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Sample records for human cannabinoid pharmacokinetics

  1. Pharmacokinetics of Cannabinoids

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    Iain J McGilveray

    2005-01-01

    Full Text Available Delta-9-tetrahydrocannabinol (Δ-9-THC is the main psychoactive ingredient of cannabis (marijuana. The present review focuses on the pharmacokinetics of THC, but also includes known information for cannabinol and cannabidiol, as well as the synthetic marketed cannabinoids, dronabinol (synthetic THC and nabilone. The variability of THC in plant material (0.3% to 30% leads to variability in tissue THC levels from smoking, which is, in itself, a highly individual process. THC bioavailability averages 30%. With a 3.55% THC cigarette, a peak plasma level of 152±86.3 ng/mL occured approximately 10 min after inhalation. Oral THC, on the other hand, is only 4% to 12% bioavailable and absorption is highly variable. THC is eliminated from plasma in a multiphasic manner, with low amounts detectable for over one week after dosing. A major active 11-hydroxy metabolite is formed after both inhalation and oral dosing (20% and 100% of parent, respectively. THC is widely distributed, particularly to fatty tissues, but less than 1% of an administered dose reaches the brain, while the spleen and body fat are long-term storage sites. The elimination of THC and its many metabolites (from all routes occurs via the feces and urine. Metabolites persist in the urine and feces for severalweeks. Nabilone is well absorbed and the pharmacokinetics, although variable, appear to be linear from oral doses of 1 mg to 4 mg (these doses show a plasma elimination half-life of approximately 2 h. As with THC, there is a high first-pass effect, and the feces to urine ratio of excretion is similar to other cannabinoids. Pharmacokineticpharmacodynamic modelling with plasma THC versus cardiac and psychotropic effects show that after equilibrium is reached, the intensity of effect is proportional to the plasma THC profile. Clinical trials have found that nabilone produces less tachycardia and less euphoria than THC for a similar antiemetic response.

  2. Cannabinoid Disposition After Human Intraperitoneal Use: An Insight Into Intraperitoneal Pharmacokinetic Properties in Metastatic Cancer.

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    Lucas, Catherine J; Galettis, Peter; Song, Shuzhen; Solowij, Nadia; Reuter, Stephanie E; Schneider, Jennifer; Martin, Jennifer H

    2018-01-06

    Medicinal cannabis is prescribed under the provision of a controlled drug in the Australian Poisons Standard. However, multiple laws must be navigated in order for patients to obtain access and imported products can be expensive. Dose-response information for both efficacy and toxicity pertaining to medicinal cannabis is lacking. The pharmacokinetic properties of cannabis administered by traditional routes has been described but to date, there is no literature on the pharmacokinetic properties of an intraperitoneal cannabinoid emulsion. A cachectic 56-year-old female with stage IV ovarian cancer and peritoneal metastases presented to hospital with fevers, abdominal distension and severe pain, vomiting, anorexia, dehydration and confusion. The patient reported receiving an intraperitoneal injection, purported to contain 12 g of mixed cannabinoid (administered by a deregistered medical practitioner) two days prior to presentation. Additionally, cannabis oil oral capsules were administered in the hours prior to hospital admission. THC concentrations were consistent with the clinical state but not with the known pharmacokinetic properties of cannabis nor of intraperitoneal absorption. THC concentrations at the time of presentation were predicted to be ~60 ng/mL. Evidence suggests that blood THC concentrations >5 ng/mL are associated with substantial cognitive and psychomotor impairment. The predicted time for concentrations to drop <5 ng/mL was 49 days after administration. The unusual pharmacokinetic properties of the case suggest that there is a large amount unknown about cannabis pharmacokinetic properties. The pharmacokinetic properties of a large amount of a lipid soluble compound given intraperitoneally gave insights into the absorption and distribution of cannabinoids, particularly in the setting of metastatic malignancy. Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.

  3. Pharmacokinetics of (synthetic) cannabinoids in pigs and their relevance for clinical and forensic toxicology.

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    Schaefer, Nadine; Wojtyniak, Jan-Georg; Kettner, Mattias; Schlote, Julia; Laschke, Matthias W; Ewald, Andreas H; Lehr, Thorsten; Menger, Michael D; Maurer, Hans H; Schmidt, Peter H

    2016-06-24

    Synthetic cannabinoids (SCs) are gaining increasing importance in clinical and forensic toxicology. They are consumed without any preclinical safety studies. Thus, controlled human pharmacokinetic (PK) studies are not allowed, although being relevant for interpretation of analytical results in cases of misuse or poisoning. As alternative, in a controlled animal experiment, six pigs per drug received a single intravenous dose of 200μg/kg BW each of Δ(9)-tetrahydrocannabinol (THC), 4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210), or 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4). In addition, six pigs received a combination of the three drugs with the identical dose each. The drugs were determined in serum using LC-MS/MS. A population (pop) PK analysis revealed that a three-compartment model described best the PK data of all three cannabinoids. Central volumes of distribution were estimated at 0.29L/kg, 0.20L/kg, and 0.67L/kg for THC, JWH-210, and RCS-4, respectively. Clearances were 0.042L/min/kg, 0.048L/min/kg, and 0.093L/min/kg for THC, JWH-210, and RCS-4, respectively. The popPK THC pig model was upscaled to humans using allometric techniques. Comparison with published human data revealed that the concentration-time profiles could successfully be predicted. These findings indicate that pigs in conjunction with PK modeling technique may serve as a tool for prediction of human PK of SCs. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. Pharmacokinetic/pharmaco-dynamic modelling and simulation of the effects of different cannabinoid receptor type 1 antagonists on (9)-tetrahydrocannabinol challenge tests

    NARCIS (Netherlands)

    Guan, Zheng; Klumpers, Linda E.; Oyetayo, Olubukayo-Opeyemi; Heuberger, Jules; van Gerven, Joop M. A.; Stevens, Jasper

    Aim: The severe psychiatric side effects of cannabinoid receptor type 1 (CB1) antagonists hampered their wide development but this might be overcome by careful management of drug development with pharmacokinetic/pharmacodynamic (PK/PD) analyses. PK/PD models suitable for direct comparison of

  5. PHARMACOKINETICS AND PHARMACOKINETIC DYNAMIC RELATIONSHIP OF ROCURONIUM BROMIDE IN HUMANS

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    WIERDA, JMKH; PROOST, JH; SCHIERE, S; HOMMES, FDM

    The existing human pharmacokinetic studies have been reviewed and compared with data derived from animals. The earliest study confirms the similarity of rocuronium to vecuronium with respect to the variables derived from the plasma concentration decay curves and the proportion excreted renally.

  6. Piperine-pro-nanolipospheres as a novel oral delivery system of cannabinoids: Pharmacokinetic evaluation in healthy volunteers in comparison to buccal spray administration.

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    Cherniakov, Irina; Izgelov, Dvora; Barasch, Dinorah; Davidson, Elyad; Domb, Abraham J; Hoffman, Amnon

    2017-11-28

    Nowadays, therapeutic indications for cannabinoids, specifically Δ 9 -tetrahydrocannabinol (THC) and Cannabidiol (CBD) are widening. However, the oral consumption of the molecules is very limited due to their highly lipophilic nature that leads to poor solubility at the aqueous environment. Additionally, THC and CBD are prone to extensive first pass mechanisms. These absorption obstacles render the molecules with low and variable oral bioavailability. To overcome these limitations we designed and developed the advanced pro-nanolipospheres (PNL) formulation. The PNL delivery system is comprised of a medium chain triglyceride, surfactants, a co-solvent and the unique addition of a natural absorption enhancer: piperine. Piperine was selected due to its distinctive inhibitory properties affecting both Phase I and Phase II metabolism. This constellation self emulsifies into nano particles that entrap the cannabinoids and the piperine in their core and thus improve their solubility while piperine and the other PNL excipients inhibit their intestinal metabolism. Another clear advantage of the formulation is that its composition of materials is approved for human consumption. The safe nature of the excipients enabled their direct evaluation in humans. In order to evaluate the pharmacokinetic profile of the THC-CBD-piperine-PNL formulation, a two-way crossover, single administration clinical study was conducted. The trial comprised of 9 healthy volunteers under fasted conditions. Each subject received a THC-CBD (10.8mg, 10mg respectively) piperine (20mg)-PNL filled capsule and an equivalent dose of the oromucosal spray Sativex® with a washout period in between treatments. Single oral administration of the piperine-PNL formulation resulted in a 3-fold increase in Cmax and a 1.5-fold increase in AUC for THC when compared to Sativex®. For CBD, a 4-fold increase in Cmax and a 2.2-fold increase in AUC was observed. These findings demonstrate the potential this formulation has

  7. Human physiologically based pharmacokinetic model for propofol

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    Schnider Thomas W

    2005-04-01

    Full Text Available Abstract Background Propofol is widely used for both short-term anesthesia and long-term sedation. It has unusual pharmacokinetics because of its high lipid solubility. The standard approach to describing the pharmacokinetics is by a multi-compartmental model. This paper presents the first detailed human physiologically based pharmacokinetic (PBPK model for propofol. Methods PKQuest, a freely distributed software routine http://www.pkquest.com, was used for all the calculations. The "standard human" PBPK parameters developed in previous applications is used. It is assumed that the blood and tissue binding is determined by simple partition into the tissue lipid, which is characterized by two previously determined set of parameters: 1 the value of the propofol oil/water partition coefficient; 2 the lipid fraction in the blood and tissues. The model was fit to the individual experimental data of Schnider et. al., Anesthesiology, 1998; 88:1170 in which an initial bolus dose was followed 60 minutes later by a one hour constant infusion. Results The PBPK model provides a good description of the experimental data over a large range of input dosage, subject age and fat fraction. Only one adjustable parameter (the liver clearance is required to describe the constant infusion phase for each individual subject. In order to fit the bolus injection phase, for 10 or the 24 subjects it was necessary to assume that a fraction of the bolus dose was sequestered and then slowly released from the lungs (characterized by two additional parameters. The average weighted residual error (WRE of the PBPK model fit to the both the bolus and infusion phases was 15%; similar to the WRE for just the constant infusion phase obtained by Schnider et. al. using a 6-parameter NONMEM compartmental model. Conclusion A PBPK model using standard human parameters and a simple description of tissue binding provides a good description of human propofol kinetics. The major advantage of a

  8. Genetic variability in the human cannabinoid receptor 1 is associated with resting state EEG theta power in humans.

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    Heitland, I; Kenemans, J L; Böcker, K B E; Baas, J M P

    2014-11-01

    It has long been postulated that exogenous cannabinoids have a profound effect on human cognitive functioning. These cannabinoid effects are thought to depend, at least in parts, on alterations of phase-locking of local field potential neuronal firing. The latter can be measured as activity in the theta frequency band (4-7Hz) by electroencephalogram. Theta oscillations are supposed to serve as a mechanism in neural representations of behaviorally relevant information. However, it remains unknown whether variability in endogenous cannabinoid activity is involved in theta rhythms and therefore, may serve as an individual differences index of human cognitive functioning. To clarify this issue, we recorded resting state EEG activity in 164 healthy human subjects and extracted EEG power across frequency bands (δ, θ, α, and β). To assess variability in the endocannabinoid system, two genetic polymorphisms (rs1049353, rs2180619) within the cannabinoid receptor 1 (CB1) were determined in all participants. As expected, we observed significant effects of rs1049353 on EEG power in the theta band at frontal, central and parietal electrode regions. Crucially, these effects were specific for the theta band, with no effects on activity in the other frequency bands. Rs2180619 showed no significant associations with theta power after Bonferroni correction. Taken together, we provide novel evidence in humans showing that genetic variability in the cannabinoid receptor 1 is associated with resting state EEG power in the theta frequency band. This extends prior findings of exogenous cannabinoid effects on theta power to the endogenous cannabinoid system. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Genetic Variations in the Human Cannabinoid Receptor Gene Are Associated with Happiness

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    Matsunaga, Masahiro; Isowa, Tokiko; Yamakawa, Kaori; Fukuyama, Seisuke; Shinoda, Jun; Yamada, Jitsuhiro; Ohira, Hideki

    2014-01-01

    Happiness has been viewed as a temporary emotional state (e.g., pleasure) and a relatively stable state of being happy (subjective happiness level). As previous studies demonstrated that individuals with high subjective happiness level rated their current affective states more positively when they experience positive events, these two aspects of happiness are interrelated. According to a recent neuroimaging study, the cytosine to thymine single-nucleotide polymorphism of the human cannabinoid receptor 1 gene is associated with sensitivity to positive emotional stimuli. Thus, we hypothesized that our genetic traits, such as the human cannabinoid receptor 1 genotypes, are closely related to the two aspects of happiness. In Experiment 1, 198 healthy volunteers were used to compare the subjective happiness level between cytosine allele carriers and thymine-thymine carriers of the human cannabinoid receptor 1 gene. In Experiment 2, we used positron emission tomography with 20 healthy participants to compare the brain responses to positive emotional stimuli of cytosine allele carriers to that of thymine-thymine carriers. Compared to thymine-thymine carriers, cytosine allele carriers have a higher subjective happiness level. Regression analysis indicated that the cytosine allele is significantly associated with subjective happiness level. The positive mood after watching a positive film was significantly higher for the cytosine allele carriers compared to the thymine-thymine carriers. Positive emotion-related brain region such as the medial prefrontal cortex was significantly activated when the cytosine allele carriers watched the positive film compared to the thymine-thymine carriers. Thus, the human cannabinoid receptor 1 genotypes are closely related to two aspects of happiness. Compared to thymine-thymine carriers, the cytosine allele carriers of the human cannabinoid receptor 1 gene, who are sensitive to positive emotional stimuli, exhibited greater magnitude

  10. Genetic variations in the human cannabinoid receptor gene are associated with happiness.

    Directory of Open Access Journals (Sweden)

    Masahiro Matsunaga

    Full Text Available Happiness has been viewed as a temporary emotional state (e.g., pleasure and a relatively stable state of being happy (subjective happiness level. As previous studies demonstrated that individuals with high subjective happiness level rated their current affective states more positively when they experience positive events, these two aspects of happiness are interrelated. According to a recent neuroimaging study, the cytosine to thymine single-nucleotide polymorphism of the human cannabinoid receptor 1 gene is associated with sensitivity to positive emotional stimuli. Thus, we hypothesized that our genetic traits, such as the human cannabinoid receptor 1 genotypes, are closely related to the two aspects of happiness. In Experiment 1, 198 healthy volunteers were used to compare the subjective happiness level between cytosine allele carriers and thymine-thymine carriers of the human cannabinoid receptor 1 gene. In Experiment 2, we used positron emission tomography with 20 healthy participants to compare the brain responses to positive emotional stimuli of cytosine allele carriers to that of thymine-thymine carriers. Compared to thymine-thymine carriers, cytosine allele carriers have a higher subjective happiness level. Regression analysis indicated that the cytosine allele is significantly associated with subjective happiness level. The positive mood after watching a positive film was significantly higher for the cytosine allele carriers compared to the thymine-thymine carriers. Positive emotion-related brain region such as the medial prefrontal cortex was significantly activated when the cytosine allele carriers watched the positive film compared to the thymine-thymine carriers. Thus, the human cannabinoid receptor 1 genotypes are closely related to two aspects of happiness. Compared to thymine-thymine carriers, the cytosine allele carriers of the human cannabinoid receptor 1 gene, who are sensitive to positive emotional stimuli, exhibited greater

