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Results for “Pharmacology and Toxicology”

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bioRxiv2017

Mercury concentrations in Double-crested Cormorant chicks across Canada

Mercury (Hg) biomagnifies in aquatic food chains and can reach high concentrations in fish-eating birds. Spatial patterns of Hg have been found in freshwater ecosystems across Canada for many taxa including fish and birds. However, it is often challenging to sample a representative population size of adult birds to monitor concentrations of contaminants over a large spatial scale. Moreover, adult birds can migrate and can show a contaminant profile that may not be representative of local resources. The aims of this study were (1) to determine if there was a spatial pattern of Hg in piscivorous birds, (2) to develop a model to estimate Hg concentrations in breeding adults using chicks as proxy, and (3) to develop predictive equations among non-lethal samples that representative of local resources in adults (blood and growing feathers). Double-crested Cormorant (Phalacrocorax auritus) chick growing feathers were sampled at 19 sites across Canada (n = 106). Adult tissues (freshly grown feathers; n = 8-16 per feather type and blood; n = 160) were sampled at five of those locations to establish correlations between age classes and between adult tissues. We found an increase in Hg concentrations with latitude up to 50{degrees}N followed by a decrease. There was a decrease in Hg concentrations from west to east, which contradicts previous studies. We found a good correlation of Hg concentrations between adults and chicks and among adult tissues. Our model showed that it is possible to estimate Hg concentrations in adults across Canada using chicks as proxy. Our study shows that chicks can be a suitable proxy for monitoring local mercury concentrations and that they are representative of adults.\n\nCapsule: Concentrations of mercury in cormorant chicks are influenced by latitude

pharmacology and toxicology↗

bioRxiv2017

An automated high-throughput system for phenotypic screening of chemical libraries on C. elegans and parasitic nematodes

Parasitic nematodes infect hundreds of millions of people and farmed livestock. Further, plant parasitic nematodes result in major crop damage. The pipeline of therapeutic compounds is limited and parasite resistance to the existing anthelmintic compounds is a global threat. We have developed an INVertebrate Automated Phenotyping Platform (INVAPP) for high-throughput, plate-based chemical screening, and an algorithm (Paragon) which allows screening for compounds that have an effect on motility and development of parasitic worms. We have validated its utility by determining the efficacy of a panel of known anthelmintics against model and parasitic nematodes: Caenorhabditis elegans, Haemonchus contortus, Teladorsagia circumcincta, and Trichuris muris. We then applied the system to screen the Pathogen Box chemical library in a blinded fashion and identified known anthelmintics, including tolfenpyrad, auranofin, and mebendazole and 14 compounds previously undescribed as anthelmintics, including benzoxaborole and isoxazole chemotypes. This system offers an effective, high-throughput system for the discovery of novel anthelmintics.

pharmacology and toxicology↗

bioRxiv2017

Zerumbone From Zingiber zerumbet (L.) Smith: A Potential Prophylactic and Therapeutic Agent Against The Cariogenic Bacterium Streptococcus mutans

BackgroundEssential oil obtained from rhizomes of the Zingiber zerumbet (L.) Smith (popularly known in Brazil as bitter ginger) is mainly constituted by the biomolecule zerumbone, which exhibit untapped antimicrobial potential. The aim of this study was to investigate the antimicrobial activity of the zerumbone from bitter ginger rhizomes against the cariogenic agent Streptococcus mutans.\n\nMethodsFirstly, the essential oil from rhizomes of Zingiber zerumbet (L.) Smith extracted by hydrodistillation was submitted to purification and recrystallization process to obtain the zerumbone compound. The purity of zerumbone was determined through high-performance liquid chromatography analysis. Different concentrations of zerumbone were tested against the standard strain S. mutans (ATCC 35668) by using microdilution method. The speed of cidal activity was determined through a time kill-curve assay. The biological cytotoxicity activity of zerumbone was assessed using Vero Cell line through MTT assay.\n\nResultsThe zerumbone showed a minimum inhibitory concentration (MIC) of [≥] 250g/ mL and a minimum bactericidal concentration (MBC) of [≥] 500g/mL against S. mutans. After six hours of bacteria-zerumbone interaction, all concentrations tested starts to kill the bacteria and all bacteria were killed between 48 and 72 hours period at the concentration of 500 g/ mL (99,99% of bacteria were killed in comparison with original inoculum). In addition, zerumbone showed no cytotoxicity activity on mammalian continuous cells line.\n\nConclusionsThese results draw attention to the great potential of zerumbone as antimicrobial agent against S. mutans infection, indicating its possible use in the phyto-pharmaceutical formulations as new approach to prevent and treat tooth decay disease.\n\nAbbreviations

