combination was the additive effect, the experimental ED50 being smaller than the theoretically calculated ED50. Interaction index of the combination was 0.89.Conclusion: The present study demonstrates the additivity antinociceptive interactions between diclofenac and the D. scandens extract drug and may be used as a combination analgesic in the treatment of pain conditions.

THE ADDITIVITY ANTINOCICEPTIVE INTERACTIONS BETWEEN DICLOFENAC AND THE DERRIS SCANDENS EXTRACT DRUG IN MICE.

Objective: Combination therapy is a valid approach in pain treatment, in which a reduction of doses could reduce side effects and still achieve optimal analgesia. The objective was to determine the effects of coadministered diclofenac and the Derris scandens extract drug.Methods: Acetic acid-induced abdominal constriction test in mice was used to determine the type of interaction between components. The effective dose that produced 50% antinociception (ED50) was calculated from the log dose-response curves of fixed ratio combinations of diclofenac with the D. scandens extract drug. The ED50 was compared to the theoretical additive ED50 calculated from the ED50 of diclofenac and of the D. scandens extract drug alone.Results: Diclofenac and the D. scandens extract drug dose‐dependently and significantly reduced the abdominal writhing. The combination was the additive effect, the experimental ED50 being smaller than the theoretically calculated ED50. Interaction index of the combination was 0.89.Conclusion: The present study demonstrates the additivity antinociceptive interactions between diclofenac and the D. scandens extract drug and may be used as a combination analgesic in the treatment of pain conditions.

A Random-allocation Graded Dose-Response Study of Norepinephrine and Phenylephrine for Treating Hypotension during Spinal Anesthesia for Cesarean Delivery.

Norepinephrine has been investigated as a potential alterative to phenylephrine for maintaining blood pressure during spinal anesthesia for cesarean delivery with the advantage of less depression of maternal heart rate and cardiac output. However, the relative potencies of these two vasopressors have not been fully determined in this context. In a random-allocation, graded dose-response study, 180 healthy patients undergoing spinal anesthesia for elective cesarean delivery received a single bolus of norepinephrine in one of six different doses ranging from 4 to 12 µg or phenylephrine in one of six different doses ranging from 60 to 200 µg to treat the first episode of hypotension. The magnitude of response was measured as the percentage of full restoration of systolic blood pressure to the baseline value. Dose-response analysis was performed using nonlinear regression to derive four-parameter logistic dose-response curves, which were compared to determine relative potency. Data were analyzed for 180 patients. The estimated ED50 values (dose giving a 50% response) were norepinephrine 10 µg (95% CI, 6 to 17 µg) and phenylephrine 137 µg (95% CI, 79 to 236 µg). The estimated relative potency ratio for the two drugs was 13.1 µg (95% CI, 10.4 to 15.8 µg). Comparative dose-response analysis was completed for norepinephrine and phenylephrine given as a bolus to treat the first episode of hypotension in patients undergoing spinal anesthesia for cesarean delivery. The estimated dose equivalent to phenylephrine 100 µg was norepinephrine 8 µg (95% CI, 6 to 10 µg). These results may be useful to inform the design of future comparative studies.

Additive and antagonistic antinociceptive interactions between magnesium sulfate and ketamine in the rat formalin test.

Because ketamine and magnesium block NMDA receptor activation by distinct mechanisms of action, we hypothesized that in a model of inflammatory pain in rats the combination of ketamine and magnesium might be more effective than ketamine alone. Antinociceptive activity was assessed by the formalin test in male Wistar rats (200-250 g). Animals were injected with 100 μL of 2.5% formalin to the plantar surface of the right hind paw. Data were recorded as the total time spent in pain-related behavior after the injection of formalin or vehicle (0.9% NaCl). Ketamine and magnesium sulfate given separately reduced nocifensive behavior in the second phase of the formalin test in rats. When ketamine was applied after magnesium sulfate, the log dose-response curves for the effects of ketamine and the magnesium sulfate-ketamine combination revealed antagonistic interaction, and about 1.6 (CL 1.2-2.4) fold increment in ketamine dosage. A low dose of magnesium sulfate (5 mg/kg, subcutaneously) administered after ketamine increased the antinociceptive effect of ketamine by a factor of only 1.2 (CL 0.95-1.38), indicating an additive interaction. There was a 1.8-fold reduction in dosage of ketamine when ketamine was administered before rather than after the magnesium sulfate. The present study revealed that both ketamine and magnesium reduced pain-related behavior in the second phase of the formalin test in rats. Ketamine, when administered before or after the magnesium, provided additive or antagonistic antinociceptive interactions, respectively. Whether there will be an additive or antagonistic antinociceptive interaction between ketamine and magnesium depends on the order of drug administration.