  11. Genetic variations in the human cannabinoid receptor gene are associated with happiness.

    Science.gov (United States)

    Matsunaga, Masahiro; Isowa, Tokiko; Yamakawa, Kaori; Fukuyama, Seisuke; Shinoda, Jun; Yamada, Jitsuhiro; Ohira, Hideki

    2014-01-01

    Happiness has been viewed as a temporary emotional state (e.g., pleasure) and a relatively stable state of being happy (subjective happiness level). As previous studies demonstrated that individuals with high subjective happiness level rated their current affective states more positively when they experience positive events, these two aspects of happiness are interrelated. According to a recent neuroimaging study, the cytosine to thymine single-nucleotide polymorphism of the human cannabinoid receptor 1 gene is associated with sensitivity to positive emotional stimuli. Thus, we hypothesized that our genetic traits, such as the human cannabinoid receptor 1 genotypes, are closely related to the two aspects of happiness. In Experiment 1, 198 healthy volunteers were used to compare the subjective happiness level between cytosine allele carriers and thymine-thymine carriers of the human cannabinoid receptor 1 gene. In Experiment 2, we used positron emission tomography with 20 healthy participants to compare the brain responses to positive emotional stimuli of cytosine allele carriers to that of thymine-thymine carriers. Compared to thymine-thymine carriers, cytosine allele carriers have a higher subjective happiness level. Regression analysis indicated that the cytosine allele is significantly associated with subjective happiness level. The positive mood after watching a positive film was significantly higher for the cytosine allele carriers compared to the thymine-thymine carriers. Positive emotion-related brain region such as the medial prefrontal cortex was significantly activated when the cytosine allele carriers watched the positive film compared to the thymine-thymine carriers. Thus, the human cannabinoid receptor 1 genotypes are closely related to two aspects of happiness. Compared to thymine-thymine carriers, the cytosine allele carriers of the human cannabinoid receptor 1 gene, who are sensitive to positive emotional stimuli, exhibited greater magnitude

  12. Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors

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    Rajasekaran, Maheswari; Brents, Lisa K.; Franks, Lirit N.; Moran, Jeffery H.; Prather, Paul L.

    2013-01-01

    K2 or Spice is an emerging drug of abuse that contains synthetic cannabinoids, including JWH-018 and JWH-073. Recent reports indicate that monohydroxylated metabolites of JWH-018 and JWH-073 retain high affinity and activity at cannabinoid type-1 receptors (CB 1 Rs), potentially contributing to the enhanced toxicity of K2 compared to marijuana. Since the parent compounds also bind to cannabinoid type-2 receptors (CB 2 Rs), this study investigated the affinity and intrinsic activity of JWH-018, JWH-073 and several monohydroxylated metabolites at human CB 2 Rs (hCB 2 Rs). The affinity of cannabinoids for hCB 2 Rs was determined by competition binding studies employing CHO-hCB 2 membranes. Intrinsic activity of compounds was assessed by G-protein activation and adenylyl cyclase (AC)-inhibition in CHO-hCB 2 cells. JWH-073, JWH-018 and several of their human metabolites exhibit nanomolar affinity and act as potent agonists at hCB 2 Rs. Furthermore, a major omega hydroxyl metabolite of JWH-073 (JWH-073-M5) binds to CB 2 Rs with 10-fold less affinity than the parent molecule, but unexpectedly, is equipotent in regulating AC-activity when compared to the parent molecule. Finally, when compared to CP-55,940 and Δ 9 -tetrahydrocannabinol (Δ 9 -THC), JWH-018, JWH-018-M5 and JWH-073-M5 require significantly less CB 2 R occupancy to produce similar levels of AC-inhibition, indicating that these compounds may more efficiently couple CB 2 Rs to AC than the well characterized cannabinoid agonists examined. These results indicate that JWH-018, JWH-073 and several major human metabolites of these compounds exhibit high affinity and demonstrate distinctive signaling properties at CB 2 Rs. Therefore, future studies examining pharmacological and toxicological properties of synthetic cannabinoids present in K2 products should consider potential actions of these drugs at both CB 1 and CB 2 Rs. - Highlights: • JWH-018 and JWH-073 are synthetic cannabinoids present in abused K2

  13. Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors

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    Rajasekaran, Maheswari; Brents, Lisa K.; Franks, Lirit N. [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States); Moran, Jeffery H. [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States); Arkansas Department of Public Health, Public Health Laboratory, Little Rock, AR 72205 (United States); Prather, Paul L., E-mail: pratherpaull@uams.edu [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States)

    2013-06-01

    K2 or Spice is an emerging drug of abuse that contains synthetic cannabinoids, including JWH-018 and JWH-073. Recent reports indicate that monohydroxylated metabolites of JWH-018 and JWH-073 retain high affinity and activity at cannabinoid type-1 receptors (CB{sub 1}Rs), potentially contributing to the enhanced toxicity of K2 compared to marijuana. Since the parent compounds also bind to cannabinoid type-2 receptors (CB{sub 2}Rs), this study investigated the affinity and intrinsic activity of JWH-018, JWH-073 and several monohydroxylated metabolites at human CB{sub 2}Rs (hCB{sub 2}Rs). The affinity of cannabinoids for hCB{sub 2}Rs was determined by competition binding studies employing CHO-hCB{sub 2} membranes. Intrinsic activity of compounds was assessed by G-protein activation and adenylyl cyclase (AC)-inhibition in CHO-hCB{sub 2} cells. JWH-073, JWH-018 and several of their human metabolites exhibit nanomolar affinity and act as potent agonists at hCB{sub 2}Rs. Furthermore, a major omega hydroxyl metabolite of JWH-073 (JWH-073-M5) binds to CB{sub 2}Rs with 10-fold less affinity than the parent molecule, but unexpectedly, is equipotent in regulating AC-activity when compared to the parent molecule. Finally, when compared to CP-55,940 and Δ{sup 9}-tetrahydrocannabinol (Δ{sup 9}-THC), JWH-018, JWH-018-M5 and JWH-073-M5 require significantly less CB{sub 2}R occupancy to produce similar levels of AC-inhibition, indicating that these compounds may more efficiently couple CB{sub 2}Rs to AC than the well characterized cannabinoid agonists examined. These results indicate that JWH-018, JWH-073 and several major human metabolites of these compounds exhibit high affinity and demonstrate distinctive signaling properties at CB{sub 2}Rs. Therefore, future studies examining pharmacological and toxicological properties of synthetic cannabinoids present in K2 products should consider potential actions of these drugs at both CB{sub 1} and CB{sub 2}Rs. - Highlights: • JWH-018

  14. The pharmacokinetics of the interstitial space in humans

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    Levitt, David G

    2003-01-01

    Background The pharmacokinetics of extracellular solutes is determined by the blood-tissue exchange kinetics and the volume of distribution in the interstitial space in the different organs. This information can be used to develop a general physiologically based pharmacokinetic (PBPK) model applicable to most extracellular solutes. Methods The human pharmacokinetic literature was surveyed to tabulate the steady state and equilibrium volume of distribution of the solutes mannitol, EDTA, morphi...

  15. Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines.

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    Massi, Paola; Vaccani, Angelo; Ceruti, Stefania; Colombo, Arianna; Abbracchio, Maria P; Parolaro, Daniela

    2004-03-01

    Recently, cannabinoids (CBs) have been shown to possess antitumor properties. Because the psychoactivity of cannabinoid compounds limits their medicinal usage, we undertook the present study to evaluate the in vitro antiproliferative ability of cannabidiol (CBD), a nonpsychoactive cannabinoid compound, on U87 and U373 human glioma cell lines. The addition of CBD to the culture medium led to a dramatic drop of mitochondrial oxidative metabolism [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide test] and viability in glioma cells, in a concentration-dependent manner that was already evident 24 h after CBD exposure, with an apparent IC(50) of 25 microM. The antiproliferative effect of CBD was partially prevented by the CB2 receptor antagonist N-[(1S)-endo-1,3,3-trimethylbicyclo[2,2,1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; SR2) and alpha-tocopherol. By contrast, the CB1 cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716; SR1), capsazepine (vanilloid receptor antagonist), the inhibitors of ceramide generation, or pertussis toxin did not counteract CBD effects. We also show, for the first time, that the antiproliferative effect of CBD was correlated to induction of apoptosis, as determined by cytofluorimetric analysis and single-strand DNA staining, which was not reverted by cannabinoid antagonists. Finally, CBD, administered s.c. to nude mice at the dose of 0.5 mg/mouse, significantly inhibited the growth of subcutaneously implanted U87 human glioma cells. In conclusion, the nonpsychoactive CBD was able to produce a significant antitumor activity both in vitro and in vivo, thus suggesting a possible application of CBD as an antineoplastic agent.

  16. HindIII identifies a two allele DNA polymorphism of the human cannabinoid receptor gene (CNR)

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    Caenazzo, L.; Hoehe, M.R.; Hsieh, W.T.; Berrettini, W.H.; Bonner, T.I.; Gershon, E.S. (National Inst. of Health, Bethesda, MD (United States))

    1991-09-11

    HCNR p5, a 0.9 kb BamHI/EcoRI fragment from the human cannabinoid receptor gene inserted into pUC19, was used as probe. The fragment is located in an intron approximately 14 kb 5{prime} of the initiation codon. This fragment is a clean single copy sequence by genomic blotting. Hybridization of human genomic DNA digested with HindIII identified a two allele RFLP with bands at 5.5 (A1) and 3.3 kb (A2). The human cannabinoid receptor gene has been genetically mapped in CEPH reference pedigrees to the centromeric/q region of chromosome 6. In situ hybridization localizes it to 6q14-q15. Codominant segregation has been observed in 26 informative two- and three-generation CEPH pedigrees and in 14 medium-sized disease families.

  17. Alcohol and cannabinoids differentially affect HIV infection and function of human monocyte-derived dendritic cells (MDDC

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    Marisela eAgudelo

    2015-12-01

    Full Text Available During human immunodeficiency virus (HIV infection, alcohol has been known to induce inflammation while cannabinoids have been shown to have an anti-inflammatory role. For instance cannabinoids have been shown to reduce susceptibility to HIV-1 infection and attenuate HIV replication in macrophages. Recently, we demonstrated that alcohol induces cannabinoid receptors and regulates cytokine production by monocyte-derived dendritic cells (MDDC. However, the ability of alcohol and cannabinoids to alter MDDC function during HIV infection has not been clearly elucidated yet. In order to study the potential impact of alcohol and cannabinoids on differentiated MDDC infected with HIV, monocytes were cultured for 7 days with GM-CSF and IL-4, differentiated MDDC were infected with HIV-1Ba-L and treated with EtOH (0.1 and 0.2%, THC (5 and 10 uM, or JWH-015 (5 and 10 uM for 4-7 days. HIV infection of MDDC was confirmed by p24 and Long Terminal Repeats (LTR estimation. MDDC endocytosis assay and cytokine array profiles were measured to investigate the effects of HIV and substances of abuse on MDDC function. Our results show the HIV+EtOH treated MDDC had the highest levels of p24 production and expression when compared with the HIV positive controls and the cannabinoid treated cells. Although both cannabinoids, THC and JWH-015 had lower levels of p24 production and expression, the HIV+JWH-015 treated MDDC had the lowest levels of p24 when compared to the HIV+THC treated cells. In addition, MDDC endocytic function and cytokine production were also differentially altered after alcohol and cannabinoid treatments. Our results show a differential effect of alcohol and cannabinoids, which may provide insights into the divergent inflammatory role of alcohol and cannabinoids to modulate MDDC function in the context of HIV infection.

  18. Nicotinamide pharmacokinetics in humans and mice

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    Horsman, M.R.; Hoyer, M.; Overgaard, J.; Honess, D.J.; Dennis, A.F.

    1993-01-01

    Healthy human volunteers orally ingested escalating doses of up to 6 g nicotinamide in capsule form on an empty stomach. Some side-effects were seen although these were mild and transient. HPLC analysis of blood samples showed peak plasma levels, typically within 45 min after ingestion, which were linearly dependent on dose ingested. The elimination half-life and AUC were also found to increase with drug dose, although these increases were non-linear. Pharmacokinetic studies were also performed to female CDF1 mice with C3H mammary carcinomas grown in the right rear foot. Analysis of blood and tumour samples taken from mice injected i.p. with nicotinamide doses between 100-1000 mg/kg showed similar characteristics as the human data, although the elimination half-lives were not dose-dependent. The average peak plasma concentration of 160 μg/ml measured in humans after taking 6 g of nicotinamide was equivalent to that seen in mice after injecting 171 mg/kg. Using a regrowth delay assay the enhancement of radiation damage by nicotinamide in this mouse tumour was found to be independent of drug dose from 100-1000 mg/kg, resulting in a constant 1.3-fold increase in radiation response. Doses of nicotinamide that can be tolerated clinically should therefore produce adequate enhancements of radiation damage in human tumours. (author)

  19. How important are sex differences in cannabinoid action?

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    Fattore, Liana; Fratta, Walter

    2010-06-01

    In humans as in animals, males and females are dissimilar in their genetic and hormonally driven behaviour; they process information differently, perceive experience and emotions in different ways, display diverse attitudes, language and social skills, and show sex-related differences in the brain anatomy and organization. Drug addiction is a widespread relapsing illness that affects both men and women. Sex-dependent differences have been frequently observed in the biological and behavioural effects of substances of abuse, including cannabis. Beside sex differences observed in the cannabinoid-induced effects related to cannabis abuse and dependence, cannabinoids have been shown to exert sex-dependent effects also in other physiological and behavioural aspects, such as food intake and energy balance (more evident in males), or anxiety and depression (more evident in females). Research has just begun to identify factors which could provide a neurobiological basis for gender-based differences in cannabinoid effects, among which, gonadal hormones seem to play a crucial role. Yet, cannabinoid pharmacodynamic and pharmacokinetic may also be important, as sex differences in cannabinoid effects might be due, at least in part, to differences in muscle mass and fat tissue distribution between males and females. Here, we will review both clinical and laboratory-based research evidence revealing important sex-related differences in cannabinoid effects, and put forward some suggestions for future studies to fill the gap in our knowledge of gender-specific bias in cannabinoid pharmacology.

