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    Recently there have been significant advances in our understanding of how cannabis and related compounds cannabinoids affect the brain and this review addresses the current state of knowledge of these effects. Cannabinoids act primarily via two types of receptor, CB1 and CB2, with CB1 receptors mediating most of the central actions of cannabinoids.

    The presence of a new type of brain cannabinoid receptor is also indicated. Important advances have been made in our understanding of cannabinoid receptor signaling pathways, their modulation of synaptic transmission and plasticity, the cellular targets of cannabinoids in different central nervous system CNS regions and, in particular, the role of the endogenous brain cannabinoid endocannabinoid system. Cannabinoids have widespread actions in the brain: Cannabinoids may also be protective against neurodegeneration and brain damage and exhibit anticonvulsant activity.

    Some of the analgesic effects of cannabinoids also appear to involve sites within the brain. These advances in our understanding of the actions of cannabinoids and the brain endocannabinoid system have led to important new insights into neuronal function which are likely to result in the development of new therapeutic strategies for the treatment of a number of key CNS disorders.

    Full Text Available Cannabinoids have been used to treat pain for many centuries. However, only during the past several decades have rigorous scientific methods been applied to understand the mechanisms of cannabinoid action. Cannabinoid receptors were discovered in the late s and have been found to mediate the effects of cannabinoids on the nervous system.

    Several endocannabinoids were subsequently identified. Many studies of cannabinoid analgesia in animals during the past century showed that cannabinoids block all types of pain studied. These effects were found to be due to the suppression of spinal and thalamic nociceptive neurons, independent of any actions on the motor systems. Spinal, supraspinal and peripheral sites of cannabinoid analgesia have been identified. Endocannabinoids are released upon electrical stimulation of the periaqueductal gray, and in response to inflammation in the extremities.

    These observations and others thus suggest that a natural function of cannabinoid receptors and their endogenous ligands is to regulate pain sensitivity. The therapeutic potential of cannabinoids remains an important topic for future investigations, with previous work suggesting utility in clinical studies of cancer and surgical pain. Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data: What have we learned?

    The pharmacokinetics PK of therapeutic antibodies is determined by target and non-target mediated mechanisms. These antibody-specific factors need to be considered during prediction of human PK based upon preclinical information. Principles of allometric scaling established for small molecules using data from multiple animal species cannot be directly applied to antibodies.

    Here, different methods for projecting human clearance CL from animal PK data for 13 therapeutic monoclonal antibodi Full Text Available Cannabinoids are used clinically on a subacute basis as prophylactic agonist antiemetics for the prevention of nausea and vomiting caused by chemotherapeutics. Cannabinoids prevent vomiting by inhibition of release of emetic neurotransmitters via stimulation of presynaptic cannabinoid CB1 receptors.

    Cannabis-induced hyperemesis is a recently recognized syndrome associated with chronic cannabis use. It is characterized by repeated cyclical vomiting and learned compulsive hot water bathing behavior. Although considered rare, recent international publications of numerous case reports suggest the contrary. The syndrome appears to be a paradox and the pathophysiological mechanism s underlying the induced vomiting remains unknown.

    Although some traditional hypotheses have already been proposed, the present review critically explores the basic science of these explanations in the clinical setting and provides more current mechanisms for the induced hyperemesis.

    In addition, human and animal findings suggest that chronic exposure to cannabis may not be a prerequisite for the induction of vomiting but is required for the intensity of emesis. Full Text Available The endocannabinoid system is comprised of cannabinoid receptors CB1 and CB2, their endogenous ligands endocannabinoids, and proteins responsible for their metabolism participate in many different functions indispensable to homeostatic regulation in several tissues, exerting also antitumorigenic effects.

    The present study aimed to evaluate the clinical significance of CB1 and CB2 expression in human benign and malignant thyroid lesions. Our data suggest that CB receptors may be involved in malignant thyroid transformation and especially CB2 receptor could serve as useful biomarker and potential therapeutic target in thyroid neoplasia. Quantitative imaging of the type 1 cannabinoid receptor CB1R opens perspectives for many neurological and psychiatric disorders.

    Tracer binding was also evaluated using irreversible kinetics and the irreversible uptake constant K i and fractional uptake rate FUR were estimated. The effect of blood flow on these parameters was evaluated. Additionally, the possibility of determining the tracer plasma kinetics using a reduced number of blood samples was also examined.

    A reversible two-tissue compartment model using a global k 4 value was necessary to describe brain kinetics. Irreversible methods adequately described brain kinetics and FUR values were equivalent to K i.

    The test-retest variability of K i and FUR was 18 F]MK specific binding can be accurately determined using FUR values requiring a short scan 90 to min after tracer administration. Our results suggest that [ 18 F]MK plasma kinetics can be assessed using a few venous samples. Nontargeted SWATH acquisition for identifying 47 synthetic cannabinoid metabolites in human urine by liquid chromatography-high-resolution tandem mass spectrometry.

    Clandestine laboratories constantly produce new synthetic cannabinoids to circumvent legislative scheduling efforts, challenging and complicating toxicological analysis. Anal Bioanal Chem Gradient chromatographic separation was achieved with a Restek Ultra Biphenyl column with a 0. Identification criteria included molecular ion mass error, isotopic profiles, retention time, and library fit criteria. Limits of detection were 0. We present a highly useful novel LC-QTOF method for simultaneously confirming 47 synthetic cannabinoid metabolites in human urine.

