Effective Dose 50 Research Articles

Paraspecific neutralization capacity of polyvalent snake antivenom against Montivipera wagneri venom

PurposeThis study aims to measure the paraspecific neutralization capacity of nationally produced HSGM polyvalent snake antivenom (HSGM-PSAV), produced using Macrovipera lebetina obtusa, Montivipera xanthina, and Vipera ammodytes montandoni venom, against the lethal effect of the venom of Montivipera wagneri, which is endemic to the Eastern Black Sea and Eastern Anatolia regions of Turkey. MethodsThe neutralization capacity of HSGM-PSAV against the lethal effect of M. wagneri venom was studied using the potency determination testing method specified in the Turkish and European Pharmacopoeia. Lethal dose 50 (LD50) values of the venoms used in immunization, M. wagneri venom in mice, and effective dose 50 (ED50) values of HSGM-PSAV against four types of venoms were calculated using two-fold dilutions. ResultsHSGM-PSAV neutralized the lethal effect of M. wagneri venom in mice. The ED50 of the HSGM-PSAV against M. wagneri venom was calculated as 304.42 LD50/mL. ConclusionAs a result of this in-vivo study, it was determined that HSGM-PSAV neutralized M.wagneri venom above the antivenom neutralization capacity threshold values (≥50 LD50/mL) specified in the Turkish and European Pharmacopoeia. This result is important preclinical data regarding the usability of HSGM-PSAV in the treatment of poisoning due to M. wagneri bites.

One-Step Synthesis, Crystallography, and Acute Toxicity of Two Boron-Carbohydrate Adducts That Induce Sedation in Mice.

Boronic acids form diester bonds with cis-hydroxyl groups in carbohydrates. The formation of these adducts could impair the physical and chemical properties of precursors, even their biological activity. Two carbohydrate derivatives from d-fructose and d-arabinose and phenylboronic acid were synthesized in a straightforward one-step procedure and chemically characterized via spectroscopy and X-ray diffraction crystallography. Additionally, an acute toxicity test was performed to determine their lethal dose 50 (LD50) values by using Lorke's method. Analytical chemistry assays confirmed the formation of adducts by the generation of diester bonds with the β-d-pyranose of carbohydrates, including signals corresponding to the formation of new bonds, such as the stretching of B-O bonds. NMR spectra yielded information about the stereoselectivity in the synthesis reaction: Just one signal was found in the range for the anomeric carbon in the 13C NMR spectra of both adducts. The acute toxicity tests showed that the LD50 value for both compounds was 1265 mg/kg, while the effective dose 50 (ED50) for sedation was 531 mg/kg. However, differences were found in the onset and lapse of sedation. For example, the arabinose derivative induced sedation for more than 48 h at 600 mg/kg, while the fructose derivative induced sedation for less than 6 h at the same dose without the death of the mice. Thus, we report for the first time two boron-containing carbohydrate derivatives inducing sedation after intraperitoneal administration. They are bioactive and highly safe agents. Further biological evaluation is desirable to explore their medical applications.

Standard Quality Characteristics and Efficacy of a New Third-Generation Antivenom Developed in Colombia Covering Micrurus spp. Venoms.