  20. Endogenous cannabinoid receptor ligand induces the migration of human natural killer cells.

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    Kishimoto, Seishi; Muramatsu, Mayumi; Gokoh, Maiko; Oka, Saori; Waku, Keizo; Sugiura, Takayuki

    2005-02-01

    2-Arachidonoylglycerol is an endogenous ligand for the cannabinoid receptors (CB1 and CB2). Evidence is gradually accumulating which shows that 2-arachidonoylglycerol plays important physiological roles in several mammalian tissues and cells, yet the details remain ambiguous. In this study, we first examined the effects of 2-arachidonoylglycerol on the motility of human natural killer cells. We found that 2-arachidonoylglycerol induces the migration of KHYG-1 cells (a natural killer leukemia cell line) and human peripheral blood natural killer cells. The migration of natural killer cells induced by 2-arachidonoylglycerol was abolished by treating the cells with SR144528, a CB2 receptor antagonist, suggesting that the CB2 receptor is involved in the 2-arachidonoylglycerol-induced migration. In contrast to 2-arachidonoylglycerol, anandamide, another endogenous cannabinoid receptor ligand, did not induce the migration. Delta9-tetrahydrocannabinol, a major psychoactive constituent of marijuana, also failed to induce the migration; instead, the addition of delta9-tetrahydrocannabinol together with 2-arachidonoylglycerol abolished the migration induced by 2-arachidonoylglycerol. It is conceivable that the endogenous ligand for the cannabinoid receptor, that is, 2-arachidonoylglycerol, affects natural killer cell functions such as migration, thereby contributing to the host-defense mechanism against infectious viruses and tumor cells.

  1. Virtual pharmacokinetic model of human eye.

    Science.gov (United States)

    Kotha, Sreevani; Murtomäki, Lasse

    2014-07-01

    A virtual pharmacokinetic 3D model of the human eye is built using Comsol Multiphysics® software, which is based on the Finite Element Method (FEM). The model considers drug release from a polymer patch placed on sclera. The model concentrates on the posterior part of the eye, retina being the target tissue, and comprises the choroidal blood flow, partitioning of the drug between different tissues and active transport at the retina pigment epithelium (RPE)-choroid boundary. Although most straightforward, in order to check the mass balance, no protein binding or metabolism is yet included. It appeared that the most important issue in obtaining reliable simulation results is the finite element mesh, while time stepping has hardly any significance. Simulations were extended to 100,000 s. The concentration of a drug is shown as a function of time at various points of retina, as well as its average value, varying several parameters in the model. This work demonstrates how anybody with basic knowledge of calculus is able to build physically meaningful models of quite complex biological systems. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Prediction of human CNS pharmacokinetics using a physiologically-based pharmacokinetic modeling approach

    NARCIS (Netherlands)

    Yamamoto, Yumi; Valitalo, Pyry A.; Wong, Yin Cheong; Huntjens, Dymphy R.; Proost, Johannes H.; Vermeulen, An; Krauwinkel, Walter; Beukers, Margot W.; Kokki, Hannu; Kokki, Merja; Danhof, Meindert; van Hasselt, Johan G. C.; de Lange, Elizabeth C. M.

    2018-01-01

    Knowledge of drug concentration-time profiles at the central nervous system (CNS) target-site is critically important for rational development of CNS targeted drugs. Our aim was to translate a recently published comprehensive CNS physiologically-based pharmacokinetic (PBPK) model from rat to human,

  3. Human pharmacokinetics of proguanil and its metabolites

    DEFF Research Database (Denmark)

    Bygbjerg, Ib Christian; Ravn, P; Rønn, A

    1987-01-01

    The pharmacokinetics of proguanil and its metabolites cycloguanil and p-chlorophenylbiguanide were studied in five healthy volunteers taking 200 mg orally for 14 days. A highly sensitive and specific high-performance liquid chromatographic assay was applied, clearly identifying all three compounds...

  4. Synthetic Cannabinoids

    Directory of Open Access Journals (Sweden)

    Aslihan Okan Ibiloglu

    2017-09-01

    Full Text Available Synthetic cannabinoids which is a subgroup of cannabinoids are commonly used for recreational drug use throughout the whole world. Although both marijuana and synthetic cannabinoids stimulate the same receptors, cannabinoid receptor 1 (CB1 and cannabinoid receptor 2 (CB2, studies have shown that synthetic cannabinoids are much more potent than marijuana. The longer use of synthetic cannabinoids can cause severe physical and psychological symptoms that might even result in death, similar to many known illicit drugs. Main treatment options mostly involve symptom management and supportive care. The aim of this article is to discuss clinical and pharmacological properties of the increasingly used synthetic cannabinoids. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2017; 9(3.000: 317-328

  5. Screening for the synthetic cannabinoid JWH-018 and its major metabolites in human doping controls.

    Science.gov (United States)

    Möller, Ines; Wintermeyer, Annette; Bender, Katja; Jübner, Martin; Thomas, Andreas; Krug, Oliver; Schänzer, Wilhelm; Thevis, Mario

    2011-09-01

    Referred to as 'spice', several new drugs, advertised as herbal blends, have appeared on the market in the last few years, in which the synthetic cannabinoids JWH-018 and a C(8) homologue of CP 47,497 were identified as major active ingredients. Due to their reported cannabis-like effects, many European countries have banned these substances. The World Anti-Doping Agency has also explicitly prohibited synthetic cannabinoids in elite sport in-competition. Since urine specimens have been the preferred doping control samples, the elucidation of the metabolic pathways of these substances is of particular importance to implement them in sports drug testing programmes. In a recent report, an in vitro phase-I metabolism study of JWH-018 was presented yielding mainly hydroxylated and N-dealkylated metabolites. Due to these findings, a urine sample of a healthy man declaring to have smoked a 'spice' product was screened for potential phase-I and -II metabolites by high-resolution/high-accuracy mass spectrometry in the present report. The majority of the phase-I metabolites observed in earlier in vitro studies of JWH-018 were detected in this urine specimen and furthermore most of their respective monoglucuronides. As no intact JWH-018 was detectable, the monohydroxylated metabolite being the most abundant one was chosen as a target analyte for sports drug testing purposes; a detection method was subsequently developed and validated in accordance to conventional screening protocols based on enzymatic hydrolysis, liquid-liquid extraction, and liquid chromatography/electrospray tandem mass spectrometry analysis. The method was applied to approximately 7500 urine doping control samples yielding two JWH-018 findings and demonstrated its capability for a sensitive and selective identification of JWH-018 and its metabolites in human urine. Copyright © 2010 John Wiley & Sons, Ltd.

  6. Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: from mice to human subjects.

    Directory of Open Access Journals (Sweden)

    Emmanuel S Onaivi

    Full Text Available BACKGROUND: Addiction and major depression are mental health problems associated with stressful events in life with high relapse and reoccurrence even after treatment. Many laboratories were not able to detect the presence of cannabinoid CB2 receptors (CB2-Rs in healthy brains, but there has been demonstration of CB2-R expression in rat microglial cells and other brain associated cells during inflammation. Therefore, neuronal expression of CB2-Rs had been ambiguous and controversial and its role in depression and substance abuse is unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study we tested the hypothesis that genetic variants of CB2 gene might be associated with depression in a human population and that alteration in CB2 gene expression may be involved in the effects of abused substances including opiates, cocaine and ethanol in rodents. Here we demonstrate that a high incidence of (Q63R but not (H316Y polymorphism in the CB2 gene was found in Japanese depressed subjects. CB2-Rs and their gene transcripts are expressed in the brains of naïve mice and are modulated following exposure to stressors and administration of abused drugs. Mice that developed alcohol preference had reduced CB2 gene expression and chronic treatment with JWH015 a putative CB2-R agonist, enhanced alcohol consumption in stressed but not in control mice. The direct intracerebroventricular microinjection of CB2 anti-sense oligonucleotide into the mouse brain reduced mouse aversions in the plus-maze test, indicating the functional presence of CB2-Rs in the brain that modifies behavior. We report for the using electron microscopy the sub cellular localization of CB2-Rs that are mainly on post-synaptic elements in rodent brain. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate the functional expression of CB2-Rs in brain that may provide novel targets for the effects of cannabinoids in depression and substance abuse disorders beyond neuro-immunocannabinoid activity.

  7. Transplacental pharmacokinetics of diclofenac in perfused human placenta.

    Science.gov (United States)

    Shintaku, Kyohei; Hori, Satoko; Tsujimoto, Masayuki; Nagata, Hideaki; Satoh, Shoji; Tsukimori, Kiyomi; Nakano, Hitoo; Fujii, Tomoyuki; Taketani, Yuji; Ohtani, Hisakazu; Sawada, Yasufumi

    2009-05-01

    The aims of this study were to evaluate the transplacental transfer properties of diclofenac and to determine the effect of L-lactic acid on the transplacental transfer of diclofenac. The maternal and fetal vessels of human placenta were perfused in a single-pass mode with a solution containing diclofenac and antipyrine. The transplacental pharmacokinetic model was fitted to the time profiles of the drug concentrations in the effluent and placenta to obtain transplacental pharmacokinetic parameters. In addition, chloride ion in the perfusate was partially replaced with L-lactic acid to see the change in the transplacental transfer properties of diclofenac. The TPT(ss) value (ratio of the rate of amount transferred across the placenta to that infused in the steady state) of diclofenac was 2.22%, which was approximately one-third that of antipyrine and was significantly reduced in the presence of L-lactic acid. The transplacental pharmacokinetic model could adequately explain the transplacental transfer of diclofenac with influx clearances from maternal and fetal perfusates to placental tissue of 0.276 and 0.0345 ml/min/g cotyledon and efflux rate constants from placental tissue to maternal and fetal perfusates of 0.406 and 0.0337 min(-1), respectively. By taking into account protein binding, the placental tissue/plasma concentration ratio in humans for diclofenac was estimated to be 0.108 ml/g of cotyledon and was smaller than that of antipyrine. In conclusion, human placental perfusion and transplacental pharmacokinetic modeling allowed us to determine the transplacental transfer properties of diclofenac quantitatively. Diclofenac may share transplacental transfer system(s) with L-lactic acid.

  8. SIMULTANEOUS DETERMINATION OF 32 NEW SYNTHETIC CANNABINOIDS IN HUMAN URINE AND HAIR BY LC-MS/MS

    OpenAIRE

    WANG, Chung-Feng

    2018-01-01

    The extraction procedure and detectionmethods of new Synthetic Cannabinoids (ex: BB-22, SDB-005, THJ-018,JZL-195……etc.) for human urine and hair samples are in great need due to thesenew drugs are abused severely in recent years all over the world. Highlysensitive analytical techniques are therefore required for trace-levelidentification and quantification of these kinds of drugs. We report a fullyvalidated method here developed by our team which could simultaneouslydetermine 32 new Synthetic...

  9. Disposition pathways and pharmacokinetics of herbal medicines in humans.

    Science.gov (United States)

    He, S-M; Li, C G; Liu, J-P; Chan, E; Duan, W; Zhou, S-F

    2010-01-01

    Pharmacokinetic studies have become an integral part of modern drug development, but these studies are not regulatory needs for herbal remedies. This paper updates our current knowledge on the disposition pathways and pharmacokinetic properties of commonly used herbal medicines in humans. To retrieve relevant data, the authors have searched through computer-based literatures by full text search in Medline (via Pubmed), ScienceDirect, Current Contents Connect (ISI), Cochrance Library, CINAHL (EBSCO), CrossRef Search and Embase (all from inception to May 2010). Many herbal compounds undergo Phase I and/or Phase II metabolism in vivo, with cytochrome P450s (CYPs) and uridine diphosphate glucuronosyltransferases (UGTs) playing a major role. Some herbal ingredients are substrates of P-glycoprotein (P-gp) which is highly expressed in the intestine, liver, brain and kidney. As such, the activities of these drug metabolizing enzymes and drug transporters are determining factors for the in vivo bioavailability, disposition and distribution of herbal remedies. There are increasing pharmacokinetic studies of herbal remedies, but these studies are mainly focused on a small number of herbal remedies including St John's wort, milk thistle, sculcap, curcumin, echinacea, ginseng, ginkgo, and ginger. The pharmacokinetic data of a small number of purified herbal ingredients, including anthocyanins, berberine, catechins, curcumin, lutein and quercetin, are available. For the majority of herbal remedies used in folk medicines, data on their disposition and biological fate in humans are lacking or in paucity. For a herbal medicine, the pharmacological effect is achieved when the bioactive agents or the metabolites reach and sustain proper levels at their sites of action. Both the dose levels and fates of active components in the body govern their target-site concentrations after administration of an herbal remedy. In this regard, a safe and optimal use of herbal medicines requires a

  10. Pharmacokinetics of bevacizumab after topical and intravitreal administration in human eyes

    OpenAIRE

    Moisseiev, Elad; Waisbourd, Michael; Ben-Artsi, Elad; Levinger, Eliya; Barak, Adiel; Daniels, Tad; Csaky, Karl; Loewenstein, Anat; Barequet, Irina S.

    2013-01-01

    Background Topical bevacizumab is a potential treatment modality for corneal neovascularization, and several recent studies have demonstrated its efficacy. No previous study of the pharmacokinetics of topical bevacizumab has been performed in human eyes. The purpose of this study is to investigate the pharmacokinetics of topical administration of bevacizumab in human eyes, and also to compare the pharmacokinetics of intravitreal bevacizumab injections with previously reported data. Methods Tw...

  11. Physiologically Based Pharmacokinetic Model for Terbinafine in Rats and Humans

    Science.gov (United States)

    Hosseini-Yeganeh, Mahboubeh; McLachlan, Andrew J.

    2002-01-01

    The aim of this study was to develop a physiologically based pharmacokinetic (PB-PK) model capable of describing and predicting terbinafine concentrations in plasma and tissues in rats and humans. A PB-PK model consisting of 12 tissue and 2 blood compartments was developed using concentration-time data for tissues from rats (n = 33) after intravenous bolus administration of terbinafine (6 mg/kg of body weight). It was assumed that all tissues except skin and testis tissues were well-stirred compartments with perfusion rate limitations. The uptake of terbinafine into skin and testis tissues was described by a PB-PK model which incorporates a membrane permeability rate limitation. The concentration-time data for terbinafine in human plasma and tissues were predicted by use of a scaled-up PB-PK model, which took oral absorption into consideration. The predictions obtained from the global PB-PK model for the concentration-time profile of terbinafine in human plasma and tissues were in close agreement with the observed concentration data for rats. The scaled-up PB-PK model provided an excellent prediction of published terbinafine concentration-time data obtained after the administration of single and multiple oral doses in humans. The estimated volume of distribution at steady state (Vss) obtained from the PB-PK model agreed with the reported value of 11 liters/kg. The apparent volume of distribution of terbinafine in skin and adipose tissues accounted for 41 and 52%, respectively, of the Vss for humans, indicating that uptake into and redistribution from these tissues dominate the pharmacokinetic profile of terbinafine. The PB-PK model developed in this study was capable of accurately predicting the plasma and tissue terbinafine concentrations in both rats and humans and provides insight into the physiological factors that determine terbinafine disposition. PMID:12069977

  12. Synthetic Cannabinoids.

    Science.gov (United States)

    Mills, Brooke; Yepes, Andres; Nugent, Kenneth

    2015-07-01

    Synthetic cannabinoids (SCBs), also known under the brand names of "Spice," "K2," "herbal incense," "Cloud 9," "Mojo" and many others, are becoming a large public health concern due not only to their increasing use but also to their unpredictable toxicity and abuse potential. There are many types of SCBs, each having a unique binding affinity for cannabinoid receptors. Although both Δ-tetrahydrocannabinol (THC) and SCBs stimulate the same receptors, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), studies have shown that SCBs are associated with higher rates of toxicity and hospital admissions than is natural cannabis. This is likely due to SCBs being direct agonists of the cannabinoid receptors, whereas THC is a partial agonist. Furthermore, the different chemical structures of SCBs found in Spice or K2 may interact in unpredictable ways to elicit previously unknown, and the commercial products may have unknown contaminants. The largest group of users is men in their 20s who participate in polydrug use. The most common reported toxicities with SCB use based on studies using Texas Poison Control records are tachycardia, agitation and irritability, drowsiness, hallucinations, delusions, hypertension, nausea, confusion, dizziness, vertigo and chest pain. Acute kidney injury has also been strongly associated with SCB use. Treatment mostly involves symptom management and supportive care. More research is needed to identify which contaminants are typically found in synthetic marijuana and to understand the interactions between different SBCs to better predict adverse health outcomes.