    Pharmacokinetic Profile of Oral Cannabis in Humans: Most research on cannabis pharmacokinetics has evaluated inhaled cannabis, but oral "edible" preparations comprise an increasing segment of the cannabis market. Whole blood and oral fluid specimens were obtained at baseline and then for 9 days post-exposure; 6 days in a residential research setting and 3 days as outpatients.

    Measures of subjective, cardiovascular and performance effects were obtained at baseline and for 8 h post-ingestion. The mean Cmax for THC in whole blood was 1, 3. The mean Tmax for THC in oral fluid occurred immediately following oral dose administration, and appear to reflect local topical residue rather than systemic bioavailbility.

    Subjective drug and cognitive performance effects were generally dose dependent, peaked at 1. Whole blood cannabinoid concentrations were significantly correlated with subjective drug effects.

    Correlations between blood cannabinoids and cognitive performance measures, and between oral fluid and all pharmacodynamic outcomes were either non-significant or not orderly by dose. Quantitative levels of cannabinoids in whole blood and oral fluid were low compared with levels observed following inhalation of. Mixed-effects modelling of the interspecies pharmacokinetic scaling of pegylated human erythropoietin.

    A total of serum concentrations from rats, 6 rabbits, 34 monkeys, and 9 dogs obtained after a single dose of PEG-EPO, administered by the i. An open two-compartment model with first-order absorption and lag time Tlag and linear elimination from the central compartment was fitted to the data using the NONMEM V software.

    Body weight WT was used as a scaling factor and the effect of brain weight BW , sex, and pregnancy status on the pharmacokinetic parameters was investigated. The final model was evaluated by means of a non-parametric bootstrap analysis and used to predict the PEG-EPO pharmacokinetic parameters in healthy male subjects.

    The systemic clearance CL in males was estimated to be 4. In females, the CL was The volumes of the central Vc and the peripheral Vp compartment were characterized as Intercompartmental flow was estimated at 2.

    Absorption rate constant Ka was estimated at 0. The interindividual variability in the population pharmacokinetic parameters was fairly low parametric bootstrap confirmed the accuracy of the NONMEM estimates. The mean model predicted pharmacokinetic parameters in healthy male subjects of 70 kg were estimated at: The population pharmacokinetic model developed was appropriate to describe the time course of PEG-EPO serum concentrations and their variability in different species.

    Full Text Available The pharmacokinetics of a liposomal subunit antigen vaccine system composed of the cationic lipid dimethyldioctadecylammonium bromide DDA and the immunostimulatory agent trehalose 6,6-dibehenate TDB 8: Compartment modelling and physiologically based pharmacokinetics PBPK were used to predict the administration site muscle and target site lymph temporal concentration profiles and factors governing these.

    Initial estimates using compartmental modelling established that quadriceps pharmacokinetics for the liposome demonstrated a long half-life A mouse minimal-PBPK model was developed and successfully predicted quadriceps liposome and antigen pharmacokinetics.

    Predictions for the popliteal lymph node PLN aligned well at earlier time-points. A local sensitivity analysis highlighted that the predicted AUCmuscle was sensitive to the antigen degradation constant kdeg resulting in a 3-log change more so than the fraction escaping the quadriceps fe resulting in a fold change, and the predicted AUCPLN was highly sensitive to fe.

    A global sensitivity analysis of the antigen in the muscle demonstrated that model predictions were within the 50th percentile for predictions and showed acceptable fits. To further translate in-vitro data previously generated by our group, the mouse minimal-PBPK model was extrapolated to humans and predictions made for antigen pharmacokinetics in muscle and PLN.

    Global analysis demonstrated that both kdeg and fe had a minimal impact on the resulting simulations in the muscle but a greater impact in the PLN. In summary, this study has predicted the in-vivo fate of DDA: H1 in humans and demonstrated the roles that formulation degradation and fraction escaping the depot site can play upon the overall depot effect within the site of administration.

    Metabolic profiles of pomalidomide in human plasma simulated with pharmacokinetic data in control and humanized -liver mice. Pomalidomide has been shown to be potentially teratogenic in thalidomide-sensitive animal species such as rabbits. In this study, plasma concentrations of pomalidomide, its primary 5-hydroxylated metabolite, and its glucuronide conjugate s were investigated in control and humanized -liver mice.

    Simulations of human plasma concentrations of pomalidomide were achieved with simplified physiologically-based pharmacokinetic models in both groups of mice in accordance with reported pomalidomide concentrations after low dose administration in humans. The results indicate that pharmacokinetic profiles of pomalidomide were roughly similar between control mice and humanized -liver mice and that control and humanized -liver mice mediated pomalidomide 5-hydroxylation in vivo.

    Introducing one aromatic amino group into thalidomide resulted in less species differences in in vivo pharmacokinetics in control and humanized -liver mice. Leuven, Laboratory of Radiopharmacy, Leuven Belgium. Models to predict short and long term accumulation of uranium in the human kidney are reviewed and summarised. These are generally first order linear compartmental models or pseudo- pharmacokinetic models such as the retention model of the ICRP.