pharmacology and toxicology↗

bioRxiv2017

Image-based profiling can discriminate the effects of inhibitors on signaling pathways under differential ligand stimulation

A major advantage of image-based phenotypic profiling of compounds is that numerous image features can be sampled and quantitatively evaluated in an unbiased way. However, since this assay is a discovery-oriented screening, it is difficult to determine the optimal experimental set-up in advance. In this study, we examined whether variable cellular stimulation affects the efficacy of image-based profiling of compounds. Seven different EGF receptor ligands were used, and the expression of EGF receptor signaling molecules was monitored at various time points. Significant quantitative differences in image features were detected among the differentially treated samples. Next, 14 different compounds that affect EGF receptor signaling were profiled. Nearly half of the compounds were classified into distinct clusters, irrespective of differential ligand stimulation. The results suggest that image-based phenotypic profiling is quite robust in its ability to predict compound interaction with its target. Although this method will have to be validated in other experimental systems, the robustness of image-based compound profiling demonstrated in this work provides a valid basis for further study and its extended application.

pharmacology and toxicology↗

bioRxiv2017

Acute and chronic toxicity assessment of benzylpenicillin G residue in cooked meat

The current level of penicillin use and its persisting residues in livestock is potentially concerning; the toxicity of penicillin residues in heat-treated animal food products (HAFP) is yet to be elucidated. In this study, the acute and chronic toxicity of benzylpenicillin G (BPG) residues in HAFP was investigated in a mouse model. The calculated LD50 of BPG heated to cooking temperature (BPHCT) was 933.04 mg kg-1 [b.w.] intraperitoneally corresponding to 3.75 times lower than its prototype. Mice fed on the experimental diet containing heat-treated beef with high BPG levels for 6 months displayed a reduction in body weight and altered serum values indicating for liver and renal function. Further, the organ ratios of intestinal and spleen were increased. Histopathological changes were observed in the liver, lung and parenchyma testis tissue. BPHCT residue induced sperm aberration and micronucleated polychromatic erythrocytes formation. Present results indicate that prolonged exposure of BPHCT at higher levels of residue might have an impact on public health. Importantly the toxic concentrations of BPHCT are relatively high compared with levels that would result from the degradation of antibiotic residues in meat from animals that have received a therapeutic dose of BPG.

pharmacology and toxicology↗

bioRxiv2017

Predicting drug safety and communicating risk: benefits of a Bayesian approach

Drug toxicity is a major source of attrition in drug discovery and development. Pharmaceutical companies routinely use preclinical data to predict clinical outcomes and continue to invest in new assays to improve predictions. However, there are many open questions about how to make the best use of available data, combine diverse data, quantify risk, and communicate risk and uncertainty to enable good decisions. The costs of suboptimal decisions are clear: resources are wasted and patients may be put at risk. We argue that Bayesian methods provide answers to all of these problems and use hERG-mediated QT prolongation as a case study. Benefits of Bayesian machine learning models include intuitive probabilistic statements of risk that incorporate all sources of uncertainty, the option to include diverse data and external information, and visualisations that have a clear link between the output from a statistical model and what this means for risk. Furthermore, Bayesian methods are easy to use with modern software, making their adoption for safety screening straightforward. We include R and Python code to encourage the adoption of these methods.