  13. First characterization of AKB-48 metabolism, a novel synthetic cannabinoid, using human hepatocytes and high-resolution mass spectrometry.

    Science.gov (United States)

    Gandhi, Adarsh S; Zhu, Mingshe; Pang, Shaokun; Wohlfarth, Ariane; Scheidweiler, Karl B; Liu, Hua-Fen; Huestis, Marilyn A

    2013-10-01

    Since the federal authorities scheduled the first synthetic cannabinoids, JWH-018 and JWH-073, new synthetic cannabinoids were robustly marketed. N-(1-Adamantyl)-1-pentylindazole-3-carboxamide (AKB-48), also known as APINACA, was recently observed in Japanese herbal smoking blends. The National Forensic Laboratory Information System registered 443 reports of AKB-48 cases in the USA from March 2010 to January 2013. In May 2013, the Drug Enforcement Administration listed AKB-48 as a Schedule I drug. Recently, AKB-48 was shown to have twice the CB1 receptor binding affinity than CB2. These pharmacological effects and the difficulty in detecting the parent compound in urine highlight the importance of metabolite identification for developing analytical methods for clinical and forensic investigations. Using human hepatocytes and TripleTOF mass spectrometry, we identified 17 novel phase I and II AKB-48 metabolites, products of monohydroxylation, dihydroxylation, or trihydroxylation on the aliphatic adamantane ring or N-pentyl side chain. Glucuronide conjugation of some mono- and dihydroxylated metabolites also occurred. Oxidation and dihydroxylation on the adamantane ring and N-pentyl side chain formed a ketone. More metabolites were identified after 3 h of incubation than at 1 h. For the first time, we present a AKB-48 metabolic scheme obtained from human hepatocytes and high-resolution mass spectrometry. These data are needed to develop analytical methods to identify AKB-48 consumption in clinical and forensic testing.

  14. Human orexin/hypocretin receptors form constitutive homo- and heteromeric complexes with each other and with human CB1 cannabinoid receptors

    International Nuclear Information System (INIS)

    Jäntti, Maria H.; Mandrika, Ilona; Kukkonen, Jyrki P.

    2014-01-01

    Highlights: • OX 1 and OX 2 orexin and CB 1 cannabinoid receptor dimerization was investigated. • Bioluminescence resonance energy transfer method was used. • All receptors readily formed constitutive homo- and heteromeric complexes. - Abstract: Human OX 1 orexin receptors have been shown to homodimerize and they have also been suggested to heterodimerize with CB 1 cannabinoid receptors. The latter has been suggested to be important for orexin receptor responses and trafficking. In this study, we wanted to assess the ability of the other combinations of receptors to also form similar complexes. Vectors for expression of human OX 1 , OX 2 and CB 1 receptors, C-terminally fused with either Renilla luciferase or GFP 2 green fluorescent protein variant, were generated. The constructs were transiently expressed in Chinese hamster ovary cells, and constitutive dimerization between the receptors was assessed by bioluminescence energy transfer (BRET). Orexin receptor subtypes readily formed homo- and hetero(di)mers, as suggested by significant BRET signals. CB 1 receptors formed homodimers, and they also heterodimerized with both orexin receptors. Interestingly, BRET efficiency was higher for homodimers than for almost all heterodimers. This is likely to be due to the geometry of the interaction; the putatively symmetric dimers may place the C-termini in a more suitable orientation in homomers. Fusion of luciferase to an orexin receptor and GFP 2 to CB 1 produced more effective BRET than the opposite fusions, also suggesting differences in geometry. Similar was seen for the OX 1 –OX 2 interaction. In conclusion, orexin receptors have a significant propensity to make homo- and heterodi-/oligomeric complexes. However, it is unclear whether this affects their signaling. As orexin receptors efficiently signal via endocannabinoid production to CB 1 receptors, dimerization could be an effective way of forming signal complexes with optimal cannabinoid concentrations

  15. Cannabinoids: Medical implications.

    Science.gov (United States)

    Schrot, Richard J; Hubbard, John R

    2016-01-01

    Herbal cannabis has been used for thousands of years for medical purposes. With elucidation of the chemical structures of tetrahydrocannabinol (THC) and cannabidiol (CBD) and with discovery of the human endocannabinoid system, the medical usefulness of cannabinoids has been more intensively explored. While more randomized clinical trials are needed for some medical conditions, other medical disorders, like chronic cancer and neuropathic pain and certain symptoms of multiple sclerosis, have substantial evidence supporting cannabinoid efficacy. While herbal cannabis has not met rigorous FDA standards for medical approval, specific well-characterized cannabinoids have met those standards. Where medical cannabis is legal, patients typically see a physician who "certifies" that a benefit may result. Physicians must consider important patient selection criteria such as failure of standard medical treatment for a debilitating medical disorder. Medical cannabis patients must be informed about potential adverse effects, such as acute impairment of memory, coordination and judgment, and possible chronic effects, such as cannabis use disorder, cognitive impairment, and chronic bronchitis. In addition, social dysfunction may result at work/school, and there is increased possibility of motor vehicle accidents. Novel ways to manipulate the endocannbinoid system are being explored to maximize benefits of cannabinoid therapy and lessen possible harmful effects.

  16. A Review of the Therapeutic Antitumor Potential of Cannabinoids.

    Science.gov (United States)

    Bogdanović, Višnja; Mrdjanović, Jasminka; Borišev, Ivana

    2017-11-01

    The aim of this review is to discuss cannabinoids from a preclinical and clinical oncological perspective and provide the audience with a concise, retrospective overview of the most significant findings concerning the potential use of cannabinoids in cancer treatment. A literature survey of medical and scientific databases was conducted with a focus on the biological and medical potential of cannabinoids in cancer treatment. Cannabis sativa is a plant rich in more than 100 types of cannabinoids. Besides exogenous plant cannabinoids, mammalian endocannabinoids and synthetic cannabinoid analogues have been identified. Cannabinoid receptors type 1 (CB1) and type 2 (CB2) have been isolated and characterized from mammalian cells. Through cannabinoid receptor and non-receptor signaling pathways, cannabinoids show specific cytotoxicity against tumor cells, while protecting healthy tissue from apoptosis. The dual antiproliferative and proapoptotic effects of cannabinoids and associated signaling pathways have been investigated on a large panel of cancer cell lines. Cannabinoids also display potent anticancer activity against tumor xenografts, including tumors that express high resistance to standard chemotherapeutics. Few studies have investigated the possible synergistic effects of cannabinoids with standard oncology therapies, and are based on the preclinically confirmed concept of "cannabinoid sensitizers." Also, clinical trials aimed to confirm the antineoplastic activity of cannabinoids have only been evaluated on a small number of subjects, with no consensus conclusions regarding their effectiveness. A large number of cannabinoid compounds have been discovered, developed, and used to study the effects of cannabinoids on cancers in model systems. However, few clinical trials have been conducted on the use of cannabinoids in the treatment of cancers in humans. Further studies require extensive monitoring of the effects of cannabinoids alone or in combination with

  17. Prediction of Human Pharmacokinetic Profile After Transdermal Drug Application Using Excised Human Skin.

    Science.gov (United States)

    Yamamoto, Syunsuke; Karashima, Masatoshi; Arai, Yuta; Tohyama, Kimio; Amano, Nobuyuki

    2017-09-01

    Although several mathematical models have been reported for the estimation of human plasma concentration profiles of drug substances after dermal application, the successful cases that can predict human pharmacokinetic profiles are limited. Therefore, the aim of this study is to investigate the prediction of human plasma concentrations after dermal application using in vitro permeation parameters obtained from excised human skin. The in vitro skin permeability of 7 marketed drug products was evaluated. The plasma concentration-time profiles of the drug substances in humans after their dermal application were simulated using compartment models and the clinical pharmacokinetic parameters. The transdermal process was simulated using the in vitro skin permeation rate and lag time assuming a zero-order absorption. These simulated plasma concentration profiles were compared with the clinical data. The result revealed that the steady-state plasma concentration of diclofenac and the maximum concentrations of nicotine, bisoprolol, rivastigmine, and lidocaine after topical application were within 2-fold of the clinical data. Furthermore, the simulated concentration profiles of bisoprolol, nicotine, and rivastigmine reproduced the decrease in absorption due to drug depletion from the formulation. In conclusion, this simple compartment model using in vitro human skin permeation parameters as zero-order absorption predicted the human plasma concentrations accurately. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  18. Population Pharmacokinetics of Tenofovir in Human Immunodeficiency Virus-Infected Patients Taking Highly Active Antiretroviral Therapy

    OpenAIRE

    Jullien, Vincent; Tréluyer, Jean-Marc; Rey, Elisabeth; Jaffray, Patrick; Krivine, Anne; Moachon, Laurence; Lillo-Le Louet, Agnès; Lescoat, Anne; Dupin, Nicolas; Salmon, Dominique; Pons, Gérard; Urien, Saïk

    2005-01-01

    The influence of renal function on tenofovir pharmacokinetics was investigated in 193 human immunodeficiency virus (HIV)-infected patients by the use of a population approach performed with the nonlinear mixed effects modeling program NONMEM. Tenofovir pharmacokinetics was well described by a two-compartment open model in which the absorption and the distribution rate constants are equal. Typical population estimates of apparent central distribution volume (Vc/F), peripheral distribution volu...

  19. Pharmacokinetics of high-dose intravenous melatonin in humans

    DEFF Research Database (Denmark)

    Andersen, Lars P H; Werner, Mads U; Rosenkilde, Mette Marie

    2016-01-01

    This crossover study investigated the pharmacokinetics and adverse effects of high-dose intravenous melatonin. Volunteers participated in 3 identical study sessions, receiving an intravenous bolus of 10 mg melatonin, 100 mg melatonin, and placebo. Blood samples were collected at baseline and 0, 60......, 120, 180, 240, 300, 360, and 420 minutes after the bolus. Quantitative determination of plasma melatonin concentrations was performed using a radioimmunoassay technique. Pharmacokinetic parameters were estimated by a compartmental pharmacokinetic analysis. Adverse effects included assessments...... of sedation and registration of other symptoms. Sedation, evaluated as simple reaction times, was measured at baseline and 120, 180, 300, and 420 minutes after the bolus. Twelve male volunteers completed the study. Median (IQR) Cmax after the bolus injections of 10 mg and 100 mg of melatonin were 221...

  20. Human orexin/hypocretin receptors form constitutive homo- and heteromeric complexes with each other and with human CB{sub 1} cannabinoid receptors

    Energy Technology Data Exchange (ETDEWEB)

    Jäntti, Maria H., E-mail: maria.jantti@helsinki.fi [Department of Veterinary Biosciences, POB 66, FIN-00014 University of Helsinki (Finland); Mandrika, Ilona, E-mail: ilona@biomed.lu.lv [Latvian Biomedical Research and Study Centre, Ratsupites Str. 1, Riga LV 1067 (Latvia); Kukkonen, Jyrki P., E-mail: jyrki.kukkonen@helsinki.fi [Department of Veterinary Biosciences, POB 66, FIN-00014 University of Helsinki (Finland)

    2014-03-07

    Highlights: • OX{sub 1} and OX{sub 2} orexin and CB{sub 1} cannabinoid receptor dimerization was investigated. • Bioluminescence resonance energy transfer method was used. • All receptors readily formed constitutive homo- and heteromeric complexes. - Abstract: Human OX{sub 1} orexin receptors have been shown to homodimerize and they have also been suggested to heterodimerize with CB{sub 1} cannabinoid receptors. The latter has been suggested to be important for orexin receptor responses and trafficking. In this study, we wanted to assess the ability of the other combinations of receptors to also form similar complexes. Vectors for expression of human OX{sub 1}, OX{sub 2} and CB{sub 1} receptors, C-terminally fused with either Renilla luciferase or GFP{sup 2} green fluorescent protein variant, were generated. The constructs were transiently expressed in Chinese hamster ovary cells, and constitutive dimerization between the receptors was assessed by bioluminescence energy transfer (BRET). Orexin receptor subtypes readily formed homo- and hetero(di)mers, as suggested by significant BRET signals. CB{sub 1} receptors formed homodimers, and they also heterodimerized with both orexin receptors. Interestingly, BRET efficiency was higher for homodimers than for almost all heterodimers. This is likely to be due to the geometry of the interaction; the putatively symmetric dimers may place the C-termini in a more suitable orientation in homomers. Fusion of luciferase to an orexin receptor and GFP{sup 2} to CB{sub 1} produced more effective BRET than the opposite fusions, also suggesting differences in geometry. Similar was seen for the OX{sub 1}–OX{sub 2} interaction. In conclusion, orexin receptors have a significant propensity to make homo- and heterodi-/oligomeric complexes. However, it is unclear whether this affects their signaling. As orexin receptors efficiently signal via endocannabinoid production to CB{sub 1} receptors, dimerization could be an effective way

  1. Cannabinoid receptor-mediated disruption of sensory gating and neural oscillations: A translational study in rats and humans.

    Science.gov (United States)

    Skosnik, Patrick D; Hajós, Mihály; Cortes-Briones, Jose A; Edwards, Chad R; Pittman, Brian P; Hoffmann, William E; Sewell, Andrew R; D'Souza, Deepak C; Ranganathan, Mohini

    2018-06-01

    Cannabis use has been associated with altered sensory gating and neural oscillations. However, it is unclear which constituent in cannabis is responsible for these effects, or whether these are cannabinoid receptor 1 (CB1R) mediated. Therefore, the present study in humans and rats examined whether cannabinoid administration would disrupt sensory gating and evoked oscillations utilizing electroencephalography (EEG) and local field potentials (LFPs), respectively. Human subjects (n = 15) completed four test days during which they received intravenous delta-9-tetrahydrocannabinol (Δ 9 -THC), cannabidiol (CBD), Δ 9 -THC + CBD, or placebo. Subjects engaged in a dual-click paradigm, and outcome measures included P50 gating ratio (S2/S1) and evoked power to S1 and S2. In order to examine CB1R specificity, rats (n = 6) were administered the CB1R agonist CP-55940, CP-55940+AM-251 (a CB1R antagonist), or vehicle using the same paradigm. LFPs were recorded from CA3 and entorhinal cortex. Both Δ 9 -THC (p < 0.007) and Δ 9 -THC + CBD (p < 0.004) disrupted P50 gating ratio compared to placebo, while CBD alone had no effect. Δ 9 -THC (p < 0.048) and Δ 9 -THC + CBD (p < 0.035) decreased S1 evoked theta power, and in the Δ 9 -THC condition, S1 theta negatively correlated with gating ratios (r = -0.629, p < 0.012 (p < 0.048 adjusted)). In rats, CP-55940 disrupted gating in both brain regions (p < 0.0001), and this was reversed by AM-251. Further, CP-55940 decreased evoked theta (p < 0.0077) and gamma (p < 0.011) power to S1, which was partially blocked by AM-251. These convergent human/animal data suggest that CB1R agonists disrupt sensory gating by altering neural oscillations in the theta-band. Moreover, this suggests that the endocannabinoid system mediates theta oscillations relevant to perception and cognition. Copyright © 2018 Elsevier Ltd. All rights reserved.