In Colombia, Micrurus snakebites are classified as severe according to the national clinical care guidelines and must be treated with specific antivenoms. Unfortunately, these types of antivenoms are scarce in certain areas of the country and are currently reported as an unavailable vital medicine. To address this issue, La Universidad de Antioquia, through its spin-off Tech Life Saving, is leading a project to develop third-generation polyvalent freeze-dried antivenom. The goal is to ensure access to this therapy, especially in rural and dispersed areas. This project aims to evaluate the physicochemical and preclinical parameters (standard quality characteristics) of a lab-scale anti-elapid antivenom batch. The antivenom is challenged against the venoms of several Micrurus species, including M. mipartitus, M. dumerilii, M. ancoralis, M. dissoleucus, M. lemniscatus, M. medemi, M. spixii, M. surinamensis, and M. isozonus, following the standard quality characteristics set by the World Health Organization (WHO). The antivenom demonstrates an appearance consistent with standards, 100% solubility within 4 min and 25 s, an extractable volume of 10.39 mL, a pH of 6.04, an albumin concentration of 0.377 mg/mL (equivalent to 1.22% of total protein), and a protein concentration of 30.97 mg/mL. Importantly, it maintains full integrity of its F(ab')2 fragments and exhibits purity over 98.5%. Furthermore, in mice toxicity evaluations, doses up to 15 mg/mouse show no toxic effects. The antivenom also demonstrates a significant recognition pattern against Micrurus venoms rich in phospholipase A2 (PLA2) content, as observed in M. dumerilii, M. dissoleucus, and M. isozonus. The effective dose 50 (ED50) indicates that a single vial (10 mL) can neutralize 2.33 mg of M. mipartitus venom and 3.99 mg of M. dumerilii venom. This new anti-elapid third-generation polyvalent and freeze-dried antivenom meets the physicochemical parameters set by the WHO and the regulators in Colombia. It demonstrates significant efficacy in neutralizing the venom of the most epidemiologically important Micrurus species in Colombia. Additionally, it recognizes seven other species of Micrurus venom with a higher affinity for venoms exhibiting PLA2 toxins. Fulfilling these parameters represents the first step toward proposing a new pharmacological alternative for treating snakebites in Colombia, particularly in dispersed rural areas, given that this antivenom is formulated as a freeze-dried product.

Neuropharmacological Effects of the Dichloromethane Extract from the Stems of Argemone ochroleuca Sweet (Papaveraceae) and Its Active Compound Dihydrosanguinarine.

Argemone ochroleuca Sweet (Papaveraceae) is used in folk medicine as a sedative and hypnotic agent. This study aimed to evaluate the anxiolytic-like, sedative, antidepressant-like, and anticonvulsant activities of a dichloromethane extract of A. ochroleuca stems (AOE), chemically standardized using gas chromatography-mass spectrometry (GC-MS), and its active compound dihydrosanguinarine (DHS). The anxiolytic-like, sedative, antidepressant-like, and anticonvulsant activities of the AOE (0.1-50 mg/kg p.o.) and DHS (0.1-10 mg/kg p.o.) were evaluated using murine models. A possible mechanism for the neurological actions induced by the AOE or DHS was assessed using inhibitors of neurotransmission pathways and molecular docking. Effective dose 50 (ED50) values were calculated by a linear regression analysis. The AOE showed anxiolytic-like activity in the cylinder exploratory test (ED50 = 33 mg/kg), and antidepressant-like effects in the forced swimming test (ED50 = 3 mg/kg) and the tail suspension test (ED50 = 23 mg/kg), whereas DHS showed anxiolytic-like activity (ED50 = 2 mg/kg) in the hole board test. The AOE (1-50 mg/kg) showed no locomotive affectations or sedation in mice. A docking study revealed the affinity of DHS for α2-adrenoreceptors and GABAA receptors. The anxiolytic-like and anticonvulsant effects of the AOE are due to GABAergic participation, whereas the antidepressant-like effects of the AOE are due to the noradrenergic system. The noradrenergic and GABAergic systems are involved in the anxiolytic-like actions of DHS.

Intramuscular Alfaxalone Effective Dose (ED) Determination and Cardiopulmonary Effects of ED99 in Sonoran Desert Toads (Incilius alvarius)

There is limited knowledge on amphibian sedation, and drug doses appear to be species-specific and affected by the administration route. Alfaxalone, a neuroactive steroid, has gained popularity in veterinary medicine and has been evaluated in some amphibian species. Previous studies in amphibians have demonstrated a sedative dose range of 10-30 mg/kg IM. No peer-review publication has investigated this drug in Sonoran Desert toads specifically. Therefore, the purpose of this study was to 1) determine the effective dose 50 (ED50) of IM alfaxalone for sedation and 2) determine the cardiopulmonary effects of the effective dose 99 (ED99) in 13 Sonoran Desert toads. Using the Dixon’s Up-and-Down method, the ED50 was calculated as 9.02 mg/kg while using a non-linear regression, the calculated ED50 was 9.65 mg/kg, and the ED99 was 9.91 mg/kg. Based on these results, 10 mg/kg IM was administered, and its cardiovascular effects were determined for 120 mins post-injection. The 10 mg/kg IM dose resulted in significant transient cardiorespiratory depression in all toads, with most toads (11/13) showing signs of sedation (recumbency and/or loss of righting reflex) within 30–40-minutes post-injection. There was no associated mortality with this study, and the side effects associated with this dosage (cardiorespiratory depression, ventral erythema, dysphoric behavior such as rolling and head pressing) resolved in all toads prior to the end of the 120-minute observation window. This study hopes to increase the understanding of the clinical application and limitations of this drug for sedation of Sonoran Desert toads.