pharmacology and toxicology↗

bioRxiv2017

Proteomic Characterization Of The Venom Of Five Bombus (Thoracobombus) Species

Venomous animals use venom; a complex biofluid composed of unique mixtures of proteins and peptides, to act on vital systems of the prey or predator. In bees, venom is solely used for defense against predators. However, the venom composition of bumble bees (Bombus sp.) is largely unknown. Thoracobombus subgenus of Bombus sp. is a diverse subgenus represented by 14 members across Turkey. In this study, we sought out to proteomically characterize the venom of five Thoracobombus species by using bottom-up proteomic techniques. We have obtained two-dimensional polyacrylamide gel (2D-PAGE) images of each venom sample. We have subsequently identified the protein spots by using matrix assisted laser desorption ionization / time of flight mass spectrometry (MALDI-TOF MS). We have identified 47 proteins for Bombus humilis; 32 for B. pascuorum, 60 for B. ruderarius; 39 for B. sylvarum and 35 for B. zonatus. Our analyses provide the primary proteomic characterization of five bumble bee species venom composition.

pharmacology and toxicology↗

bioRxiv2017

Genetic differences in the aryl hydrocarbon receptor and CYP1A2 affect susceptibility to developmental polychlorinated biphenyl exposure in mice: Relevance to studies of human neurological disorders

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that remain a human health concern with the discovery of new sources of contamination and ongoing bioaccumulation and biomagnification. Children exposed during early brain development are at highest risk of neurological deficits, but there is some evidence that high PCB exposure in adults increases the risk of Parkinsons disease. Our previous studies found allelic differences in the aryl hydrocarbon receptor and cytochrome P450 1A2 (CYP1A2) affect susceptibility to developmental PCB exposure, resulting in cognitive deficits and motor dysfunction. High-affinity AhrbCyp1a2(-/-) mice were most susceptible compared with poor-affinity AhrdCyp1a2(-/-) and wild type AhrbCyp1a2(+/+) mice. Our follow-up studies assessed biochemical, histological and gene expression changes to identify the brain regions and pathways affected. We also measured PCB and metabolite levels in multiple tissues to determine if genotype altered toxicokinetics. We found evidence of AHR-mediated immune suppression with reduced thymus and spleen weights and significantly reduced thyroxine at P14. In the brain, the greatest changes were seen in the cerebellum where a foliation defect was over-represented in Cyp1a2(-/-) mice. In contrast, we found no difference in tyrosine hydroxylase immuno-staining in the striatum. Gene expression patterns varied across the three genotypes, but there was clear evidence of AHR activation. Distribution of parent PCB congeners also varied by genotype with strikingly high levels of PCB 77 in poor-affinity AhrdCyp1a2(-/-) while AhrbCyp1a2(+/+) mice effectively sequestered coplanar PCBs in the liver. Together, our data suggest that the AHR pathway plays a role in developmental PCB neurotoxicity, but we found little evidence that developmental exposure is a risk factor for Parkinsons disease.

pharmacology and toxicology↗

bioRxiv2017

Inhaled nicotine equivalent to cigarette smoking disrupts systemic and uterine hemodynamics and induces cardiac arrhythmia in pregnant rats

Maternal smoking with obligatory nicotine inhalation is associated with preterm delivery, low birth weight, fetal growth retardation and developmental defects. We tested the hypothesis that cigarette smoking-relevant nicotine inhalation during pregnancy impairs cardiovascular function and uterine hemodynamics with consequential fetal ischemia. Pregnant rats exposed to episodic inhaled nicotine via a novel lung alveolar region-targeted aerosol method produced nicotine pharmacokinetics resembling cigarette smoking in humans. This clinically relevant nicotine aerosol inhalation (NAI) induced transient reduction and irregular fluctuations in uterine artery blood flow associated with cardiac arrhythmia and high magnitude irregular fluctuations of systemic blood pressure. The arrhythmia included sinoatrial (SA) block, sinus arrest, 2o and 3o atrioventricular (A-V) block and supraventricular escape rhythm. These effects were blocked by the nicotinic receptor (nAChR) antagonist mecamylamine. Resection of the ovarian nerve, which innervates uterine blood vessels, counteracted the NAI-induced reduction in uterine blood flow. We suggest that the rapid rise pattern of arterial blood nicotine concentration stimulates and then desensitizes autonomic nAChRs leading to disruptions of cardiac function as well as systemic and uterine hemodynamics that reduces uteroplacental blood flow, a mechanism underlying maternal smoking-associated pregnancy complications and developmental disorders. These findings challenge the safety of pure nicotine inhalation, i.e., E-cigarettes.