  2. METHODS FOR RECOMBINANT EXPRESSION AND FUNCTIONAL CHARACTERIZATION OF HUMAN CANNABINOID RECEPTOR CB2

    Directory of Open Access Journals (Sweden)

    Alexei A. Yeliseev

    2013-03-01

    Full Text Available Cannabinoid receptor CB2 is a seven transmembrane-domain integral membrane protein that belongs to a large superfamily of G protein-coupled receptors (GPCR. CB2 is a part of the endocannabinoid system that plays vital role in regulation of immune response, inflammation, pain sensitivity, obesity and other physiological responses. Information about the structure and mechanisms of functioning of this receptor in cell membranes is essential for the rational development of specific pharmaceuticals. Here we review the methodology for recombinant expression, purification, stabilization and biochemical characterization of CB2 suitable for preparation of multi-milligram quantities of functionally active receptor. The biotechnological protocols include expression of the recombinant CB2 in E. coli cells as a fusion with the maltose binding protein, stabilization with a high affinity ligand and a derivative of cholesterol in detergent micelles, efficient purification by tandem affinity chromatography, and reconstitution of the receptor into lipid bilayers. The purified recombinant CB2 receptor is amenable to functional and structural studies including nuclear magnetic resonance spectroscopy and a wide range of biochemical and biophysical techniques.

  3. PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR HUMAN EXPOSURES TO METHYL TERTIARY-BUTYL ETHER

    Science.gov (United States)

    Humans can be exposed by inhalation, ingestion, or dermal absorption to methyl tertiary-butyl ether (MTBE), an oxygenated fuel additive, from contaminated water sources. The purpose of this research was to develop a physiologically based pharmacokinetic model describing in human...

  4. First Characterization of AKB-48 Metabolism, a Novel Synthetic Cannabinoid, Using Human Hepatocytes and High-Resolution Mass Spectrometry

    OpenAIRE

    Gandhi, Adarsh S.; Zhu, Mingshe; Pang, Shaokun; Wohlfarth, Ariane; Scheidweiler, Karl B.; Liu, Hua-fen; Huestis, Marilyn A.

    2013-01-01

    Since the federal authorities scheduled the first synthetic cannabinoids, JWH-018 and JWH-073, new synthetic cannabinoids were robustly marketed. N-(1-Adamantyl)-1-pentylindazole-3-carboxamide (AKB-48), also known as APINACA, was recently observed in Japanese herbal smoking blends. The National Forensic Laboratory Information System registered 443 reports of AKB-48 cases in the USA from March 2010 to January 2013. In May 2013, the Drug Enforcement Administration listed AKB-48 as a Schedule I ...

  5. Bioavailability and Pharmacokinetics of Oral Cocaine in Humans.

    Science.gov (United States)

    Coe, Marion A; Jufer Phipps, Rebecca A; Cone, Edward J; Walsh, Sharon L

    2018-06-01

    The pharmacokinetic profile of oral cocaine has not been fully characterized and prospective data on oral bioavailability are limited. A within-subject study was performed to characterize the bioavailability and pharmacokinetics of oral cocaine. Fourteen healthy inpatient participants (six males) with current histories of cocaine use were administered two oral doses (100 and 200 mg) and one intravenous (IV) dose (40 mg) of cocaine during three separate dosing sessions. Plasma samples were collected for up to 24 h after dosing and analyzed for cocaine and metabolites by gas chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by non-compartmental analysis, and a two-factor model was used to assess for dose and sex differences. The mean ± SEM oral cocaine bioavailability was 0.32 ± 0.04 after 100 and 0.45 ± 0.06 after 200 mg oral cocaine. Volume of distribution (Vd) and clearance (CL) were both greatest after 100 mg oral (Vd = 4.2 L/kg; CL = 116.2 mL/[min kg]) compared to 200 mg oral (Vd = 2.9 L/kg; CL = 87.5 mL/[min kg]) and 40 mg IV (Vd = 1.3 L/kg; CL = 32.7 mL/[min kg]). Oral cocaine area-under-thecurve (AUC) and peak concentration increased in a dose-related manner. AUC metabolite-to-parent ratios of benzoylecgonine and ecgonine methyl ester were significantly higher after oral compared to IV administration and highest after the lower oral dose. In addition, minor metabolites were detected in higher concentrations after oral compared to IV cocaine. Oral cocaine produced a pharmacokinetic profile different from IV cocaine, which appears as a rightward and downward shift in the concentration-time profile. Cocaine bioavailability values were similar to previous estimates. Oral cocaine also produced a unique metabolic profile, with greater concentrations of major and minor metabolites.

  6. Phase I metabolism of the recently emerged synthetic cannabinoid CUMYL-PEGACLONE and detection in human urine samples.

    Science.gov (United States)

    Mogler, Lukas; Wilde, Maurice; Huppertz, Laura M; Weinfurtner, Georg; Franz, Florian; Auwärter, Volker

    2018-05-01

    Indole-, indazole-, or azaindole-based synthetic cannabinoids (SCs), bearing a cumyl substituent are a widespread, recreationally used subgroup of new psychoactive substances (NPS). The latest cumyl-derivative, CUMYL-PEGACLONE, emerged in December 2016 on the German drug market. The substance features a novel γ-carboline core structure, which is most likely synthesized to bypass generic legislative approaches to control SCs by prohibiting distinct core structures. Using liquid chromatography-tandem mass spectrometry and liquid chromatography-high resolution mass spectrometry techniques, the main in vivo phase I metabolites of this new substance were detected. A pooled human liver microsome assay was applied to generate in vitro reference spectra of CUMYL-PEGACLONE phase I metabolites. Additionally, 30 urine samples were investigated leading to 22 in vivo metabolites. A metabolite mono-hydroxylated at the γ-carbolinone core system and a metabolite with an additional carbonyl group at the pentyl side chain were evaluated as highly specific and sensitive markers to proof CUMYL-PEGACLONE uptake. Moreover, 3 immunochemical assays commonly used for SC screening in urine were tested for their capability of detecting the new drug but failed due to insufficient cross-reactivity. Copyright © 2018 John Wiley & Sons, Ltd.

  7. Deuterium labeled cannabinoids

    International Nuclear Information System (INIS)

    Driessen, R.A.

    1979-01-01

    Complex reactions involving ring opening, ring closure and rearrangements hamper complete understanding of the fragmentation processes in the mass spectrometric fragmentation patterns of cannabinoids. Specifically labelled compounds are very powerful tools for obtaining more insight into fragmentation mechanisms and ion structures and therefore the synthesis of specifically deuterated cannabinoids was undertaken. For this, it was necessary to investigate the preparation of cannabinoids, appropriately functionalized for specific introduction of deuterium atom labels. The results of mass spectrometry with these labelled cannabinoids are described. (Auth.)

  8. Development of a physiologically based pharmacokinetic model for assessment of human exposure to bisphenol A

    International Nuclear Information System (INIS)

    Yang, Xiaoxia; Doerge, Daniel R.; Teeguarden, Justin G.; Fisher, Jeffrey W.

    2015-01-01

    A previously developed physiologically based pharmacokinetic (PBPK) model for bisphenol A (BPA) in adult rhesus monkeys was modified to characterize the pharmacokinetics of BPA and its phase II conjugates in adult humans following oral ingestion. Coupled with in vitro studies on BPA metabolism in the liver and the small intestine, the PBPK model was parameterized using oral pharmacokinetic data with deuterated-BPA (d 6 -BPA) delivered in cookies to adult humans after overnight fasting. The availability of the serum concentration time course of unconjugated d 6 -BPA offered direct empirical evidence for the calibration of BPA model parameters. The recalibrated PBPK adult human model for BPA was then evaluated against published human pharmacokinetic studies with BPA. A hypothesis of decreased oral uptake was needed to account for the reduced peak levels observed in adult humans, where d 6 -BPA was delivered in soup and food was provided prior to BPA ingestion, suggesting the potential impact of dosing vehicles and/or fasting on BPA disposition. With the incorporation of Monte Carlo analysis, the recalibrated adult human model was used to address the inter-individual variability in the internal dose metrics of BPA for the U.S. general population. Model-predicted peak BPA serum levels were in the range of pM, with 95% of human variability falling within an order of magnitude. This recalibrated PBPK model for BPA in adult humans provides a scientific basis for assessing human exposure to BPA that can serve to minimize uncertainties incurred during extrapolations across doses and species. - Highlights: • A PBPK model predicts the kinetics of bisphenol A (BPA) in adult humans. • Serum concentrations of aglycone BPA are available for model calibration. • Model predicted peak BPA serum levels for adult humans were in the range of pM. • Model predicted 95% of human variability fell within an order of magnitude.

  9. Development of a physiologically based pharmacokinetic model for assessment of human exposure to bisphenol A

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Xiaoxia, E-mail: xiaoxia.yang@fda.hhs.gov [Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Doerge, Daniel R. [Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Teeguarden, Justin G. [Health Effects and Exposure Science, Pacific Northwest National Laboratory, Richland, WA 99352 (United States); Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331 (United States); Fisher, Jeffrey W. [Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States)

    2015-12-15

    A previously developed physiologically based pharmacokinetic (PBPK) model for bisphenol A (BPA) in adult rhesus monkeys was modified to characterize the pharmacokinetics of BPA and its phase II conjugates in adult humans following oral ingestion. Coupled with in vitro studies on BPA metabolism in the liver and the small intestine, the PBPK model was parameterized using oral pharmacokinetic data with deuterated-BPA (d{sub 6}-BPA) delivered in cookies to adult humans after overnight fasting. The availability of the serum concentration time course of unconjugated d{sub 6}-BPA offered direct empirical evidence for the calibration of BPA model parameters. The recalibrated PBPK adult human model for BPA was then evaluated against published human pharmacokinetic studies with BPA. A hypothesis of decreased oral uptake was needed to account for the reduced peak levels observed in adult humans, where d{sub 6}-BPA was delivered in soup and food was provided prior to BPA ingestion, suggesting the potential impact of dosing vehicles and/or fasting on BPA disposition. With the incorporation of Monte Carlo analysis, the recalibrated adult human model was used to address the inter-individual variability in the internal dose metrics of BPA for the U.S. general population. Model-predicted peak BPA serum levels were in the range of pM, with 95% of human variability falling within an order of magnitude. This recalibrated PBPK model for BPA in adult humans provides a scientific basis for assessing human exposure to BPA that can serve to minimize uncertainties incurred during extrapolations across doses and species. - Highlights: • A PBPK model predicts the kinetics of bisphenol A (BPA) in adult humans. • Serum concentrations of aglycone BPA are available for model calibration. • Model predicted peak BPA serum levels for adult humans were in the range of pM. • Model predicted 95% of human variability fell within an order of magnitude.

  10. Metabolites of 5F-AKB-48, a synthetic cannabinoid receptor agonist, identified in human urine and liver microsomal preparations using liquid chromatography high-resolution mass spectrometry.

    Science.gov (United States)

    Holm, Niels Bjerre; Pedersen, Anders Just; Dalsgaard, Petur Weihe; Linnet, Kristian

    2015-03-01

    New types of synthetic cannabinoid designer drugs are constantly introduced to the illicit drug market to circumvent legislation. Recently, N-​(1-Adamant​yl)-​1-​(5-​fluoropentyl)-​1H-​indazole-​3-​carboxamide (5F-AKB-48), also known as 5F-APINACA, was identified as an adulterant in herbal products. This compound deviates from earlier JHW-type synthetic cannabinoids by having an indazole ring connected to an adamantyl group via a carboxamide linkage. Synthetic cannabinoids are completely metabolized, and identification of the metabolites is thus crucial when using urine as the sample matrix. Using an authentic urine sample and high-resolution accurate-mass Fourier transform Orbitrap mass spectrometry, we identified 16 phase-I metabolites of 5F-AKB-48. The modifications included mono-, di-, and trihydroxylation on the adamantyl ring alone or in combination with hydroxylation on the N-fluoropentylindazole moiety, dealkylation of the N-fluoropentyl side chain, and oxidative loss of fluorine as well as combinations thereof. The results were compared to human liver microsomal (HLM) incubations, which predominantly showed time-dependent formation of mono-, di-, and trihydroxylated metabolites having the hydroxyl groups on the adamantyl ring. The results presented here may be used to select metabolites specific of 5F-AKB-48 for use in clinical and forensic screening. Copyright © 2014 John Wiley & Sons, Ltd.

  11. An Atmospheric Pressure Chemical Ionization MS/MS Assay Using Online Extraction for the Analysis of 11 Cannabinoids and Metabolites in Human Plasma and Urine.

    Science.gov (United States)

    Klawitter, Jelena; Sempio, Cristina; Mörlein, Sophie; De Bloois, Erik; Klepacki, Jacek; Henthorn, Thomas; Leehey, Maureen A; Hoffenberg, Edward J; Knupp, Kelly; Wang, George S; Hopfer, Christian; Kinney, Greg; Bowler, Russell; Foreman, Nicholas; Galinkin, Jeffrey; Christians, Uwe; Klawitter, Jost

    2017-10-01

    Although, especially in the United States, there has been a recent surge of legalized cannabis for either recreational or medicinal purposes, surprisingly little is known about clinical dose-response relationships, pharmacodynamic and toxicodynamic effects of cannabinoids such as Δ9-tetrahydrocannabinol (THC). Even less is known about other active cannabinoids. To address this knowledge gap, an online extraction, high-performance liquid chromatography coupled with tandem mass spectrometry method for simultaneous quantification of 11 cannabinoids and metabolites including THC, 11-hydroxy-Δ9-tetrahydrocannabinol, 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid, 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide (THC-C-gluc), cannabinol, cannabidiol, cannabigerol, cannabidivarin, Δ9-tetrahydrocannabivarin (THCV), and 11-nor-9-carboxy-Δ9-tetrahydrocannabivarin (THCV-COOH) was developed and validated in human urine and plasma. In contrast to atmospheric pressure chemical ionization, electrospray ionization was associated with extensive ion suppression in plasma and urine samples. Thus, the atmospheric pressure chemical ionization assay was validated showing a lower limit of quantification ranging from 0.39 to 3.91 ng/mL depending on study compound and matrix. The upper limit of quantification was 400 ng/mL except for THC-C-gluc with an upper limit of quantification of 2000 ng/mL. The linearity was r > 0.99 for all analyzed calibration curves. Acceptance criteria for intrabatch and interbatch accuracy (85%-115%) and imprecision (<15%) were met for all compounds. In plasma, the only exceptions were THCV (75.3%-121.2% interbatch accuracy) and cannabidivarin (interbatch imprecision, 15.7%-17.2%). In urine, THCV did not meet predefined acceptance criteria for intrabatch accuracy. This assay allows for monitoring not only THC and its major metabolites but also major cannabinoids that are of interest for marijuana research and clinical practice.