    Pharmacokinetic models account not only for transfer from blood to organs, but also recirculation from the organ to blood. The most recent information on mammalian and human metabolism of uranium is used to establish a revised model. The model is applied to the short term accumulation of uranium in the human kidney after a single rapid dosage to the blood, such as that obtained by inhaling UF6 or its hydrolysis products.

    It is shown that the maximum accumulation in the kidney under these conditions is less than the fraction of the material distributed from the blood to kidney if a true pharmacokinetic model is used. The best coefficients applicable to man in the authors' view are summarised in model V. We conclude that one must use true pharmacokinetic models, which incorporate recirculation from the organs to the blood, in order to realistically predict time dependent uptake in the kidneys and other organs.

    Information is presented showing that the half-time for urinary excretion of soluble uranium in man after inhalation of UF6 is about one quarter of a day. Preclinical pharmacokinetics , interspecies scaling, and pharmacokinetics of a Phase I clinical trial of TTAC, a fully human monoclonal antibody against vascular endothelial growth factor 2.

    VEGF is a highly selective mitogen that serves as the central regulator of tumor angiogenesis by mediating endothelial proliferation, permeability, and survival. In the present study, we conducted intravenous pharmacokinetic studies of TTAC in mice, rats, and cynomolgus monkeys. Pharmacokinetic data in mice, rats, and cynomolgus monkeys were used to predict the pharmacokinetics of TTAC in humans using allometric scaling.

    The predicted serum clearance of TTAC in humans was The maximum life span-corrected clearance value was The observed clearance in humans was more similar to the predicted scaled clearance. We investigated the pharmacokinetics of TTAC in mice, rats, and cynomolgus monkeys after intravenous administration. At the doses studied, TTAC exhibited dose proportionality in mice and monkeys. The scaled pharmacokinetics of TTAC reported here was useful for designing first-in- human studies.

    Allometric scaling in the therapeutic antibody is feasible. Impact of cannabis, cannabinoids and endocannabinoids in the lungs. Full Text Available Since the identification of cannabinoid receptors in the s, a research field has been dedicated to exploring the role of the cannabinoid system in immunity and the inflammatory response in human tissues and animal models.

    Although the cannabinoid system is present and crucial in many human tissues, studying the impact of cannabinoids on the lungs is particularly relevant because of their contact with exogenous cannabinoids is the context of marijuana consumption. In the past two decades, the scientific community has gathered a large body of evidence supporting that the activation of the cannabinoid system alleviates pain and reduces inflammation.

    In the context of lung inflammation, exogenous and endogenous cannabinoids have shown therapeutic potential because of their inhibitory effects on immune cell recruitment and functions. On the other hand, cannabinoids were shown to be deleterious to lung function and to impact respiratory pathogen clearance. In this review, we present the existing data on the regulation of lung immunity and inflammation by phytocannabinoids, synthetic cannabinoids and endocannabinoids.

    Time-dependent pharmacokinetics of dexamethasone and its efficacy in human breast cancer xenograft mice: Tumor volumes were recorded daily. Based on the experimental data, a two-compartment model with first order absorption and time-dependent clearance was established, and the time-dependence of clearance was modeled by a sigmoid E max equation. The model may serve as a reference for DEX dose adjustments or optimization in future preclinical or clinical studies. Multiple sclerosis following treatment with a cannabinoid receptor-1 antagonist.

    Laboratory research including animal models of human disease suggests that cannabinoids might have therapeutic potential in multiple sclerosis MS. We have recently seen a year-old woman who developed MS after starting treatment with a cannabinoid receptor antagonist for obesity. Human plasma concentrations of tolbutamide and acetaminophen extrapolated from in vivo animal pharmacokinetics using in vitro human hepatic clearances and simple physiologically based pharmacokinetic modeling for radio-labeled microdose clinical studies.

    The aim of the current study was to extrapolate the pharmacokinetics of drug substances orally administered in humans from rat pharmacokinetic data using tolbutamide and acetaminophen as model compounds. Adjusted animal biomonitoring equivalents from rat studies based on reported plasma concentrations were scaled to human biomonitoring equivalents using known species allometric scaling factors. In this extrapolation, in vitro metabolic clearance data were obtained using liver preparations.

    Rates of tolbutamide elimination were roughly similar in rat and human liver microsome experiments, but acetaminophen elimination by rat liver microsomes and cytosolic preparations showed a tendency to be faster than those in humans. Using a simple physiologically based pharmacokinetic PBPK model, estimated human plasma concentrations of tolbutamide and acetaminophen were consistent with reported concentrations.

    Tolbutamide cleared in a roughly similar manner in humans and rats, but medical-dose levels of acetaminophen cleared dependent on liver metabolism more slowly from plasma in humans than it did in rats. A human life-stage physiologically based pharmacokinetic and pharmacodynamic model for chlorpyrifos: Sensitivity to some chemicals in animals and humans are known to vary with age.

    Age-related changes in sensitivity to chlorpyrifos have been reported in animal models. In this model, previously measured age-dependent metabolism of chlorpyrifos and chlorpyrifos-oxon were integrated into age-related descriptions of human anatomy and physiology. Simulations suggest age-dependent pharmacokinetics and response may exist. At lower doses more relevant to environmental exposures, simulations predict that adults will have slightly higher levels of chlorpyrifos-oxon in blood and greater cholinesterase inhibition.