pharmacology and toxicology↗

bioRxiv2017

Improving the Generation and Selection of Virtual Populations in Quantitative Systems Pharmacology Models

Quantitative systems pharmacology (QSP) models aim to describe mechanistically the pathophysiology of disease and predict the effects of therapies on that disease. For most drug development applications, it is important to predict not only the mean response to an intervention but also the distribution of responses, due to inter-patient variability. Given the necessary complexity of QSP models, and the sparsity of relevant human data, the parameters of QSP models are often not well determined. One approach to overcome these limitations is to develop alternative virtual patients (VPs) and virtual populations (Vpops), which allow for the exploration of parametric uncertainty and reproduce inter-patient variability in response to perturbation. Here we evaluated approaches to improve the efficiency of generating Vpops. We aimed to generate Vpops without sacrificing diversity of the VPs pathophysiologies and phenotypes. To do this, we built upon a previously published approach (Allen, Rieger et al. 2016) by (a) incorporating alternative optimization algorithms (genetic algorithm and Metropolis-Hastings) or alternatively (b) augmenting the optimized objective function. Each method improved the baseline algorithm by requiring significantly fewer plausible patients (precursors to VPs) to create a reasonable Vpop. #ddct #qsp

pharmacology and toxicology↗

bioRxiv2017

Safety evaluation of soy leghemoglobin protein preparation derived from Pichia pastoris, intended for use as a flavor catalyst in plant-based meat

The leghemoglobin protein (LegH) from soy (Glycine max) expressed in Pichia pastoris (LegH Prep) imparts a meat-like flavor profile onto plant-based food products. The safety of LegH Prep was evaluated through a series of in vitro and in vivo tests. The genotoxic potential of LegH Prep was assessed using the bacterial reverse mutation assay (Ames test) and the in vitro chromosome aberration test. LegH Prep was non-mutagenic and non-clastogenic in each test, respectively. Systemic and female reproductive toxicity were assessed in two separate 28-day dietary studies in Sprague Dawley rats. There were no mortalities associated with the administration of LegH Prep. There were no clinical observations, body weight, ophthalmological, clinical pathology, or histopathological changes attributable to LegH Prep administration. Female reproductive parameters were comparable between rats treated with LegH Prep and concurrent control rats. These studies establish an NOAEL of 750 mg/kg/day LegH, which is over 100 times greater than the 90th percentile estimated daily intake (EDI). Collectively, this work demonstrates that LegH Prep is safe for its intended use in ground beef analogue products at concentrations up to 0.8% LegH.\n\nAbbreviations

pharmacology and toxicology↗

bioRxiv2017

Behavioral and biochemical effects of ethanol withdrawal in zebrafish

Chronic alcohol use induces adaptations and toxicity that can induce symptoms of anxiety, autonomic hyperarousal, and epileptic seizures when alcohol is removed (withdrawal syndrome). Zebrafish has recently gained wide attention as a behavioral model to study the neurobehavioral effects of acute and chronic alcohol use, including withdrawal. The literature, however, is very contradictory on findings regarding withdrawal effects, with some studies reporting increased anxiety, while others report no effect. A meta-analytic approach was taken to find the sources of this heterogeneity, and ethanol concentration during exposure and exposure duration were found to be the main sources of variation. A conceptual replication was also made using continuous exposure for 16 days in waterborne ethanol (0.5%) and assessing anxiety-like behavior in the light/dark test after 60 min withdrawal. Withdrawal was shown to reduce preference for darkness, consistent with decreased anxiety, but to increase risk assessment, consistent with increased anxiety. Animals were also subjected to the withdrawal protocol and injected with pilocarpine in a sub-convulsive dose to assess susceptibility to epileptic seizure-like behavior. The protocol was sufficient to increase susceptibility to epileptic seizure-like behavior in animals exposed to ethanol. Finally, withdrawal also decreased catalase activity in the brain, but not in the head kidney, suggesting mechanisms associated with the behavioral effects of ethanol withdrawal.