  12. Human pharmacokinetics of iohexol. A new nonionic contrast medium

    International Nuclear Information System (INIS)

    Olsson, B.; Aulie, A.; Sveen, K.; Andrew, E.

    1983-01-01

    The pharmacokinetics of iohexol, a new nonionic, water-soluble contrast medium, have been determined after intravenous injection in 20 healthy volunteers, at four different dose levels (125-500 mg I/kg). The apparent volume of distribution was 0.27 1/kg, indicating distribution in the extracellular water. The biologic half-life was 121 minutes, comparable with that of other intravascular contrast media. Iohexol was excreted completely unmetabolized in the urine, with a 100% recovery 24 hours after injection. A comparison of iohexol and chromium-51 ( 51 Cr)-EDTA clearances indicates that iohexol is mainly excreted by glomerular filtration. The 51 Cr-EDTA clearance was the same when injected separately and concomitantly with iohexol, indicating that glomerular filtration rate is not affected by iohexol. No dose dependency was observed in the investigated parameters t1/2 alpha, t1/2 beta, Vd, ClT or ClR. Iohexol pharmacokinetics are in correspondence with previously reported data on intravascular contrast media

  13. Effect of the Cannabinoid Receptor-1 antagonist SR141716A on human adipocyte inflammatory profile and differentiation

    Directory of Open Access Journals (Sweden)

    Murumalla Ravi

    2011-11-01

    Full Text Available Abstract Background Obesity is characterized by inflammation, caused by increase in proinflammatory cytokines, a key factor for the development of insulin resistance. SR141716A, a cannabinoid receptor 1 (CB1 antagonist, shows significant improvement in clinical status of obese/diabetic patients. Therefore, we studied the effect of SR141716A on human adipocyte inflammatory profile and differentiation. Methods Adipocytes were obtained from liposuction. Stromal vascular cells were extracted and differentiated into adipocytes. Media and cells were collected for secretory (ELISA and expression analysis (qPCR. Triglyceride accumulation was observed using oil red-O staining. Cholesterol was assayed by a fluorometric method. 2-AG and anandamide were quantified using isotope dilution LC-MS. TLR-binding experiments have been conducted in HEK-Blue cells. Results In LPS-treated mature adipocytes, SR141716A was able to decrease the expression and secretion of TNF-a. This molecule has the same effect in LPS-induced IL-6 secretion, while IL-6 expression is not changed. Concerning MCP-1, the basal level is down-regulated by SR141716A, but not the LPS-induced level. This effect is not caused by a binding of the molecule to TLR4 (LPS receptor. Moreover, SR141716A restored adiponectin secretion to normal levels after LPS treatment. Lastly, no effect of SR141716A was detected on human pre-adipocyte differentiation, although the compound enhanced adiponectin gene expression, but not secretion, in differentiated pre-adipocytes. Conclusion We show for the first time that some clinical effects of SR141716A are probably directly related to its anti-inflammatory effect on mature adipocytes. This fact reinforces that adipose tissue is an important target in the development of tools to treat the metabolic syndrome.

  14. Identification and quantification of predominant metabolites of synthetic cannabinoid MAB-CHMINACA in an authentic human urine specimen.

    Science.gov (United States)

    Hasegawa, Koutaro; Minakata, Kayoko; Gonmori, Kunio; Nozawa, Hideki; Yamagishi, Itaru; Watanabe, Kanako; Suzuki, Osamu

    2018-02-01

    An autopsy case in which the cause of death was judged as drug poisoning by two synthetic cannabinoids, including MAB-CHMINACA, was investigated. Although unchanged MAB-CHMINACA could be detected from solid tissues, blood and stomach contents in the case, the compound could not be detected from a urine specimen. We obtained six kinds of reference standards of MAB-CHMINACA metabolites from a commercial source. The MAB-CHMINACA metabolites from the urine specimen of the abuser were extracted using a QuEChERS method including dispersive solid-phase extraction, and analyzed by liquid chromatography-tandem mass spectrometry with or without hydrolysis with β-glucuronidase. Among the six MAB-CHMINACA metabolites tested, two predominant metabolites could be identified and quantified in the urine specimen of the deceased. After hydrolysis with β-glucuronidase, an increase of the two metabolites was not observed. The metabolites detected were a 4-monohydroxycyclohexylmethyl metabolite M1 (N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-((4-hydroxycyclohexyl)methyl)-1H-indazole-3-carboxamide) and a dihydroxyl (4-hydroxycyclohexylmethyl and tert-butylhydroxyl) metabolite M11 (N-(1-amino-4-hydroxy-3,3-dimethyl-1-oxobutan-2-yl)-1-((4-hydroxycyclohexyl)methyl)-1H-indazole-3-carboxamide). Their concentrations were 2.17 ± 0.15 and 10.2 ± 0.3 ng/mL (n = 3, each) for M1 and M11, respectively. Although there is one previous in vitro study showing the estimation of metabolism of MAB-CHMINACA using human hepatocytes, this is the first report dealing with in vivo identification and quantification of MAB-CHMINACA metabolites in an authentic human urine specimen. Copyright © 2017 John Wiley & Sons, Ltd.

  15. Cannabinoids on the Brain

    Directory of Open Access Journals (Sweden)

    Andrew J. Irving

    2002-01-01

    Full Text Available Cannabis has a long history of consumption both for recreational and medicinal uses. 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: in the hippocampus they influence learning and memory; in the basal ganglia they modulate locomotor activity and reward pathways; in the hypothalamus they have a role in the control of appetite. 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.

  16. Cannabinoids and Pain

    Directory of Open Access Journals (Sweden)

    J Michael Walker

    2001-01-01

    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 1980s 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. New modes of delivery and/or new compounds lacking the psychotropic properties of the standard cannabinoid ligands offer promise for cannabinoid therapeutics for pain.

  17. Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data: What have we learned?

    OpenAIRE

    Deng, Rong; Iyer, Suhasini; Theil, Frank-Peter; Mortensen, Deborah L; Fielder, Paul J; Prabhu, Saileta

    2011-01-01

    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...

  18. Cannabinoid-Induced Hyperemesis: A Conundrum—From Clinical Recognition to Basic Science Mechanisms

    Directory of Open Access Journals (Sweden)

    Nissar A. Darmani

    2010-07-01

    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. These encompass: (1 pharmacokinetic factors such as long half-life, chronic exposure, lipid solubility, individual variation in metabolism/excretion leading to accumulation of emetogenic cannabinoid metabolites, and/or cannabinoid withdrawal; and (2 pharmacodynamic factors including switching of the efficacy of Δ9-THC from partial agonist to antagonist, differential interaction of Δ9-THC with Gs and Gi signal transduction proteins, CB1 receptor desensitization or downregulation, alterations in tissue concentrations of endocannabinoid agonists/inverse agonists, Δ9-THC-induced mobilization of emetogenic metabolites of the arachidonic acid cascade, brainstem versus enteric actions of Δ9-THC, and/or hypothermic versus hyperthermic actions of Δ9-THC. 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.

  19. Clinical Significance of Cannabinoid Receptors CB1 and CB2 Expression in Human Malignant and Benign Thyroid Lesions

    Directory of Open Access Journals (Sweden)

    Eleftheria Lakiotaki

    2015-01-01

    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. CB1 and CB2 proteins’ expression was assessed immunohistochemically on paraffin-embedded thyroid tissues obtained from 87 patients with benign (n=43 and malignant (n=44 lesions and was statistically analyzed with clinicopathological parameters, follicular cells’ proliferative capacity, and risk of recurrence rate estimated according to the American Thyroid Association (ATA staging system. Enhanced CB1 and CB2 expression was significantly more frequently observed in malignant compared to benign thyroid lesions (p=0.0010 and p=0.0005, resp.. Enhanced CB1 and CB2 expression was also significantly more frequently observed in papillary carcinomas compared to hyperplastic nodules (p=0.0097 and p=0.0110, resp.. In malignant thyroid lesions, elevated CB2 expression was significantly associated with the presence of lymph node metastases (p=0.0301. Enhanced CB2 expression was also more frequently observed in malignant thyroid cases with presence of capsular (p=0.1165, lymphatic (p=0.1989, and vascular invasion (p=0.0555, as well as in those with increased risk of recurrence rate (p=0.1165, at a nonsignificant level though, whereas CB1 expression was not associated with any of the clinicopathological parameters examined. 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.

  20. Kinetic analysis of the cannabinoid-1 receptor PET tracer [18F]MK-9470 in human brain

    International Nuclear Information System (INIS)

    Sanabria-Bohorquez, Sandra Marina; Hamill, Terence G.; Burns, H.D.; Goffin, Karolien; Laere, Koen van; Lepeleire, Inge de; Bormans, Guy

    2010-01-01

    Quantitative imaging of the type 1 cannabinoid receptor (CB1R) opens perspectives for many neurological and psychiatric disorders. We characterized the kinetics and reproducibility of the CB1R tracer [ 18 F]MK-9470 in human brain. [ 18 F]MK-9470 data were analysed using reversible models and the distribution volume V T and V ND k 3 (V ND k 3 = K 1 k 2 ) were estimated. 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. Both V T and V ND k 3 were estimated satisfactorily and their test-retest variability was between 10% and 30%. Irreversible methods adequately described brain kinetics and FUR values were equivalent to K i . The linear relationship between K i and V ND k 3 demonstrated that K i or FUR and thus the simple measure of tracer brain uptake provide CB1R availability information. The test-retest variability of K i and FUR was 18 F]MK-9470 specific binding can be accurately determined using FUR values requiring a short scan 90 to 120 min after tracer administration. Our results suggest that [ 18 F]MK-9470 plasma kinetics can be assessed using a few venous samples. (orig.)

  1. Nontargeted SWATH acquisition for identifying 47 synthetic cannabinoid metabolites in human urine by liquid chromatography-high-resolution tandem mass spectrometry.

    Science.gov (United States)

    Scheidweiler, Karl B; Jarvis, Michael J Y; Huestis, Marilyn A

    2015-01-01

    Clandestine laboratories constantly produce new synthetic cannabinoids to circumvent legislative scheduling efforts, challenging and complicating toxicological analysis. Sundstrom et al. (Anal Bioanal Chem 405(26):8463-8474, [9]) and Kronstrand et al. (Anal Bioanal Chem 406(15):3599-3609, [10]) published nontargeted liquid chromatography, high-resolution, quadrupole/time-of-flight mass spectrometric (LC-QTOF) assays with validated detection of 18 and 38 urinary synthetic cannabinoid metabolites, respectively. We developed and validated a LC-QTOF urine method for simultaneously identifying the most current 47 synthetic cannabinoid metabolites from 21 synthetic cannabinoid families (5-fluoro AB-PINACA, 5-fluoro-AKB48, 5-fluoro PB-22, AB-PINACA, ADB-PINACA, AKB48, AM2201, JWH-018, JWH-019, JWH-073, JWH-081, JWH-122, JWH-200, JWH-210, JWH-250, JWH-398, MAM2201, PB-22, RCS-4, UR-144, and XLR11). β-Glucuronidase-hydrolyzed urine was extracted with 1-mL Biotage SLE+ columns. Specimens were reconstituted in 150-μL mobile phase consisting of 80% A (0.1% formic acid in water) and 20% B (0.1% formic acid in acetonitrile). Fifty microliters was injected, and SWATH™ MS data were acquired in positive electrospray mode. The LC-QTOF instrument consisted of a Shimadzu UFLCxr system and an ABSciex 5600+ TripleTOF® mass spectrometer. Gradient chromatographic separation was achieved with a Restek Ultra Biphenyl column with a 0.5-mL/min flow rate and an overall run time of 15 min. Identification criteria included molecular ion mass error, isotopic profiles, retention time, and library fit criteria. Limits of detection were 0.25-5 μg/L (N = 10 unique fortified urine samples), except for two PB-22 metabolites with limits of 10 and 20 μg/L. Extraction efficiencies and matrix effects (N = 10) were 55-104 and -65-107%, respectively. We present a highly useful novel LC-QTOF method for simultaneously confirming 47 synthetic cannabinoid metabolites in human urine.

  2. Pharmacokinetic Profile of Oral Cannabis in Humans: Blood and Oral Fluid Disposition and Relation to Pharmacodynamic Outcomes.

    Science.gov (United States)

    Vandrey, Ryan; Herrmann, Evan S; Mitchell, John M; Bigelow, George E; Flegel, Ronald; LoDico, Charles; Cone, Edward J

    2017-03-01

    Most research on cannabis pharmacokinetics has evaluated inhaled cannabis, but oral ("edible") preparations comprise an increasing segment of the cannabis market. To assess oral cannabis pharmacokinetics and pharmacodynamics, healthy adults (N = 6 per dose) were administered cannabis brownies containing 10, 25 or 50 mg 9-tetrahydrocannabinol (THC). 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, 3.5 and 3.3 ng/mL for the 10, 25 and 50 mg THC doses, respectively. The mean maximum concentration (Cmax) and mean time to maximum concentration (Tmax) of 11-OH-THC in whole blood were similar to THC. Cmax blood concentrations of THCCOOH were generally higher than THC and had longer Tmax values. 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. Mean Cmax oral fluid concentrations of THCCOOH were lower than THC, erratic over time and mean Tmax occurred at longer times than THC. The window of THC detection ranged from 0 to 22 h for whole blood (limit of quantitation (LOQ) = 0.5 ng/mL) and 1.9 to 22 h for oral fluid (LOQ = 1.0 ng/mL). Subjective drug and cognitive performance effects were generally dose dependent, peaked at 1.5-3 h post-administration, and lasted 6-8 h. 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

  3. Mixed-effects modelling of the interspecies pharmacokinetic scaling of pegylated human erythropoietin.

    Science.gov (United States)

    Jolling, Koen; Perez Ruixo, Juan Jose; Hemeryck, Alex; Vermeulen, An; Greway, Tony

    2005-04-01

    The aim of this study was to develop a population pharmacokinetic model for interspecies allometric scaling of pegylated r-HuEPO (PEG-EPO) pharmacokinetics to man. A total of 927 serum concentrations from 193 rats, 6 rabbits, 34 monkeys, and 9 dogs obtained after a single dose of PEG-EPO, administered by the i.v. (dose range: 12.5-550 microg/kg) and s.c. (dose range: 12.5-500 microg/kg) routes, were pooled in this analysis. 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 4.08WT1.030xBW-0.345 ml/h. In females, the CL was 90.7% of the CL in males. The volumes of the central (Vc) and the peripheral (Vp) compartment were characterized as 57.8WT0.959 ml, and 48.1WT1.150 ml, respectively. Intercompartmental flow was estimated at 2.32WT0.930 ml/h. Absorption rate constant (Ka) was estimated at 0.0538WT-0.149. The absolute s.c. bioavailability F was calculated at 52.5, 80.2, and 49.4% in rat, monkey, and dog, respectively. 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: CL: 26.2 ml/h; Vc: 3.6l; Q: 286 l/h; Vp: 6.9l, and Ka: 0.031 h-1. The population pharmacokinetic model developed was appropriate to describe the time course of PEG-EPO serum concentrations and their variability in different species. The model predicted pharmacokinetics of PEG-EPO in

  4. Application of Pharmacokinetics Modelling to Predict Human Exposure of a Cationic Liposomal Subunit Antigen Vaccine System

    Directory of Open Access Journals (Sweden)

    Raj K. S. Badhan

    2017-12-01

    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 (8:1 molar ratio combined with the Ag85B-ESAT-6 (H1 antigen were modelled using mouse in-vivo data. 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 (22.6 days compared to the associated antigen (2.62 days. 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 10-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:TDB: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.