Effect of Allicin and Artesunate Combination Treatment on Experimental Mice Infected with Plasmodium berghei.

Malaria is still a significant health problem in endemic countries and increases Plasmodium resistance to the available antimalarial drugs. Hence, this study aimed to investigate the antimalarial activity of allicin and its combination with artesunate (ART) against rodent malaria Plasmodium berghei ANKA (PbANKA) infected mice. Allicin was prepared in 20% Tween-80. Balb/c mice were inoculated intraperitoneally with 1×107 PbANKA-infected erythrocytes and orally given by gavage with the chosen doses of 1, 10, 50, and 100 mg/kg of allicin and 1, 5, 10, and 20 mg/kg of ART once a day for 4 consecutive days. Effective dose 50 (ED50) of allicin and ART was subsequently investigated. Moreover, the combination (1 : 1) of allicin and ART at the doses of their respective ED50, ED50 1/2, ED50 1/4, and ED50 1/8 was also carried out. The untreated control was given 20% Tween-80. The results showed that allicin presented a dose-dependent antimalarial activity with significance (p < 0.05). The ED50 values of allicin and ART were about 14 and 5 mg/kg, respectively. For combination, allicin and ART showed a synergistic effect at the combination doses of ED50, ED50 1/2, and ED50 1/4 with significantly (p < 0.01) prevented reduction of packed cell volume, bodyweight loss, rapid dropping of rectal temperature, and markedly prolonged mean survival time, compared with the untreated control and single treatment. It can be concluded that allicin exerted potential antimalarial activity in single and its combination with ART.

Evaluation of the basophil activation test as diagnostic method in pediatric peanut allergy

Peanut allergy diagnosis relies on various tests including the oral food challenge (OFC), which is potentially associated with severe symptoms such as anaphylaxis. An alternative has emerged, the basophil activation test (BAT), which allows to determine the basophil allergen threshold sensitivity in vitro. We aimed to determine the discriminative ability of BAT between, first, OFC reactive and non-reactive patient, and secondly low or high cumulative dose-reactive patients in comparison with other diagnostic tools for peanut allergy. The ability of BAT to discriminate patient with mild or severe OFC clinical reactions was also evaluated. We performed a prospective study, from February 2018 to October 2020, evaluating in 79 peanut allergic children the basophils allergen reactivity (CDmax) and the basophils allergen sensitivity [CDsens or area under the curve (AUC)] in BAT (CD63+ or CD203c+) as well as specific IgE level and skin prick-test in relation to OFC performed the same day. Based on ROC curve analyses, optimal cutoff of CDmax, CDsens and AUC to peanut and Ara h 2 were defined by the Youden index. Among the 79 children included, ROC curve analysis showed that f13- or Ara h 2-CDmax and AUC appeared to be the best markers associated with reactivity on OFC. We defined positive cutoff [i.e. Closet to 100% positive predictive value (PPV)] and demonstrated that 21% of the OFC could have been avoided. Also, by discriminating peanut-reactive patients according to low (< 200 mg) or high (> 200 mg) cumulative dose of peanut proteins in OFC [corresponding to effective dose 50 (ED50)], basophils allergen sensitivity monitored with AUC to f13 and Ara h 2 were the best biomarkers predicting cumulative dose with 92% and 88% specificity and 88% and 91% sensitivity, respectively. BAT to f13 and Ara h 2 may be a useful diagnostic tool to predict the allergic status and could reduce dangerous OFC. Then, BAT may be useful for risk assessment of clinical reactions during OFC and could significantly improve management by integrating a personalized approach.

The Antibacterial, Insecticidal and Nematocidal Activities and Toxicity Studies of Tanacetum falconeri Hook. f.