    This model provides a computational framework for age-comparative simulations that can be utilized to predict chlorpyrifos disposition and biological response over various postnatal life stages. PET scanning after injection of 6-[ 18 F]fluorodopamine visualizes tissue sympathetic innervation. Organ dosimetric estimates for 6-[ 18 F]fluorodopamine have relied on studies of rats and dogs and on literature about the fate of other radiolabeled catecholamines.

    This report uses empirical clinical findings in healthy volunteers to refine and extend these estimates. Thoracic PET scanning was conducted and arterial blood and urine samples were obtained after intravenous injection of 6-[ 18 F]fluorodopamine into 10 normal volunteers.

    The main target organs for 6-[ 18 F]fluorodopamine-derived radioactivity were the wall of the urinary bladder 3. The estimates were about one-fourth those predicted from studies of laboratory animals. At administered doses required to visualize the left ventricular myocardium in humans , a 6-[ 18 F]fluorodopamine injection produces acceptable absorbed radiation doses, with the highest doses to the urinary collecting system.

    The predicted metabolites were assigned to analytical For 5C-AKB48, the main metabolic pathways were hydroxylation s of the adamantyl moiety and oxidative dechlorination with subsequent A series of new synthetic cannabinoids SC has been consumed without any toxicological testing. Specimens were analyzed by liquid-chromatography tandem mass spectrometry and multiple-reaction monitoring with three transitions per compound.

    Full validation was carried out for the pig specimens and cross-validation for the human specimens concerning precision and bias. For the pig studies, the limits of detection were between 0.

    The cross-validation data for human serum, whole blood, and urine showed that this approach should also be suitable for human specimens, e. The main analytical targets of synthetic cannabinoids are often metabolites. With the high number of new psychoactive substances entering the market, suitable workflows are needed for analytical target identification in biological samples. The predicted metabolites were assigned to analytical components supported by the UNIFI in silico fragmentation tool.

    The matrix components in the metabolite spectra were reduced with IMS, which improved the accuracy of the spectral interpretation; however, this left fewer fragment ions for assigning sites of metabolism. Meteor was able to predict the majority of the metabolites, with the most notable exception being the oxidative dechlorination and, consequently, all metabolites that underwent that transformation pathway.

    The postulated metabolites can be used for screening of biological samples, with four-dimensional identification based on retention time, collision cross section, precursor ion, and fragment ions. Chimeric mice with humanized liver: Application in drug metabolism and pharmacokinetics studies for drug discovery. Predicting human drug metabolism and pharmacokinetics PK is key to drug discovery. In particular, it is important to predict human PK, metabolite profiles and drug-drug interactions DDIs.

    Further, the prediction methods have changed from qualitative to quantitative to solve these issues. Chimeric mice with humanized liver have been developed, in which mouse liver cells are mostly replaced with human hepatocytes. Since human drug metabolizing enzymes are expressed in the liver of these mice, they are regarded as suitable models for mimicking the drug metabolism and PK observed in humans ; therefore, these mice are useful for predicting human drug metabolism and PK.

    In this review, we discuss the current state, issues, and future directions of predicting human drug metabolism and PK using chimeric mice with humanized liver in drug discovery.

    Published by Elsevier Ltd. Buagafuran is a novel anxiolytic agent and phase I clinical trials of buagafuran have been completed. In this paper, a potentially effective dose for buagafuran of 30 mg t. Buagafuran concentrations in human plasma were fitted and brain tissue concentrations were predicted by using a human PBPK model in which the predicted plasma profiles were in good agreement with observations. The results provided supportive data for the rational use of buagafuran in clinic.

    Hemp nuts are mature cannabis seeds obtained after shelling and that are commonly used in traditional Chinese medicine for treating functional constipation. In this work, we screened hemp nut products, classified them, and verified the legality of consuming them. A total of 18 products were purchased from Taiwan, China, and Canada. Validated high-performance liquid chromatography with tandem mass spectrometry methods were developed for analyzing the cannabinoid i.

    Chemometric techniques, namely hierarchical clustering analysis HCA and principal component analysis PCA , were applied for rapidly classifying 11 concentrated powder products in Taiwan. A pilot human study comprising single and multiple administrations of a product with 1.

    Determination of flurbiprofen in human plasma by gas chromatography with mass spectrometry and its pharmacokinetics. Flurbiprofen and internal standard ibuprofen were extracted from plasma by using a liquid-liquid extraction method. Derivatization was carried out using N-Methyl-N- trimethylsilyl trifluoroacetamide. The calibration curve was linear between the concentration range of 0.

    Intraday and interday precision values for flurbiprofen in plasma were less than 5. The extraction recoveries of flurbiprofen from human plasma were between This assay was applied to determine the pharmacokinetic parameters of flurbiprofen in healthy Turkish volunteers who had been given mg of flurbiprofen.

    Development and application of a multiroute physiologically based pharmacokinetic model for oxytetracycline in dogs and humans.