  5. Metabolic profiles of pomalidomide in human plasma simulated with pharmacokinetic data in control and humanized-liver mice.

    Science.gov (United States)

    Shimizu, Makiko; Suemizu, Hiroshi; Mitsui, Marina; Shibata, Norio; Guengerich, F Peter; Yamazaki, Hiroshi

    2017-10-01

    1. Pomalidomide has been shown to be potentially teratogenic in thalidomide-sensitive animal species such as rabbits. Screening for thalidomide analogs devoid of teratogenicity/toxicity - attributable to metabolites formed by cytochrome P450 enzymes - but having immunomodulatory properties is a strategic pathway towards development of new anticancer drugs. 2. 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. Following oral administration of pomalidomide (100 mg/kg), plasma concentrations of 7-hydroxypomalidomide and 5-hydroxypomalidomide glucuronide were slightly higher in humanized-liver mice than in control mice. 3. 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. 4. 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.

  6. Kinetic analysis of the cannabinoid-1 receptor PET tracer [{sup 18}F]MK-9470 in human brain

    Energy Technology Data Exchange (ETDEWEB)

    Sanabria-Bohorquez, Sandra Marina; Hamill, Terence G.; Burns, H.D. [Merck Research Laboratories, Imaging, West Point, PA (United States); Goffin, Karolien; Laere, Koen van [University Hospital and K.U. Leuven, Division of Nuclear Medicine, Leuven (Belgium); Lepeleire, Inge de [Merck Research Laboratories, Brussels (Belgium); Bormans, Guy [K.U. Leuven, Laboratory of Radiopharmacy, Leuven (Belgium)

    2010-05-15

    Quantitative imaging of the type 1 cannabinoid receptor (CB1R) opens perspectives for many neurological and psychiatric disorders. We characterized the kinetics and reproducibility of the CB1R tracer [{sup 18}F]MK-9470 in human brain. [{sup 18}F]MK-9470 data were analysed using reversible models and the distribution volume V{sub T} and V{sub ND} k{sub 3} (V{sub ND} k{sub 3} = K{sub 1} k{sub 2}) were estimated. Tracer binding was also evaluated using irreversible kinetics and the irreversible uptake constant K{sub 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{sub 4} value was necessary to describe brain kinetics. Both V{sub T} and V{sub ND} k{sub 3} were estimated satisfactorily and their test-retest variability was between 10% and 30%. Irreversible methods adequately described brain kinetics and FUR values were equivalent to K{sub i}. The linear relationship between K{sub i} and V{sub ND} k{sub 3} demonstrated that K{sub i} or FUR and thus the simple measure of tracer brain uptake provide CB1R availability information. The test-retest variability of K{sub i} and FUR was <10% and estimates were independent of blood flow. Brain uptake can be used as a receptor availability index, albeit at the expense of potential bias due to between-subject differences in tracer plasma kinetics. [{sup 18}F]MK-9470 specific binding can be accurately determined using FUR values requiring a short scan 90 to 120 min after tracer administration. Our results suggest that [{sup 18}F]MK-9470 plasma kinetics can be assessed using a few venous samples. (orig.)

  7. Pharmacokinetic models relevant to toxicity and metabolism for uranium in humans and animals

    International Nuclear Information System (INIS)

    Wrenn, M.E.

    1989-01-01

    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. For a half-time of two days in the mammalian kidney, the maximum concentration in kidney is 75% of that predicted by a retention model such as that used by the ICRP following a single acute intake. 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. (author)

  8. Preclinical pharmacokinetics, interspecies scaling, and pharmacokinetics of a Phase I clinical trial of TTAC-0001, a fully human monoclonal antibody against vascular endothelial growth factor 2

    Directory of Open Access Journals (Sweden)

    Lee WS

    2018-03-01

    Full Text Available Weon Sup Lee,1 Sang Ryeol Shim,1 Seon Young Lee,1 Jin San Yoo,1 Sung Kweon Cho2 1PharmAbcine, Inc., Daejeon, Republic of Korea; 2Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea Background: VEGF is a highly selective mitogen that serves as the central regulator of tumor angiogenesis by mediating endothelial proliferation, permeability, and survival. Tanibirumab (TTAC-0001 is a fully human IgG1 monoclonal antibody derived from a fully human naïve single-chain variable fragment (ScFv phage library that was developed to inhibit the effects of VEGF in the treatment of solid tumors, especially those of the brain. Methods: In the present study, we conducted intravenous pharmacokinetic studies of TTAC-0001 in mice, rats, and cynomolgus monkeys. At the doses studied (3 mg/kg, 10 mg/kg, 30 mg/kg, TTAC-0001 exhibited dose proportionality in mice and monkeys. At a dose of ~10 mg/kg, the clearance of TTAC-0001 from serum was 0.017 mL/h in mice, 0.35 mL/h in rats, and 2.19 mL/h in cynomolgus monkeys, and the terminal half-life ranged from 20–30 h among the three species. Pharmacokinetic data in mice, rats, and cynomolgus monkeys were used to predict the pharmacokinetics of TTAC-0001 in humans using allometric scaling. The predicted serum clearance of TTAC-0001 in humans was 102.45 mL/h and the terminal half-life was 27.52 h. Results: The maximum life span-corrected clearance value was 72.92 mL/h. The observed clearance in humans was more similar to the predicted scaled clearance. Conclusion: We investigated the pharmacokinetics of TTAC-0001 in mice, rats, and cynomolgus monkeys after intravenous administration. At the doses studied, TTAC-0001 exhibited dose proportionality in mice and monkeys. The scaled pharmacokinetics of TTAC-0001 reported here was useful for designing first-in-human studies. Allometric scaling in the therapeutic antibody is feasible. Keywords: VEGF2, tanibirumab, pharmacokinetics

  9. Impact of cannabis, cannabinoids and endocannabinoids in the lungs

    Directory of Open Access Journals (Sweden)

    Caroline Turcotte

    2016-09-01

    Full Text Available Since the identification of cannabinoid receptors in the 1990s, 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.

  10. Time-dependent pharmacokinetics of dexamethasone and its efficacy in human breast cancer xenograft mice: a semi-mechanism-based pharmacokinetic/pharmacodynamic model.

    Science.gov (United States)

    Li, Jian; Chen, Rong; Yao, Qing-Yu; Liu, Sheng-Jun; Tian, Xiu-Yun; Hao, Chun-Yi; Lu, Wei; Zhou, Tian-Yan

    2018-03-01

    Dexamethasone (DEX) is the substrate of CYP3A. However, the activity of CYP3A could be induced by DEX when DEX was persistently administered, resulting in auto-induction and time-dependent pharmacokinetics (pharmacokinetics with time-dependent clearance) of DEX. In this study we investigated the pharmacokinetic profiles of DEX after single or multiple doses in human breast cancer xenograft nude mice and established a semi-mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for characterizing the time-dependent PK of DEX as well as its anti-cancer effect. The mice were orally given a single or multiple doses (8 mg/kg) of DEX, and the plasma concentrations of DEX were assessed using LC-MS/MS. 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. Moreover, a semi-mechanism-based PK/PD model was developed, in which the auto-induction effect of DEX on its metabolizing enzyme CYP3A was integrated and drug potency was described using an E max equation. The PK/PD model was further used to predict the drug efficacy when the auto-induction effect was or was not considered, which further revealed the necessity of adding the auto-induction effect into the final PK/PD model. This study established a semi-mechanism-based PK/PD model for characterizing the time-dependent pharmacokinetics of DEX and its anti-cancer effect in breast cancer xenograft mice. The model may serve as a reference for DEX dose adjustments or optimization in future preclinical or clinical studies.

  11. Multiple sclerosis following treatment with a cannabinoid receptor-1 antagonist

    NARCIS (Netherlands)

    van Oosten, B. W.; Killestein, J.; Mathus-Vliegen, E. M. H.; Polman, C. H.

    2004-01-01

    Laboratory research including animal models of human disease suggests that cannabinoids might have therapeutic potential in multiple sclerosis (MS). We have recently seen a 46-year-old woman who developed MS after starting treatment with a cannabinoid receptor antagonist for obesity. The occurrence

  12. 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

    International Nuclear Information System (INIS)

    Yamazaki, Hiroshi; Kunikane, Eriko; Nishiyama, Sayako; Murayama, Norie; Shimizu, Makiko; Sugiyama, Yuichi; Chiba, Koji; Ikeda, Toshihiko

    2015-01-01

    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. The data presented here illustrate how pharmacokinetic data in combination with a simple PBPK model can be used to assist evaluations of the pharmacological/toxicological potential of new drug substances and for estimating human radiation exposures from radio-labeled drugs when planning human studies. (author)

  13. A human life-stage physiologically based pharmacokinetic and pharmacodynamic model for chlorpyrifos: development and validation.

    Science.gov (United States)

    Smith, Jordan Ned; Hinderliter, Paul M; Timchalk, Charles; Bartels, Michael J; Poet, Torka S

    2014-08-01

    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. A life-stage physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed to predict disposition of chlorpyrifos and its metabolites, chlorpyrifos-oxon (the ultimate toxicant) and 3,5,6-trichloro-2-pyridinol (TCPy), as well as B-esterase inhibition by chlorpyrifos-oxon in humans. In this model, previously measured age-dependent metabolism of chlorpyrifos and chlorpyrifos-oxon were integrated into age-related descriptions of human anatomy and physiology. The life-stage PBPK/PD model was calibrated and tested against controlled adult human exposure studies. Simulations suggest age-dependent pharmacokinetics and response may exist. At oral doses ⩾0.6mg/kg of chlorpyrifos (100- to 1000-fold higher than environmental exposure levels), 6months old children are predicted to have higher levels of chlorpyrifos-oxon in blood and higher levels of red blood cell cholinesterase inhibition compared to adults from equivalent doses. 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. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. 6-[Fluorine-18]Fluorodopamine pharmacokinetics and dosimetry in humans

    International Nuclear Information System (INIS)

    Goldstein, D.S.; Coronado, L.; Kopin, I.J.

    1994-01-01

    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 (3.3 rem for a 4-mCi dose and 3.31-hr voiding interval) and the kidneys (2.9 rem for a 4-mCi dose) due to urinary excretion of radioactive metabolites of [ 18 F]-6F-DA. 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. 22 refs., 2 figs., 5 tabs

  15. Metabolism of the synthetic cannabinoids AMB-CHMICA and 5C-AKB48 in pooled human hepatocytes and rat hepatocytes analyzed by UHPLC-(IMS)-HR-MSE

    DEFF Research Database (Denmark)

    Mardal, Marie; Dalsgaard, Petur Weihe; Qi, Bing

    2018-01-01

    metabolites of the synthetic cannabinoids, AMB-CHMICA and 5C-AKB48, using an in silico-assisted workflow with analytical data acquired using ultra-high-performance liquid chromatography–(ion mobility spectroscopy)–high resolution–mass spectrometry in data-independent acquisition mode (UHPLC......-(IMS)-HR-MSE). The metabolites were identified after incubation with rat and pooled human hepatocytes using UHPLC-HR-MSE, followed by UHPLC-IMS-HR-MSE. Metabolites of AMB-CHMICA and 5C-AKB48 were predicted with Meteor (Lhasa Ltd) and imported to the UNIFI software (Waters). The predicted metabolites were assigned to analytical...... components supported by the UNIFI in silico fragmentation tool. The main metabolic pathway of AMB-CHMICA was O-demethylation and hydroxylation of the methylhexyl moiety. For 5C-AKB48, the main metabolic pathways were hydroxylation(s) of the adamantyl moiety and oxidative dechlorination with subsequent...

  16. Simultaneous LC-MS/MS determination of JWH-210, RCS-4, ∆(9)-tetrahydrocannabinol, and their main metabolites in pig and human serum, whole blood, and urine for comparing pharmacokinetic data.

    Science.gov (United States)

    Schaefer, Nadine; Kettner, Mattias; Laschke, Matthias W; Schlote, Julia; Peters, Benjamin; Bregel, Dietmar; Menger, Michael D; Maurer, Hans H; Ewald, Andreas H; Schmidt, Peter H

    2015-05-01

    A series of new synthetic cannabinoids (SC) has been consumed without any toxicological testing. For example, pharmacokinetic data have to be collected from forensic toxicological case work and/or animal studies. To develop a corresponding model for assessing such data, samples of controlled pig studies with two selected SC (JWH-210, RCS-4) and, as reference, ∆(9)-tetrahydrocannabinol (THC) should be analyzed as well as those of human cases. Therefore, a method for determination of JWH-210, RCS-4, THC, and their main metabolites in pig and human serum, whole blood, and urine samples is presented. 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 0.05 and 0.50 ng/mL in serum and whole blood and between 0.05 and 1.0 ng/mL in urine, the lower limits of quantification between 0.25 and 1.0 ng/mL in serum and 0.50 and 2.0 ng/mL in whole blood and urine, and the intra- and interday precision values lower than 15% and bias values within ±15%. The applicability was tested with samples taken from a pharmacokinetic pilot study with pigs following intravenous administration of a mixture of 200 μg/kg body mass dose each of JWH-210, RCS-4, and THC. The cross-validation data for human serum, whole blood, and urine showed that this approach should also be suitable for human specimens, e.g., of clinical or forensic cases.

  17. Metabolism of the synthetic cannabinoids AMB-CHMICA and 5C-AKB48 in pooled human hepatocytes and rat hepatocytes analyzed by UHPLC-(IMS)-HR-MSE.