Secondary bioactive metabolites from plants may be realistic alternatives to conventional synthetic chemicals. The aim of the present research was to test the Tanacetum falconeri Hook. f. in different bioassays to evaluate its potential as nematocidal, insecticidal, antibacterial, cytotoxic, and phytotoxic agent. The plant T. falconeri was further studied for its chemical constituents. The methanolic extract from T. falconeri was fractionated into various solvent fractions. All solvent fractions were further subjected to different bioassays. Antibacterial activity and cytotoxicity were determined by broth micro-dilution method and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, respectively. Nematocidal activity was evaluated by using second-stage juvenile of Meloidogyne incognita. Insecticidal activity and phytotoxicity were measured with the help of Rhyzopertha dominica and Tribolium castaneum and fronds of Lemna minor L., respectively. Compound-1 was isolated by using liquid chromatography and its structure was determined by spectroscopic data as cis-dehydromatricaria ester. The excellent nematocidal activity (reduction in 100% motility) of the compound-1 against a root-knot nematode was obtained at 1% concentration after 72 h incubation time, whereas the reductions in motilities were 95% and 75% at concentrations 0.5% (w/v) and 0.125% (w/v), respectively. Similarly, the mortalities were 90% and 82% at 1% and 0.5% concentrations, respectively, after 24 h of the treatment. Compound-1 also exhibited the excellent insecticidal activity against Sitophilus oryzae at 1% concentration (providing 100% mortality) with effective dose 50 (EC50) of 0.08 mg/L. The EC50 of phosphine, which was used as standard, was 0.07 mg/L. Two fractions of T. falconeri showed a moderate cytotoxic activity against 3T3 cells lines at the concentration of 30 mg/mL with inhibitory concentration 50 values of 22.4 and 25.8 mg/L corresponding to TfP and TfM, respectively. This study demonstrates that cis-dehydromatricaria ester-1 provides nematocidal activity (100% mortality) against the root-knot nematodes. Its insecticidal activity against S. oryzae may enable its use as marketable insecticide.

Effective dose 50 method as the minimal clinically important difference: Evidence from depression trials

ObjectivePrevious research on the minimal clinically important difference (MCID) for depression and anxiety is based on population averages. The present study aimed to identify the MCID across the spectrum of baseline severity. Study Design and SettingsThe present analysis used secondary data from 2 randomized controlled trials for depression (n = 1,122) to calibrate the Global Rating of Change with the PHQ–9 and GAD–7. The MCID was defined as a change in scores corresponding to a 50% probability of patients "feeling better", given their baseline severity, referred to as Effective Dose 50 (ED50). ResultsMCID estimates depended on baseline severity and ranged from no change for very mild up to 14 points (52%) on the PHQ–9 and up to 10 points (48%) on the GAD–7 for very high severity. The average MCID estimates were 3.7 points (23%) and 3.3 (28%) for the PHQ–9 and GAD–7 respectively. ConclusionThe ED50 method generates MCID estimates across the spectrum of baseline severity, offering greater precision but at the cost of greater complexity relative to population average estimates. This has important implications for evaluations of treatments and clinical practice where users can use these results to tailor the MCID to specific populations according to baseline severities.

Minimum Alveolar Concentration of Sevoflurane as a Single Hypnotic Agent to Maintain BIS Below 50 in Patients During Normothermic Cardiopulmonary Bypass

Minimum alveolar concentration (MAC) of volatile anesthetic agents to maintain bispectral index (BIS) below 50 in 50% of patients was defined as MACBIS50. The primary objective of this study was to determine the minimum alveolar concentration of sevoflurane as a single hypnotic agent to maintain BIS below 50 in patients during normothermic cardiopulmonary bypass. Prospective and observational study. Dante Pazzanese Institute of Cardiology, Brazil. Eighteen consecutive patients scheduled for elective coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB) under general anesthesia, American Society of Anesthesiologists physical status classes III and IV, between the ages of 40 and 70, were included in the study. All patients underwent inhalation induction with facial mask using sevoflurane (Cristália) in 100% oxygen, pancuronium (Cristália) 0.1 mg/kg, and sufentanil (Cristália) 0.5 µg/kg intravenously (IV) administered. A single bolus dose of sufentanil, 1.0 µg/kg IV, was administered before surgical incision. MACBIS50 was calculated using the midpoint concentration of patients involving a crossover (BIS < or ≥50) according to Dixon's Up-and-Down method. The Up-and-Down sequence also was analyzed by probit test that enabled the authors to obtain the effective dose 50 (ED50) and effective dose 95 (ED95) of sevoflurane to maintain a BIS value <50, with a 95% confidence interval (95% CI) of the mean. A total of 15 patients were analyzed in this study. MACBIS50 of sevoflurane as a single hypnotic agent was 0.82% (95% CI 0.47-1.16) in patients aged 40 to 70 undergoing CABG during normothermic CPB. The ED50 and ED95 of sevoflurane to maintain a BIS value <50 for the same context were 0.73% (95% CI 0.45-1.00) and 1.39 (95% CI 0.42-2.37) by means of probit analysis, respectively. MACBIS50 of sevoflurane as a single hypnotic agent was 0.82% in patients undergoing CABG during normothermic CPB.