pharmacology and toxicology↗

bioRxiv2017

Mid-Infrared Spectroscopy Study of Effects of Neonicotinoids on Forager Honey Bee (Apis mellifera) Fat Bodies and Their Connection to Colony Collapse Disorder

This study investigated the negative effects of neonicotinoid pesticides on honey bees in environment surrounding areas of pesticide use. The aim of the experiment is to identify possible contributors to the sudden decrease in honey bee population over the past 60 years, a phenomenon known as Colony Collapse Disorder. Analysis was performed on three sets of bees: the control group which was not in contact with pesticides, the infected dead group which was a set of bees suspected to have died due to neonicotinoids, and the infected alive group which was suspected to be under the influence of neonicotinoids. After dissecting the bee samples and extracting their fat bodies, the chemical composition and protein structures of the samples were analyzed using Mid-Infrared Beamline at the Canadian Light Source. Results from the spectra of bee samples exposed to neonicotinoids demonstrated possible residual pesticide chemicals within fat bodies. Several spectral peaks were also correlated with a possible change in protein secondary structures from primarily {beta}-sheet to -helix within fat bodies of neonicotinoid-affected bees. It is likely that the pesticides caused the growth of additional -helical structures, which is consistent with consequences of the inhibition of nicotinic acetylcholine receptors (nAChRs) a current pathway of harm of Colony Collapse Disorder as identified in past literature.

pharmacology and toxicology↗

bioRxiv2017

Enhanced intestinal reabsorption due to reduced metabolism of ceftriaxone

The polyherbal drug (Fibrosin(R)) is often used as supportive therapy with intramuscular ceftriaxone injection for treatment of mastitis. A single dose of ceftriaxone at 50 mg kg-1 was administered intramuscularly in six healthy lactating goats and a single oral dose of Fibrosin(R) (1.9 gm) was given 1 hr prior to intramuscular ceftriaxone injection to study disposition of ceftriaxone. Plasma and urine samples were collected at predetermined time schedule and ceftriaxone/ceftizoxime was extracted and analyzed by HPLC. Ceftriaxone persisted for 3 hr in plasma of fibrosin treated healthy lactating goats. Mean t[1/2] K (distribution half life) following absorption phase and t[1/2] K'(elimination half life) following intestinal re-absorption phase were respectively, 0.091 {+/-} 0.01 and 0.43 {+/-} 0.03 hr with a re-absorption half life (t[1/2]Ka') of 0.18 {+/-} 0.003 hr.Ceftriaxone at a lower concentration (67.91 {+/-} 9.42 g ml-1) was recovered at 24 hr post dosing from urine. This is the first report of pharmacokinetic interaction of intramuscular ceftriaxone injection and the oral polyherbal drug (which was found to be a cytochrome P450 inhibitor).

pharmacology and toxicology↗

bioRxiv2017

Complex versus simple models: ion-channel cardiac toxicity prediction

There is growing interest in applying detailed mathematical models of the heart for ion-channel related cardiac toxicity prediction. However, a debate as to whether such complex models are required exists. Here an assessment in the predictive performance between two established cardiac models, gold-standard and cardiac safety simulator, and a simple linear model Bnet was conducted. Three ion-channel data-sets were extracted from literature. Each compound was designated a cardiac risk category based on information within CredibleMeds. The predictive performance of each model within each data-set was assessed via a leave-one-out cross validation. In two of the data-sets Bnet performed equally as well as the leading cardiac model, cardiac safety simulator, both of these outperformed the gold-standard model. In the 3rd data-set, which contained the most detailed ion-channel pharmacology, Bnet outperformed both cardiac models. These results highlight the importance of benchmarking models but also encourage the development of simple models.