    Oxytetracycline OTC is a commonly used tetracycline antibiotic in veterinary and human medicine. To establish a quantitative model for predicting OTC plasma and tissue exposure, a permeability-limited multiroute physiologically based pharmacokinetic model was developed in dogs.

    The model predicted other available dog data well, including drug concentrations in the liver, kidney, and muscle after repeated exposure, and data in the mixed-breed dog. The model was extrapolated to humans and the human model adequately simulated measured plasma OTC concentrations after intravenous 7.

    The dog model was applied to predict h OTC area-under-the-curve after three therapeutic treatments. This model can be used to predict plasma and tissue concentrations to aid in designing optimal therapeutic regimens with OTC in veterinary, and potentially, human medicine; and as a foundation for scaling to other tetracycline antibiotics and to other animal species. Full Text Available The discovery of cannabinoid receptors and endocannabinoid system has led to the potential therapeutic use of cannabis derivatives.

    Cannabinoids acting through the CB1 receptors modulate the release of other neurotransmitters in central nervous system, whereas the activation of peripheral CB2 receptors results in decreased inflammatory response and increased apoptosis of some tumor cells populations. The cannabinoids have been authorized for chemotherapy-induced nausea and vomiting; stimulation of appetite; to alleviate neuropathic pain and spasticity in multiple sclerosis, and to reduce pain in cancer patients. Efficacy in other diseases and clinical conditions should be proven in ongoing or future clinical trials.

    Isolation and identification of different cannabinoids from cannabis and synthesis of novel, more selective, derivatives widens their therapeutic potential. However, there are numerous adverse effects reported, especially when cannabinoids formulations with unknown quantitative and qualitative composition are used.

    Addiction, tolerance, withdrawal symptoms, increased risk of acute myocardial re-infarction, and increased risk of psychosis or worsening of psychosis are the most common adverse effects of cannabinoids. Acute adverse effects e. Potential cannabinoid medicines should be subject to the same regulations as other potential drugs. Safety and efficacy of any potential drug candidate, regardless whether it is plant-derived or synthesized, should be proven in non-clinical studies and clinical trials, as well as the marketing authorization must be issued by the appropriate drug authority.

    Patients deserve a quality manufactured product, which always contains the specified amount of "Remedium cardinale. Pharmacokinetic models relevant to toxicity and metabolism for uranium in humans and animals. The aim of this paper is to summarize pharmacokinetic models of uranium metabolism. Fortunately, others have recently reviewed metabolic models of all types, not just pharmacokinetic models. Their papers should be consulted for greater biological detail than is possible here.

    Improvements in the models since these other papers are noted. Models for assessing the biological consequences of exposure should account for the kinetics of intake by ingestion, inhalation, and injection, and the chemical form of uranium; predict the time dependent concentration in red blood cells, plasma, urine, kidney, bone and other organs or compartments ; and be adaptable to calculating these concentrations for varying regimens of intake.

    The biological parameters in the models come from metabolic data in humans and animals. Some of these parameters are reasonably well defined. Implications on Clinical Pharmacokinetic Monitoring in Humans.

    We conducted a systematic search to describe the current state of knowledge regarding the utility of saliva for clinical pharmacokinetic monitoring CPM of antibiotics. No clear pattern of correlation was observed between physiochemical properties that favor drug distribution into saliva and the likelihood of the antibiotic being classified as suitable for CPM in saliva and vice versa. Insufficient data were available to determine if pathophysiological conditions affected salivary distribution of antibiotics.

    Additional confirmatory data are required for drugs especially in patients that are deemed likely suitable for CPM in saliva because only a few studies were available and many focused only on healthy subjects. All studies identified had relatively small sample sizes and exhibited large variability. Very few studies reported salivary collection parameters e. The available data are heavily weighted on healthy subjects, and insufficient data were available to determine if pathophysiology had effects on saliva drug distribution.

    Some studies also lacked assay sensitivity for detecting antibiotics in saliva. Overall, this review can be useful to clinicians who desire an overview on the suitability of saliva for conducting CPM of specific antibiotics, or for researchers who wish to fill the identified knowledge gaps to move the science of salivary CPM further.

    Sensitivity to chemicals in animals and humans are known to vary with age. In this model, age-dependent body weight was calculated from a generalized Gompertz function, and compartments liver, brain, fat, blood, diaphragm, rapid, and slow were scaled based on body weight from polynomial functions on a fractional body weight basis. Blood flows among compartments were calculated as a constant flow per compartment volume.

    Model simulations suggest age-dependent pharmacokinetics and response may exist. At lower doses that are more relevant to environmental exposures, the model predicts that adults will have slightly higher levels of chlorpyrifos-oxon in blood and greater cholinesterase inhibition. This model provides a computational framework for age-comparative simulations that can be utilized to predict CPF disposition and biological response over various postnatal life-stages.

    Comparison of predictability for human pharmacokinetics parameters among monkeys, rats, and chimeric mice with humanised liver. The aim of the present study was to evaluate the usefulness of chimeric mice with humanised liver PXB mice for the prediction of clearance CL t and volume of distribution at steady state Vd ss , in comparison with monkeys, which have been reported as a reliable model for human pharmacokinetics PK prediction, and with rats, as a conventional PK model.