A new pharmacodynamic approach to study antibiotic combinations against enterococci in vivo: Application to ampicillin plus ceftriaxone.

The combination of ampicillin (AMP) and ceftriaxone (CRO) is considered synergistic against Enterococcus faecalis based on in vitro tests and the rabbit endocarditis model, however, in vitro assays are limited by the use of fixed antibiotic concentrations and the rabbit model by poor bacterial growth, high variability, and the use of point dose-effect estimations, that may lead to inaccurate assessment of antibiotic combinations and hinder optimal translation. Here, we tested AMP+CRO against two strains of E. faecalis and one of E. faecium in an optimized mouse thigh infection model that yields high bacterial growth and allows to define the complete dose-response relationship. By fitting Hill's sigmoid model and estimating the parameters maximal effect (Emax) and effective dose 50 (ED50), the following interactions were defined: synergism (Emax increase ≥2 log10 CFU/g), antagonism (Emax reduction ≥1 log10 CFU/g) and potentiation (ED50 reduction ≥50% without changes in Emax). AMP monotherapy was effective against the three strains, yielding valid dose-response curves in terms of dose and the index fT>MIC. CRO monotherapy showed no effect. The combination AMP+CRO against E. faecalis led to potentiation (59-81% ED50 reduction) and not synergism (no changes in Emax). Against E. faecium, the combination was indifferent. The optimized mouse infection model allowed to obtain the complete dose-response curve of AMP+CRO and to define its interaction based on pharmacodynamic parameter changes. Integrating these results with the pharmacokinetics will allow to derive the PK/PD index bound to the activity of the combination, essential for proper translation to the clinic.

Anti-inflammatory, antinociceptive, and cytotoxic activity of methanolic extract of Mansoa hymenaea (DC.) A.H. Gentry

ABSTRACT Mansoa hymenaea (DC.) A.H. Gentry is used in traditional medicine to treat pain, arthritis, and rheumatoid disease. It has also been demonstrated that species belonging to the Mansoa genus exert cytotoxic activity. Despite this data, biological properties and phytochemistry of M. hymenaea remain poorly understood. Therefore, we determined the metabolite profile of the methanolic extract of M. hymenaea leaves and evaluated its anti-inflammatory, antinociceptive, and cytotoxic activity. Phytochemical analysis was carried out by conventional methods and gas chromatography-mass spectrometry. Anti-inflammatory and antinociceptive effects were assessed in the TPA‑induced ear edema model and acetic acid-induced writhing test, respectively. Cytotoxic activity was determined in vitro against SW-620, MDA-MB231, SiHa, SKLU1, and PC-3 cancer cell lines. The results revealed that M. hymenaea methanolic extract at 2 mg/ear reduced inflammation significantly (p ≤ 0.05) by 50.4 ± 5.9 %, and decreased visceral pain with an effective dose 50 (ED50) of 148.9 ± 14.1 mg kg−1. Moreover, M. hymenaea exerted cytotoxic activity against the breast carcinoma cell line (MDA-MB231) with IC50 = 125.8 ± 16.7 µg mL−1. Chemical analyses revealed that M. hymenaea methanolic extract contained alkaloids, glycosides, tannins, sterols, and saponins. Likewise, trans-13-octadecenoic acid, n-hexadecanoic acid, diallyl disulfide, diallyl trisulfide, β-sitosterol, methyl ursolate, stigmasterol, and phytol were detected by CG-MS in the M. hymenaea methanolic extract. These compounds were previously reported with anti-inflammatory, antinociceptive, or cytotoxic effects. Therefore, the methanolic extract of M. hymenaea leaves is a good source of natural compounds with anti-inflammatory, antinociceptive, and cytotoxic properties.