pharmacology and toxicology↗

bioRxiv2017

Cadmium exposure inhibits branching morphogenesis and causes alterations consistent with HIF-1α inhibition in human primary breast organoids

BackgroundDevelopmental cadmium exposure in vivo disrupts mammary gland differentiation, while exposure of breast cell lines to cadmium causes invasion consistent with the epithelial-mesenchymal transition (EMT). The effects of cadmium on normal human breast stem cell development have not been measured.\n\nObjectiveThe objective of this study was to quantify the effects of cadmium exposure on normal breast stem cell proliferation and differentiation.\n\nMethodsWe tested the effects of two physiologically relevant doses of cadmium: 250M and 2.5M on reduction mammoplasty patient-derived breast cells using the mammosphere assay, organoid formation in 3D hydrogels, and tested for molecular alterations using RNA-seq. We functionally validated our RNA-seq findings with a HIF-1 transcription factor activity reporter line and pharmaceutical inhibition of HIF-1 in mammosphere and organoid formation assays.\n\nResults2.5M cadmium reduced primary and secondary mammosphere formation and branching structure organoid formation rates by 33%, 40%, and 83%, respectively. Despite no changes in mammosphere formation, 0.25M cadmium treatment inhibited branching organoid formation in hydrogels by 68%. RNA-seq revealed that cadmium treatment downregulated genes associated with extracellular matrix formation and EMT, while upregulating genes associated with metal response including metallothioneins and zinc transporters. In the RNA-seq data, cadmium treatment also downregulated HIF-1 target genes including LOXL2, ZEB1, and VIM. Cadmium treatment significantly inhibited HIF-1 activity in a luciferase assay, and the HIF-1 inhibitor acriflavine ablated mammosphere and organoid formation.\n\nDiscussionThese findings show that cadmium, at doses relevant to human exposure, inhibited human mammary gland development, potentially through disruption of HIF-1 activity. These findings do not support cadmium being a breast cancer initiator via induction of stem cell proliferation, but instead implicate cadmium as an inhibitor of mammary gland morphogenesis.

pharmacology and toxicology↗

bioRxiv2017

Bioassay of derived components from venom of Iranian medically important scorpions to identify the bradykinin potentiating factors

The venom of animals, including snakes, scorpions and spiders is a complex combination of proteins, peptides, and other biomolecules as well as some minerals. Among the biomolecules, some peptides prevent converting of angiotensin 1 to angiotensin 2 by inhibiting of the Angiotensin Converting Enzyme (ACE) and finally reducing the blood pressure in the victims. The aim of the present study was to isolate venom components of the three species of Iranian medically important scorpions and to study the bradykinin potentiating effect of them. Separation of the venom components for each scorpion was carried out using high performance liquid chromatography (HPLC). The range of fractions (zones) obtained in several replicates on Guinea pig ileum and rat uterus tissues were performed using organ bath instrument. The bioassays were resulted in the peptides including Z1 and Z2 regions of venom chromatogram of the Hottentotta sulcyi, Z2 for Odontobutus doriea and Z2 and Z3 in Mesobutus eupeus venom demonstrated bradykinin potentiating effect.

pharmacology and toxicology↗

bioRxiv2017

Potential clinical benefits of CBD-rich Cannabis extracts over purified CBD in treatment-resistant epilepsy: observational data meta-analysis