    CL t and Vd ss values in PXB mice, monkeys and rats were determined following intravenous administration of 30 compounds known to be mainly eliminated in humans via the hepatic metabolism by various drug-metabolising enzymes. Using single-species allometric scaling, human CL t and Vd ss values were predicted from the three animal models. For predicted human Vd ss values, the number of compounds falling within a three-fold range was 23 for PXB mice, 24 for monkeys, and 16 for rats among 29 compounds.

    Many PBPK models are available, but they are not easily accessible for field use. This toolkit, when fully developed, will provide a platform that consists of a series of priority PBPK models of environmental pollutants. Good agreement was generally obtained between the original and the recoded models. This toolkit will be available for ATSDR scientists and public health assessors to perform simulations of exposures from contaminated environmental media at sites of concern and to help interpret biomonitoring data.

    It can be used as screening tools that can provide useful information for the protection of the public. Development of a simple chromatographic method for the determination of piracetam in human plasma and its pharmacokinetic evaluation. The objective of study was to develop an accurate and reproducible HPLC method for determination of piracetam in human plasma and to evaluate pharmacokinetic parameters of mg piracetam.

    A simple, rapid, accurate, precise and sensitive high pressure liquid chromatography method has been developed and subsequently validated for determination of piracetam. This study represents the results of a randomized, single-dose and single-period in 18 healthy male volunteers to assess pharmacokinetic parameters of mg piracetam tablets.

    Various pharmacokinetic parameters were determined from plasma for piracetam and found to be in good agreement with previous reported values. The major pharmacokinetic parameters for piracetam were as follows: A rapid, accurate and precise high pressure liquid chromatography method was developed and validated before the study.

    It is concluded that this method is very useful for the analysis of pharmacokinetic parameters, in human plasma and assured the safety and efficacy of piracetam, can be effectively used in medical practice.

    The purpose of the present study was to assess the effect of resveratrol RSV treatment on the pharmacokinetics of diclofenac DIC in healthy human volunteers.

    The open-label, two period, sequential study was conducted in 12 healthy human volunteers. A single dose of RSV mg was administered daily for 10 days during treatment phase. A single dose of DIC mg was administered during control and after treatment phases under fasting conditions. Treatment with RSV significantly enhanced maximum plasma concentration Cmax 1.

    The pharmacokinetics and metabolism of lumiracoxib in chimeric humanized and murinized FRG mice. In the chimeric humanized mice, lumiracoxib reached peak observed concentrations in the blood of 1. In the case of the murinized animals peak observed concentrations in the blood were determined as 1. Analysis of blood indicated only the presence of unchanged lumiracoxib.

    Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected.

    The profiles obtained in humanized mice were different compared to murinized animals with e. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Chronic cannabis marijuana, hashish smoking can result in dependence. Rodent studies show reversible downregulation of brain cannabinoid CB1 cannabinoid receptor type 1 receptors after chronic exposure to cannabis.

    However, whether downregulation occurs in humans who chronically smoke cannabis is unknown. Here we show, using positron emission tomography imaging, reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in human subjects who chronically smoke ca Biodistribution and dosimetry in humans of two inverse agonists to image cannabinoid CB1 receptors using positron emission tomography. Cannabinoid subtype 1 CB 1 receptors are found in nearly every organ in the body, may be involved in several neuropsychiatric and metabolic disorders, and are therefore an active target for pharmacotherapy and biomarker development.

    Here we describe the biodistribution and dosimetry estimates for these two radioligands. Residence times were acquired from regions of interest drawn on tomographic images of visually identifiable organs for both radioligands and from radioactivity excreted in urine for 18 F-FMPEP-d 2.

    Both radioligands demonstrated high uptake of radioactivity in liver, lung, and brain shortly after injection and accumulated radioactivity in bone marrow towards the end of the scan. The high uptake in brain confirms the utility of these two radioligands to image CB 1 receptors in brain, and both may also be useful to image CB 1 receptors in the periphery. Recombinant human tripeptidyl peptidase-1 infusion to the monkey CNS: Safety, pharmacokinetics , and distribution.

    CLN2 disease is caused by deficiency in tripeptidyl peptidase-1 TPP1 , leading to neurodegeneration and death. Necropsies occurred at 3, 7, and 14 days post-infusion.

    Isolated histological changes related to catheter placement and infusion were observed in ICV treated animals, including vehicle controls. TPP1 levels peaked at the end of infusion, at which point the enzyme was present in plasma at 0.

    TPP1 was detected in brain tissues with half-lives of 3—14 days. Plasma pharmacokinetics and synovial concentrations of S-flurbiprofen plaster in humans. The purpose of this study is to investigate the pharmacokinetics and deep tissue penetration capability of the newly developed S-flurbiprofen plaster SFPP in humans. Deep tissues synovial tissue and synovial fluid were collected during surgery to compare SFP concentrations after application of SFPP or a commercially available flurbiprofen FP gel-type patch.

    The plasma concentration of SFP was sustained during h topical application of the SFPP, showing a high percutaneous absorption ratio of The serum pharmacokinetics and the major organs of accumulation of recombinant human tumor necrosis factor-alpha rHuTNF were determined in BDF1 mice after intravenous and intramuscular administration.