In vitro and in vivo antiplasmodial activity of hydroethanolic bark extract of Bridelia atroviridis müll. Arg. (Euphorbiaceae) and lc-ms-based phytochemical analysis

Ethnopharmacological relevanceMalaria is a life-threatening health problem worldwide and treatment remains a major challenge. Natural products from medicinal plants are credible sources for better anti-malarial drugs.Aim of the study: This study aimed at assessing the in vitro and in vivo antiplasmodial activities of the hydroethanolic extract of Bridelia atroviridis bark. Materials and methodsThe phytochemical characterization of Bridelia atroviridis extract was carried out by High-Performance Liquid Chromatography-Mass spectrometry (HPLC-MS). The cytotoxicity test on Vero cells was carried out using the resazurin-based assay while the in vitro antiplasmodial activity was determined on Plasmodium falciparum (Dd2 strain, chloroquine resistant) using the SYBR green I-based fluorescence assay. The in vivo assay was performed on Plasmodium berghei-infected rats daily treated for 5 days with distilled water (10 mL/kg) for malaria control, 25 mg/kg of chloroquine sulfate for positive control and 50, 100 and 200 mg/kg of B. atroviridis extract for the three test groups. Parasitaemia was daily monitored using 10% giemsa-staining thin blood smears. At the end of the treatment, animals were sacrificed, blood was collected for hematological and biochemical analysis while organs were removed for biochemical and histopathological analyses. ResultsThe HPLC-MS analysis data of B. atroviridis revealed the presence of bridelionoside D, isomyricitrin, corilagin, myricetin and 5 others compounds not yet identified. Bridelia atroviridis exhibited good in vitro antiplasmodial activity with the IC50 evaluated at 8.08 μg/mL and low cytotoxicity with the median cytotoxic concentration (CC50) higher than 100 μg/mL. B. atroviridis extract significantly reduced the parasitemia (p < 0.05) with an effective dose-50 (ED-50) of 89 mg/kg. B. atroviridis also prevented anemia, leukocytosis and liver and kidneys impairment by decrease of transaminases, ALP, creatinine, uric acid, and triglycerides concentrations. As well, B. atroviridis extract decreased some pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) levels and significantly improved the anti-inflammatory status (P < 0.01) of infected animals marked by a decrease of IL-10 concentration. These results were further confirmed by the improved of antioxidant status and the quasi-normal microarchitecture of the liver, kidneys and spleen in test groups. Overall, the hydroethanolic bark extract of Bridelia atroviridis demonstrated antimalarial property and justified its use in traditional medicine to manage malaria disease.

Inhalation sedation for postoperative patients in the intensive care unit: initial sevoflurane concentration and comparison of opioid use with propofol sedation.

BackgroundAlthough the use of volatile sedatives in the intensive care unit (ICU) is increasing in Europe, it remains infrequent in Asia. Therefore, there are no clinical guidelines available. This study investigates the proper initial concentration of sevoflurane, a volatile sedative that induces a Richmond agitation-sedation scale (RASS) score of –2 to –3, in patients who underwent head and neck surgery with tracheostomy. We also compared the amount of postoperative opioid consumption between volatile and intravenous (IV) sedation.MethodsWe planned a prospective study to determine the proper initial sevoflurane concentration and a retrospective analysis to compare postoperative opioid consumption between volatile sedation and propofol sedation. Patients scheduled for head and neck surgery with tracheostomy and subsequent postoperative sedation in the ICU were enrolled.ResultsIn this prospective study, the effective dose 50 (ED50) of initial end-tidal sevoflurane concentration was 0.36% (95% confidence interval [CI], 0.20 to 0.60%), while the ED 95 was 0.69% (95% CI, 0.60 to 0.75%) based on isotonic regression methods. In this retrospective study, remifentanil consumption during postoperative sedation was significantly lower in the sevoflurane group (2.52±1.00 µg/kg/hr, P=0.001) than it was in the IV propofol group (3.66±1.30 µg/kg/hr).ConclusionsWe determined the proper initial end-tidal concentration setting of sevoflurane for patients with tracheostomy who underwent head and neck surgery. Postoperative sedation with sevoflurane appears to be a valid and safe alternative to IV sedation with propofol.