The toxicity of HCrO4− and CrO42− to barley root elongation in solution culture: pH effect and modelling

The influence of pH on the toxicity of Cr(VI) to barley root elongation was studied in solution culture to better understand the toxicity of different species of Cr(VI). Results showed that the values of EC50{CrO42−} (the free CrO42− that results in50% of barley root elongation with respect to the control) increased when the pH increased from 4.5 to 6.5; however, it was not significantly different in the high-pH range from 7.0 to 8.5. The nonlinear relationship between EC50{CrO42−} and OH− activity indicated that OH− competition with Cr(VI) on cell membrane ligands was not strong. There was a good linear relationship (R2 = 0.99) between the ratio of HCrO4− activity to CrO42− activity and Cr(VI) toxicity to barley root elongation when the toxicity of HCrO4− were considered, indicating that the observed toxicity of Cr(VI) in the high pH range may be caused by HCrO4− and CrO42− in solution. It was found that HCrO4− had a greater binding affinity than CrO42− on the biotic ligand sites. The logistic dose–response curves showed that consideration of Cr(VI) dose as HCrO4− and CrO42− significantly improved the data fit compared to consideration of the activity of HCrO4− or CrO42− only. The present study suggested that HCrO4− was highly toxic to the root of barely, and both HCrO4− and CrO42− species needed to be considered when predicting the toxicity of Cr(VI) under different pH conditions.

Root distribution by depth for temperate agricultural crops

Root distribution pattern plays an important role in understanding and estimating of soil C allocation and the effect of crop roots C input on soil carbon balance in agroecosystems. A database of 96 profiles was compiled and root distribution pattern were fitted to a modified logistic dose response curve for 11 temperate crops. A slight linear decrease between the root mass: length distribution ratio and the soil depth was found for monocotyledons while an exponential decrease with depth was found for dicotyledons. These results indicated that roots were thicker at upper soil layers with the effect much larger for dicotyledons. The estimated depth at which 50% of total root was accumulated for different crops varied from 8cm to 20cm. Alfalfa (Medicago sativa L.) showed the deepest rooting profile with a fitted maximum rooting depth (dmax) of 177cm but another perennial, fescue (Festuca arundinacea Shreb.), had the shallowest dmax of 78cm. In general, cereal and pulse crop roots were distributed more evenly in soil profile while more roots were accumulated in the upper soil layers for oilseed crops. The estimated root distribution patterns from the present study could be incorporated into agroecosystem models for good representations of belowground processes and enhance the accuracy of carbon and water cycling estimation in agroecosystem.

Effect of Salvia sahendica Extracts on Neuromuscular Transmission in Chick Biventer Cervicis Muscle

The Salvia sahendica, a known folk medicine, possesses antibacterial, antifungal, anticancer properties and the improvement effect on the memory system. Because memory improving effects of the other species of this genus (salvia officinalis) is mediated by interacting with muscarinic and nicotinic cholinergic systems. It seems that S. sahendica may also follow the same mechanisms.The purpose of the present study is to investigate the anticholinesterase effect of Salvia sahendica extracts,in the pharmacologic methods. Method: The study was done by using the Dose-response curves and Twitch tension techniques in chick biventer cervicis. The ability of extracts to modulate cholinesterase activity were assessed by obtaining concentration–response curves to acetylcholine and carbacol in the absence or presence of extracts. The isolated tissues were exposed to extracts (methanol, dichloromethane and hexane extracts) and responses were recorded, with p < 0.05 indicating significance. Results: Based on our finding, methanol extract of S. sahendica, has not significant change in the dose-response curve for acetylcholine, enzyme but elicited reduction effect at carbacol dose-response curve. All other extracts showed the significant reduction in Dose-response curves and Twitch tension. There was a direct relationship between hexane extract´s concentration and reduction of contraction on log dose-response curves for acetylcholine and carbachol. Hexane extract (75µg/ml) blocked muscle twitching and yield in a complete blockage in the presence of tubocurarine, dichloromethane extract decreased twitch height. The effect of tubocurarine was not abolished by extract but also had cumulative effects. Conclusion: These results suggest that the relaxant effects of S. sahendica extracts on neuromuscular junction are elicited by post junctionally and curare–mimetic effects. It seems that, methanol extract has anticholinsterase activity but this effect will be affected by the inhibitory effect of the extract and inhibited.