    Serum concentrations of immunoreactive protein were determined by enzyme-linked immunosorbent assay, and radioactivity was quantitated by beta and gamma scintigraphy. The serum pharmacokinetics of labeled and unlabeled rHuTNF were identical when administered by the intravenous route. The data suggest that the disposition of this protein may be biexponential. Since serum concentrations in the terminal phase are at the sensitivity limit of the assay, a single half-life is reported.

    After intravenous I-rHuTNF administration, the rank order of accumulation of the I-radiolabel in the major organs per cent dose per organ over min was: Since , a new drugs-of-abuse trend attempts to bypass drug legislation by marketing isomers of scheduled synthetic cannabinoids SCs , e. It is much more challenging to confirm a specific isomer's intake and distinguish it from its structural analog because the isomers and their major metabolites usually have identical molecular weights and display the same product ions.

    We identified 35 metabolites generated by oxidative defluorination, further carboxylation, hydroxylation, dihydrodiol formation, glucuronidation, and their combinations. Optimized chromatographic conditions to achieve different retention times and careful selection of specific product ion spectra enabled differentiation of isomeric metabolites, in this case FUBIMINA from THJ Our HR-MS approach should be applicable for differentiating future isomeric SCs, which is especially important when different isomers have different legal status.

    What Are Synthetic Cannabinoids? Anandamide induces matrix metalloproteinase-2 production through cannabinoid -1 receptor and transient receptor potential vanilloid-1 in human dental pulp cells in culture. Anandamide N-arachidonoylethanolamine [AEA] is one of the main endocannabinoids. Endocannabinoids are implicated in various physiological and pathologic functions, inducing not only nociception but also regeneration and inflammation.

    The role of the endocannabinoid system in peripheral organs was recently described. MMP-2 concentrations in supernatants were determined by enzyme-linked immunosorbent assay. Chimeric mice transplanted with human hepatocytes as a model for prediction of human drug metabolism and pharmacokinetics. Preclinical studies in animal models are used routinely during drug development, but species differences of pharmacokinetics PK between animals and humans have to be taken into account in interpreting the results.

    Human hepatocytes are also widely used to examine metabolic activities mediated by cytochrome P P and other enzymes, but such in vitro metabolic studies also have limitations. Recently, chimeric mice with humanized liver h-chimeric mice , generated by transplantation of human donor hepatocytes, have been developed as a model for the prediction of metabolism and PK in humans , using both in vitro and in vivo approaches.

    The expression of human -specific metabolic enzymes and metabolic activities was confirmed in humanized liver of h-chimeric mice with high replacement ratios, and several reports indicate that the profiles of P and non-P metabolism in these mice adequately reflect those in humans. Further, the combined use of h-chimeric mice and r-chimeric mice, in which endogenous hepatocytes are replaced with rat hepatocytes, is a promising approach for evaluation of species differences in drug metabolism.

    Recent work has shown that data obtained in h-chimeric mice enable the semi-quantitative prediction of not only metabolites, but also PK parameters, such as hepatic clearance, of drug candidates in humans , although some limitations remain because of differences in the metabolic activities, hepatic blood flow and liver structure between humans and mice.

    In addition, fresh h-hepatocytes can be isolated reproducibly from h-chimeric mice for metabolic studies. Ocular pharmacokinetics of besifloxacin following topical administration to rabbits, monkeys, and humans.

    Studies were conducted to evaluate the ocular penetration and systemic exposure to besifloxacin, a fluoroquinolone antibiotic, following topical ocular administration to animals and humans. Besifloxacin ophthalmic suspension 0.

    Besifloxacin demonstrated good ocular penetration in rabbits and monkeys, with rapid absorption and sustained concentrations observed in anterior ocular tissues through 24 h after a single administration.

    Maximum besifloxacin concentrations in conjunctiva, cornea, and aqueous humor of monkeys were 6. Following repeated 3-times daily TID topical ocular administration to human subjects with clinically diagnosed bacterial conjunctivitis, maximum besifloxacin concentrations in plasma were less than 0.

    A physiologically based pharmacokinetic model for ethylene oxide in mouse, rat, and human. Ethylene oxide EO is widely used as a gaseous sterilant and industrial intermediate and is a direct-acting mutagen and carcinogen. The objective of these studies was to develop physiologically based pharmacokinetic PB-PK models for EO to describe the exposure-tissue dose relationship in rodents and humans.

    We previously reported results describing in vitro and in vivo kinetics of EO metabolism in male and female F rats and B6C3F1 mice. These studies were extended by determining the kinetics of EO metabolism in human liver cytosol and microsomes.

    The results indicate enzymatically catalyzed GSH conjugation via cytosolic glutathione S-transferase cGST and hydrolysis via microsomal epoxide hydrolase mEH occur in both rodents and humans.

    The in vitro kinetic constants were scaled to account for cytosolic cGST and microsomal mEH protein content and incorporated into PB-PK descriptions for mouse, rat, and human. Flow-limited models adequately predicted blood and tissue EO levels, disposition, and elimination kinetics determined experimentally in rats and mice, with the exception of testis concentrations, which were overestimated.

    Incorporation of a diffusion-limited description for testis improved the ability of the model to describe testis concentrations. The model accounted for nonlinear increases in blood and tissue concentrations that occur in mice on exposure to EO concentrations greater than ppm.