Correlation Between Rift Valley Fever Virus (RVFV) Neutralizing Antibody Titers in Vaccinated Sheep and Effective Dose 50 (ED50) in Vaccinated Mice

Rift valley fever is an arthropod-born, multispecies zoonotic viral disease. Control of RVF disease depends mainly on vector control and vaccination of susceptible animals. The present work aims to detect the correlation between Rift Valley Fever Virus (RVFV) neutralizing antibody titers in vaccinated sheep using Serum Neutralization test as in vitro test and effective dose fifty in vaccinated mice as in vivo potency test and determine if they can be alternative to each other. In this work,17 inactivated RVFV vaccine batches were evaluated, applying SNT for serum samples of vaccinated sheep and ED50 in vaccinated mice. The two models of tests showed compatible results, where the same 14 vaccine batches showed satisfactory results [(SNT &gt;1.5) and (ED50 less than 0.02)], while the other three batches revealed unsatisfactory results in both two tests. Statistical analysis of results using Wilcoxon’s test was (0.0001), indicating a significant correlation between the tests so it could be recommended to depend on SNT instead of mice inoculation in the evaluation of RVF vaccine to reduce the numbers of animals being used and to avoid the possible public health hazard.

Response of Annual Weeds to Glyphosate: Evaluation and Optimization of Application Rate Based on Fecundity-Avoidance Biomass Threshold Criterion

The increased availability and high adoption rate of glyphosate-tolerant crops have selected for several glyphosate-resistant weed species. The response of representative weed species to glyphosate was assessed to provide insights and tools for optimizing glyphosate use for economic, agronomic and environmental reasons. Anoda cristata, Chenopodium album, Digitaria sanguinalis, Eleusine indica and Portulaca oleracea were grown outdoors in pots containing commercial potting medium. An increasing dose of glyphosate was applied to these species at three growth stages. Weed response was evaluated visually compared to the nontreated control and shoot dry weights were recorded. Fecundity was also determined. Based on visual evaluations, the dose of glyphosate required to attain 90% control of the species tested exhibited an application rate margin up to 28.5-fold compared to recommended rate, denoting a potential for rate optimization. Except for A. cristata, the recommended dose of glyphosate could be reduced by 30%–60% and still achieve 90% or greater control. The order of species sensitivity, based on effective dose 50 (ED50 )values, was E. indica &gt; C. album &gt; D. sanguinalis &gt; P. oleracea &gt; A. cristata. The ratio of ED90/ED50 was constant, indicating that increasing the glyphosate dose 8.7-fold would reduce weed biomass 1.8-fold. In most cases, the fecundity-avoidance biomass threshold (i.e., the maximum allowable weed biomass for herbicide application in order to prevent weed seed production and dispersal) for glyphosate was below the ED90 value. Complimentary measures such as fecundity-avoidance biomass threshold will improve herbicide evaluation procedures and preserve the effectiveness of herbicides, including glyphosate, on sensitive species, an important issue particularly when action to reduce herbicide resistance development is highly required.

Why maximum tolerated dose?

A long-established approach to the pharmacological treatment of disease has been to start low and go slow. However, clinicians often prescribe up to maximum tolerated dose (MTD), especially when treating acute and more severe disease, without evidence to show that MTD is more likely to improve outcomes. Cardiovascular guidelines for some indications advocate MTD even in prevention, for example hypercholesterolaemia, without compelling evidence of better outcomes. This review explores the origins and potential problems of prescribing medications at MTD. Oral effective dose 50 (ED50) may be a useful guide for balancing efficacy and safety.