Potential clinical benefits of CBD-rich Cannabis extracts over purified CBD in treatment-resistant epilepsy: observational data meta-analysis\n\nDifferent therapies involving cannabinoid compounds have become popular on the past few years, particularly the use of canabidiol (CBD) based products for the treatment of child refractory epilepsy. In this segment we highlight genetic disorders such as the Dravet Syndrome, which has received a lot of attention in Brazil. Our country has been giving visibility for this issue after the public discussion regarding the patient Anne Fischer, who benefited from a treatment with hemp based products, imported from the United States of America as a nutritional supplement, and still unregistered in Brazil. To this moment there is no cannabinoid based product registered for clinical indication for epilepsy, so patients have at their disposal products considered nutritional supplements, in general produced from a type of Cannabis known as \"hemp\", which are commercialized in Brazil through medical prescription. Despite several anecdotal evidences from patients and family members, until now there is no consensus on medical literature over the efficacy and safety of these products. Some observational studies are available on scientific literature, but there is still a scarcity of clinical studies conducted under the logic, rigor and organization necessary for clinical trial dedicated to the register of a pharmaceutical product. The objective of this paper is to describe the analysis of several observational clinical studies available on the literature regarding the treatment of child refractory epilepsy with cannabinoid based products. Beyond attempting to establish the safety and efficacy of such products, when possible, the present analysis also intended to investigate if there is enough evidence between the different aspects of safety and efficacy between CBD enriched extracts compared to purified CBD products. Results: a systematic search for papers in the \"PubMed\" search system with the words \"Dravet\", \"Lennox-Gastaut\" and \"epilepsy\" combined with the terms \"Cannabis\", \"cannabinoid\" and \"child\" yielded 30 papers. From those, 24 were not considered for the systematic review, for not having valid content (13), for being opinion only papers (6), showed not clinical data (4) and reported different subjects (1), resulting in 6 valid papers published between 2013 and 2016. One additional study was in press at the moment of the search was added manually (1) resulting in 7 valid references for analysis, with an average impact factor of 5,9 (2,3 to 21,8). Public data from partial reports of controlled randomized studies conducted in order to register a medication (2) were also considered, when appropriated and were mentioned in the text. The categorical data were analyzed by the Fischer test. Overall, the papers analyzed report observational clinical data of 442 patients, treated with CBD rich extracts or purified CBD, with he average daily dose between 1 and 50 mg/kg, with treatment length from 3 to 12 months (average of 6,2 months). A considerable amount of 66% (292/442) of the patients reported improvement in the frequency of convulsive crisis. There were more reports of improvement from patients treated with purified CBD (242/285) than patients treated with purified CBD (68/157), with statistical significance (p<0,0001). Nevertheless, when the standard clinical threshold of a \"50% reduction or more in the frequency of convulsive crisis\" was applied, only 40% of the individuals are considered respondent, and there were no difference (p=0,57) between the treatments with extract (64/168) and purified CBD (65/157). However, even that both treatments have similar efficacy, the patients treated with CBD enriched extracts reported a lower average dose than purified CBD patients. The average CBD equivalent dose on the extracts was 7,1 mg/kg/day, while the purified CBD was 22,9 mg/kg/day, suggesting that CBD is about 3x more potent in the extract than in its purified form. Looking only at the data relative to genetic originated disorders, there is evidence of a superior efficacy on Dravet Syndrome patients (37/72, p=0,01), but not for Lennox-Gastaut Syndrome (78/188, p=0,18), compared to the number of refractory epilepsy respondents in general (107/305). There is also an advantage of the CBD enriched extracts related to the occurrence of side effects. The report of mild side effects (109/285 vs. 291/346, p<0,0001) and severe (23/285 vs. 77/346, p<0,0001) are more frequent in products containing purified CBD than on CBD enriched extracts. Important to mention that these are the numbers of total reports of side effects, it is not possible to infer which fraction of these numbers are related to the treatment. In conclusion, this meta analysis suggests that treatments using CBD enriched extracts are more potent and have a better profile of adverse effects (but not more efficacy) than products containing purified CBD, at least in this population of patients with refractory epilepsy. The lack of standardization between extracts containing Cannabis does not allow us to infer directly which characteristics of the product that confer this therapeutic advantage, but it is likely related to other compounds present in the formulation that act sinergistically with CBD. Controlled studies with standardized Cannabis based extracts are necessary to confirm these observations.\n\n*Presented as an abstract and lecture to the 2017 CannMed event, at the Harvard Medical School, Boston, USA, in may 2017.

pharmacology and toxicology↗