    Species differences are predicted in the metabolism and exposure-dose relationship, with a nonlinear relationship observed in the mouse as a result of GSH depletion. These models represent an essential step in developing a mechanistically based EO exposure-dose-response description for estimating human risk from exposure to EO. Copyright Academic Press. The usage and dosage of Chinese patent medicine are determined by rigorous evaluation which include four clinical trail stages: But the usage and dosage of Chinese patent medicine are lacked re-evaluation after marketing.

    And this lead to unchanging or fixed of the usage and dosage of Chinese patent medicine instead of different quantity based on different situations in individual patients. The situation of Chinese patent medicine used in clinical application is far away from the idea of the "Treatment based on syndrome differentiation" in traditional Chinese medicine and personalized therapy.

    Human population pharmacokinetics provides data support to the personalized therapy in clinical application, and achieved the postmarking reevaluating of the usage and dosage of Chinese patent medicine.

    This paper briefly introduced the present situation, significance and the application of human population pharmacokinetics about re-evaluation of the usage and dosage of Chinese patent medicine after marketing. Cannabinoids as modulators of cancer cell viability, neuronal differentiation, and embryonal development. CB receptors mediate many different physiological functions, and cannabinoids have been reported to decrease tumor cell viability, proliferation, migration, as well as to modulate metastasis.

    In both cell lines, the compounds examined produced a concentr Suboptimal tone of the ECS in certain regions of the nervous system may be associated with disorders that are also associated with pain. Pain and inflammation processes can be modulated by the exogenous supply of cannabinoids. Low-to-moderate pain-relieving effects and in individual cases large pain-relieving effects were observed in randomized, controlled studies of various types of chronic pain.

    People with chronic neuropathic pain and stress symptoms seem to particularly benefit. The therapeutic range of cannabinoids is small; often small doses are sufficient for clinically significant effects.

    The "Cannabis-als-Medizin-Gesetz" cannabis as medicine law allows the prescription of cannabis preparations under certain conditions. Available data indicate good long-term efficacy and tolerability. However, there is little systematic long-term experience from clinical studies. Estimated cancer risk of dioxins to humans using a bioassay and physiologically based pharmacokinetic model.

    The health risk of dioxins and dioxin-like compounds to humans was analyzed quantitatively using experimental data and mathematical models.

    To quantify the toxicity of a mixture of three dioxin congeners, we calculated the new relative potencies REPs for 2,3,7,8-tetrachlorodibenzo-p-dioxin TCDD , 1,2,3,7,8-pentachlorodibenzo-p-dioxin PeCDD , and 2,3,4,7,8- pentachlorodibenzofuran PeCDF , focusing on their tumor promotion activity. We applied a liver foci formation assay to female SD rats after repeated oral administration of dioxins. The REP of dioxin for a rat was determined using dioxin concentration and the number of the foci in rat liver.

    A physiologically based pharmacokinetic model PBPK model was used for interspecies extrapolation targeting on dioxin concentration in liver. Toxic dose for human was determined by back-estimation with a human PBPK model, assuming that the same concentration in the target tissue may cause the same level of effect in rats and humans , and the REP for human was determined by the toxic dose obtained.

    The relative risk of excess liver cancer for Japanese people in general was 1. Bioavailability and pharmacokinetic profile of grape pomace phenolic compounds in humans.

    Grape pomace, the major byproduct of the wine and juice industry, is a relevant source of bioactive phenolic compounds. However, polyphenol bioavailability in humans is not well understood, and the inter-individual variability in the production of phenolic metabolites has not been comprehensively assessed to date. The pharmacokinetic and excretive profiles of phenolic metabolites after the acute administration of a drink made from red grape pomace was here investigated in ten volunteers.

    A total of 35 and 28 phenolic metabolites were quantified in urine and plasma, respectively. A high inter-individual variability was shown both in urine and plasma samples, and different patterns of circulating metabolites were unravelled by applying unsupervised multivariate analysis. Besides the huge variability in the production of microbial metabolites of colonic origin, an important variability was observed due to phase II conjugates.

    These results are of interest to further understand the potential health benefits of phenolic metabolites on individual basis.

    Full Text Available STX is an exploratory drug comprising the single, active R-enantiomer of baclofen which is in later stage clinical trials for the treatment of fragile x syndrome FXS and autism spectrum disorders ASD. New clinical data in this article on the metabolism and pharmacokinetics of the R- and S-enantiomers of baclofen presents scientific evidence for stereoselective metabolism of only S-baclofen to an abundant oxidative deamination metabolite that is sterically resolved as the S-enantiomeric configuration.

    This metabolite undergoes some further metabolism by glucuronide conjugation. Consequences of this metabolic difference are a lower Cmax and lower early plasma exposure of S-baclofen compared to R-baclofen and marginally lower urinary excretion of S-baclofen after racemic baclofen administration. These differences introduce compound-related exposure variances in humans in which subjects dosed with racemic baclofen are exposed to a prominent metabolite of baclofen whilst subjects dosed with STX are not.

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    There are 5 major cannabinoids THC, CBD, CBN, CBC and CBG. Each strain of . How To Make Olive Oil Infused with Cannabis / Medical Marijuana. In short.


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