Determination of midazolam dose for co-induction with alfaxalone in sedated cats

ObjectiveTo investigate the median effective dose 50 (ED50) of midazolam required for endotracheal intubation when used for co-induction of anesthesia with a low dose of alfaxalone in sedated cats. Study designRandomized up-and-down study. AnimalsA group of 14 mixed-breed cats (eight males, six females), aged 5–12 years and weighing 4.4–6.8 kg. MethodsThe cats were randomly assigned in a sequential allocation numbers from one to 14. Cats were sedated with dexmedetomidine (3 μg kg–1) and methadone (0.3 mg kg–1) intramuscularly. After 15 minutes, the quality of sedation was subjectively evaluated. Anesthesia induction was performed by intravenous (IV) administration of alfaxalone (0.25 mg kg–1) over a 60 second interval, followed by another 60 second interval, and then an IV dose of midazolam was administered over a 5 second interval. The initial midazolam dose was 0.3 mg kg–1; then, the midazolam dose was adjusted by ±0.1 mg kg–1 for each consecutive cat based on successful or unsuccessful endotracheal intubation of the previous animal following an up-and-down method. This sequence was followed until six nonsequential crossovers were observed. Crossover was defined as two opposite outcomes in two sequential animals. Data were analyzed using isotonic regression with bootstrapping for determination of midazolam ED50 and logistic regression for correlations (p < 0.05). ResultsOverall, six independent crossovers were found, and ED50 of midazolam was 0.08 ± 0.04 mg kg–1. Sedation score and successful tracheal intubation had a strong positive correlation (p = 0.02). Conclusions and clinical relevanceThis study determined that 0.08 ± 0.04 mg kg–1 of midazolam co-administered with 0.25 mg kg–1 of alfaxalone IV allowed smooth endotracheal intubation in half of the cats sedated with methadone and dexmedetomidine at the doses used in this study.

Antihyperlipidemic Activity of Ethanol Extract Mindi’s Leaves (Melia azedarach Linn.) in Male Wistar Rats Induced Propiltiouracil

Mindi’s leaves (Melia azedarach Linn.) is an Indonesian medicinal plant that used as traditional medicine. Mindi leaves contains some secondary metabolites which have potency to decreased total cholesterol and LDL level. The study purposed to know antihyperlipidemic effect of ethanol extract of mindi’s leaves (Melia azedarach Linn.) seen from total cholesterol, and LDL in male albino rats. Male wistar albino rats were divided into 5 groups, negative control group (sodium CMC 0.5%), positive control group (simvastatin 0.193 mg/200 gBW), group I (ethanol extract mindi’s leaves with dosage 300 mg/200 gBW), group II (ethanol extract mindi’s leaves with dosage 600 mg/200 gBW), and group III (ethanol extract mindi’s leaves with dosage 1200 mg/200 gBW). The rats were given high-fat supplement and propylthiouracil for 15 days to increase cholesterol, and the extract was given for the next 15 days. Average cholesterol level, LDL, and body weight after induction was 90.28 mg/dL, 31.09 mg/dL, and 222.32 g. The result showed ethanol extract mindi’s leaves could decreased total cholesterol level and LDL level with % decreased in total cholesterol (%PDTC) and % decreased in LDL (%PDLDL) of group I is 37.78% and 35.57%, group II is 45.99% and 40.39%, and for group III is 56.29% and 52.42%. The result showed that ethanol extract of mindi’s leaves has antihyperlipidemic activity and significantly different from negative control (p&gt;0.05). Based on the percentage relation of decreased total cholesterol and LDL levels to dose, then the effective dose 50 (ED50) value of ethanol extract mindi’s leave is 869 mg/200 gBW for total cholesterol and for LDL reduction level is 1086.84 mg/200 gBW

In vivo antimicrobial activity of the hybrid peptide H4: a follow-up study.

BackgroundThe consistent upsurge in antimicrobial resistance globally is threatening the world population with the prospect of facing the post-antibiotic era. Dry pipelines and a drastic decrease of antimicrobial drug development accompany this rise in antimicrobial resistance. Governments and health authorities are calling for the development of novel classes of antimicrobial agents that would tackle this problem. Antimicrobial peptides represent a promising group of molecules for antimicrobial drug development due to their potency and rapid mode of killing. However, several obstacles, such as high mammalian cell toxicity and lack of target selectivity, have challenged the development of such agents.MethodsWe have recently designed a novel hybrid peptide named H4 that exhibits potent antimicrobial activity and low toxicity in vitro. In order to confirm the potential therapeutic efficacy and safety of the peptide, we evaluated the in vivo activity and toxicity of H4 against Staphylococcus aureus peritonitis mice model.ResultsOur results indicate that H4 is highly potent in eradicating bacterial infections in vivo with an effective dose50 value of 4.55±0.89 mg/kg. Additionally, the acute systemic toxicity results indicate that the peptide exhibits a high therapeutic index with no significant negative effects on the function of major body organs.ConclusionH4 is a novel hybrid peptide with great potential for antimicrobial drug development.