    Science.gov (United States)

    Mardal, Marie; Dalsgaard, Petur Weihe; Qi, Bing; Mollerup, Christian Brinch; Annaert, Pieter; Linnet, Kristian

    2018-04-15

    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 aims of this study were to identify the main metabolites of the synthetic cannabinoids, AMB-CHMICA and 5C-AKB48, using an in silico-assisted workflow with analytical data acquired using ultra-high-performance liquid chromatography-(ion mobility spectroscopy)-high resolution-mass spectrometry in data-independent acquisition mode (UHPLC-(IMS)-HR-MS E ). The metabolites were identified after incubation with rat and pooled human hepatocytes using UHPLC-HR-MS E , followed by UHPLC-IMS-HR-MS E . Metabolites of AMB-CHMICA and 5C-AKB48 were predicted with Meteor (Lhasa Ltd) and imported to the UNIFI software (Waters). The predicted metabolites were assigned to analytical components supported by the UNIFI in silico fragmentation tool. The main metabolic pathway of AMB-CHMICA was O-demethylation and hydroxylation of the methylhexyl moiety. For 5C-AKB48, the main metabolic pathways were hydroxylation(s) of the adamantyl moiety and oxidative dechlorination with subsequent oxidation to the ω-COOH. 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. Oxidative dechlorination of ω-chloroalkanes in humans has not been previously reported in the literature. 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. Copyright © 2018 Elsevier B.V. All

  18. Chimeric mice with humanized liver: Application in drug metabolism and pharmacokinetics studies for drug discovery.

    Science.gov (United States)

    Naritomi, Yoichi; Sanoh, Seigo; Ohta, Shigeru

    2018-02-01

    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). Various methods have been used for such predictions, including in vitro metabolic studies using human biological samples, such as hepatic microsomes and hepatocytes, and in vivo studies using experimental animals. However, prediction studies using these methods are often inconclusive due to discrepancies between in vitro and in vivo results, and interspecies differences in drug metabolism. 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. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  19. UNCERTAINTIES IN TRICHLOROETHYLENE PHARMACOKINETIC MODELS

    Science.gov (United States)

    Understanding the pharmacokinetics of a chemical¯its absorption, distribution, metabolism, and excretion in humans and laboratory animals ¯ is critical to the assessment of its human health risks. For trichloroethylene (TCE), numerous physiologically-based pharmacokinetic (PBPK)...

  20. Prediction of a Therapeutic Dose for Buagafuran, a Potent Anxiolytic Agent by Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling Starting from Pharmacokinetics in Rats and Human

    Directory of Open Access Journals (Sweden)

    Fen Yang

    2017-10-01

    Full Text Available Physiologically based pharmacokinetic (PBPK/pharmacodynamic (PD models can contribute to animal-to-human extrapolation and therapeutic dose predictions. 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.i.d. in human was estimated based on the human brain concentration predicted by a PBPK/PD modeling. The software GastroPlusTM was used to build the PBPK/PD model for buagafuran in rat which related the brain tissue concentrations of buagafuran and the times of animals entering the open arms in the pharmacological model of elevated plus-maze. 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.

  1. Determination of cannabinoids in hemp nut products in Taiwan by HPLC-MS/MS coupled with chemometric analysis: quality evaluation and a pilot human study.

    Science.gov (United States)

    Chang, Chih-Wei; Tung, Chun-Wei; Tsai, Chin-Chuan; Wu, Yu-Tse; Hsu, Mei-Chich

    2017-06-01

    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.e., Δ 9 -tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol) content of the products and the concentration of urinary 11-nor-9-carboxy-THC. 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 1.5 µg/g of THC was conducted to examine the urinary 11-nor-9-carboxy-THC concentration. Through optimization of 3 2 full factorial design, using 60% isopropanol as the extraction solvent exhibited the highest yield of cannabinoids and was applied as the optimal condition in further analysis. The results of HCA and PCA on quality evaluation were in good agreement; however, the tested products possessed distinct CBD-to-THC ratios which ranged widely from 0.1:1 to 46.8:1. Particularly, the products with CBD-to-THC ratios higher than 1:1 were the majority in Taiwan. Our data suggested that all the tested hemp nut products met the Taiwan restriction criterion of 10 µg/g of THC. We propose a usual consumption amount of hemp nut products in Taiwan would unlikely to violate the cut-off point of 15 ng/mL of urinary 11-nor-9-carboxy-THC. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  2. Determination of flurbiprofen in human plasma by gas chromatography with mass spectrometry and its pharmacokinetics.

    Science.gov (United States)

    Yilmaz, Bilal; Sahin, Huseyin; Akba, Vedat; Erdem, Ali Fuat

    2014-01-01

    This paper describes a GCIMS method for the determination of flurbiprofen in human plasma. 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 0.10 and 5.0 microg/mL. Intraday and interday precision values for flurbiprofen in plasma were less than 5.49%, and accuracy (relative error) was better than 5.33%. The extraction recoveries of flurbiprofen from human plasma were between 93.6 and 98.6%. The LOD and LOQ of flurbiprofen were 0.03 and 0.10 microg/mL, respectively. This assay was applied to determine the pharmacokinetic parameters of flurbiprofen in healthy Turkish volunteers who had been given 100 mg of flurbiprofen.

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

    Science.gov (United States)

    Lin, Zhoumeng; Li, Mengjie; Gehring, Ronette; Riviere, Jim E

    2015-01-01

    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 was calibrated with plasma pharmacokinetic data in beagle dogs following single intravenous (5 mg/kg), oral (100 mg/kg), and intramuscular (20 mg/kg) administrations. 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 (7.14 mg/kg) and oral exposures (6.67 mg/kg). The dog model was applied to predict 24-h OTC area-under-the-curve after three therapeutic treatments. Results were 27.75, 51.76, and 64.17 μg/mL*h in the plasma, and 120.93, 225.64, and 279.67 μg/mL*h in the kidney for oral (100 mg/kg), intravenous (10 mg/kg), and intramuscular (20 mg/kg) administrations, respectively. 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. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:233-243, 2015. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  4. PHARMACOLOGY OF CANNABINOIDS

    Directory of Open Access Journals (Sweden)

    Ilonka Ferjan

    2015-06-01

    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. g. severe central nervous system depression, are more pronounced in children than in adults. 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."

  5. Pharmacokinetic models relevant to toxicity and metabolism for uranium in humans and animals

    International Nuclear Information System (INIS)

    Wrenn, M.E.; Lipsztein, J.; Bertelli, L.

    1988-01-01

    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. For example, the cumulative urinary excretion at 24 hours post injection of soluble uranium in man is about 70%, the absorbed fraction for soluble uranium ingested by man in drinking water during normal dietary conditions is about 1%, and the half time in the mammalian kidney is several days. 17 refs., 8 figs

  6. A Qualitative Review on the Pharmacokinetics of Antibiotics in Saliva: Implications on Clinical Pharmacokinetic Monitoring in Humans.

    Science.gov (United States)

    Kiang, Tony K L; Ensom, Mary H H

    2016-03-01

    We conducted a systematic search to describe the current state of knowledge regarding the utility of saliva for clinical pharmacokinetic monitoring (CPM) of antibiotics. Although the majority of identified studies lacked sufficient pharmacokinetic data needed to assign an appropriate suitability classification, most aminoglycosides, fluoroquinolones, macrolides, penicillins/cephalosporins, and tetracyclines are likely not suitable for CPM in saliva. 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.g., salivary flow, pH) that could potentially have some impact on drug distribution into saliva. 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.

  7. A Human Life-Stage Physiologically Based Pharmacokinetic and Pharmacodynamic Model for Chlorpyrifos: Development and Validation

    Energy Technology Data Exchange (ETDEWEB)

    Smith, Jordan N.; Hinderliter, Paul M.; Timchalk, Charles; Bartels, M. J.; Poet, Torka S.

    2014-08-01

    Sensitivity to chemicals in animals and humans are known to vary with age. Age-related changes in sensitivity to chlorpyrifos have been reported in animal models. A life-stage physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed to computationally predict disposition of CPF and its metabolites, chlorpyrifos-oxon (the ultimate toxicant) and 3,5,6-trichloro-2-pyridinol (TCPy), as well as B-esterase inhibition by chlorpyrifos-oxon in humans. 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. The life-stage PBPK/PD model was calibrated and tested against controlled adult human exposure studies. Model simulations suggest age-dependent pharmacokinetics and response may exist. At oral doses ≥ 0.55 mg/kg of chlorpyrifos (significantly higher than environmental exposure levels), 6 mo old children are predicted to have higher levels of chlorpyrifos-oxon in blood and higher levels of red blood cell cholinesterase inhibition compared to adults from equivalent oral doses of chlorpyrifos. 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.

  8. Comparison of predictability for human pharmacokinetics parameters among monkeys, rats, and chimeric mice with humanised liver.

    Science.gov (United States)

    Miyamoto, Maki; Iwasaki, Shinji; Chisaki, Ikumi; Nakagawa, Sayaka; Amano, Nobuyuki; Hirabayashi, Hideki

    2017-12-01

    1. 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. 2. 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. 3. Predicted CL t values from PXB mice exhibited the highest predictability: 25 for PXB mice, 21 for monkeys and 14 for rats were predicted within a three-fold range of actual values among 30 compounds. 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. PXB mice indicated a higher predictability for CL t and Vd ss values than the other animal models. 4. These results demonstrate the utility of PXB mice in predicting human PK parameters.

  9. Development of a Human Physiologically Based Pharmacokinetic (PBPK Toolkit for Environmental Pollutants

    Directory of Open Access Journals (Sweden)

    Patricia Ruiz

    2011-10-01

    Full Text Available Physiologically Based Pharmacokinetic (PBPK models can be used to determine the internal dose and strengthen exposure assessment. Many PBPK models are available, but they are not easily accessible for field use. The Agency for Toxic Substances and Disease Registry (ATSDR has conducted translational research to develop a human PBPK model toolkit by recoding published PBPK models. This toolkit, when fully developed, will provide a platform that consists of a series of priority PBPK models of environmental pollutants. Presented here is work on recoded PBPK models for volatile organic compounds (VOCs and metals. 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.

  10. Development of a simple chromatographic method for the determination of piracetam in human plasma and its pharmacokinetic evaluation.

    Science.gov (United States)

    Barkat, K; Ahmad, M; Minhas, M U; Malik, M Z; Sohail, M

    2014-07-01

    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 800 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 800 mg piracetam tablets. Various pharmacokinetic parameters were determined from plasma for piracetam and found to be in good agreement with previous reported values. The data was analyzed by using Kinetica® version 4.4 according to non-compartment model of pharmacokinetic analysis and after comparison with previous studies, no significant differences were found in present study of tested product. The major pharmacokinetic parameters for piracetam were as follows: t1/2 was (4.40 ± 0.179) h; Tmax value was (2.33 ± 0.105) h; Cmax was (14.53 ± 0.282) µg/mL; the AUC(0-∞) was (59.19 ± 4.402) µg · h/mL. AUMC(0-∞) was (367.23 ± 38.96) µg. (h)(2)/mL; Ke was (0.16 ± 0.006) h; MRT was (5.80 ± 0.227) h; Vd was (96.36 ± 8.917 L). 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. © Georg Thieme Verlag KG Stuttgart · New York.

  11. Effect of Resveratrol Treatment on the Pharmacokinetics of Diclofenac in Healthy Human Volunteers.

    Science.gov (United States)

    Bedada, Satish Kumar; Yellu, Narsimha Reddy; Neerati, Prasad

    2016-03-01

    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 500 mg was administered daily for 10 days during treatment phase. A single dose of DIC 100 mg was administered during control and after treatment phases under fasting conditions. The blood samples were collected after DIC dosing and analyzed by HPLC. Treatment with RSV significantly enhanced maximum plasma concentration (Cmax) (1.73 to 2.91 µg/mL), area under the curve (AUC) (5.05 to 9.95 g h/mL), half life (T1/2) (1.12 to 1.76 h) and significantly decreased elimination rate constant (Kel ) (0.71 to 0.41 h(-1)), apparent oral clearance (CL/F) (14.58 to 6.48 L/h) of DIC as compared to control. The geometric mean ratios for Cmax, AUC, T1/2, Kel and CL/F of DIC were 1.75, 2.12, 1.65, 0.61 and 0.47, respectively were outside the limits of 0.8-1.25, which indicates clinically significant interaction between DIC and RSV. The results suggest that the altered pharmacokinetics of DIC might be attributed to RSV mediated inhibition of CYP2C9 enzyme. Therefore, combination therapy of DIC along with RSV may represent a novel approach to reduce dosage and results in reduced gastrointestinal side effects of DIC. Copyright © 2015 John Wiley & Sons, Ltd.

  12. The pharmacokinetics and metabolism of lumiracoxib in chimeric humanized and murinized FRG mice.

    Science.gov (United States)

    Dickie, A P; Wilson, C E; Schreiter, K; Wehr, R; Wilson, E M; Bial, J; Scheer, N; Wilson, I D; Riley, R J

    2017-07-01

    The pharmacokinetics and metabolism of lumiracoxib were studied, after administration of single 10mg/kg oral doses to chimeric liver-humanized and murinized FRG mice. In the chimeric humanized mice, lumiracoxib reached peak observed concentrations in the blood of 1.10±0.08μg/mL at 0.25-0.5h post-dose with an AUC inf of 1.74±0.52μgh/mL and an effective half-life for the drug of 1.42±0.72h (n=3). In the case of the murinized animals peak observed concentrations in the blood were determined as 1.15±0.08μg/mL at 0.25h post-dose with an AUC inf of 1.94±0.22μgh/mL and an effective half-life of 1.28±0.02h (n=3). 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.g., a higher proportion of the dose detected in the form of acyl glucuronide metabolites and much reduced amounts of taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57bl/6J mice and humans, revealed a greater though not complete match between chimeric humanized mice and humans, such that the liver-humanized FRG model may represent a useful approach to assessing the biotransformation of such compounds in humans. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers

    OpenAIRE

    Hirvonen, J; Goodwin, RS; Li, C-T; Terry, GE; Zoghbi, SS; Morse, C; Pike, VW; Volkow, ND; Huestis, MA; Innis, RB

    2011-01-01

    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...

  14. Biodistribution and dosimetry in humans of two inverse agonists to image cannabinoid CB1 receptors using positron emission tomography

    International Nuclear Information System (INIS)

    Terry, Garth E.; Hirvonen, Jussi; Liow, Jeih-San; Seneca, Nicholas; Morse, Cheryl L.; Pike, Victor W.; Innis, Robert B.; Tauscher, Johannes T.; Schaus, John M.; Phebus, Lee; Felder, Christian C.; Halldin, Christer

    2010-01-01

    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. We recently reported brain imaging of CB 1 receptors with two PET radioligands: 11 C-MePPEP and 18 F-FMPEP-d 2 . Here we describe the biodistribution and dosimetry estimates for these two radioligands. Seven healthy subjects (four men and three women) underwent whole-body PET scans for 120 min after injection with 11 C-MePPEP. Another seven healthy subjects (two men and five women) underwent whole-body PET scans for 300 min after injection with 18 F-FMPEP-d 2 . 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 . The effective doses of 11 C-MePPEP and 18 F-FMPEP-d 2 are 4.6 and 19.7 μSv/MBq, respectively. 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. After injection of 11 C-MePPEP, radioactivity apparently underwent hepatobiliary excretion only, while radioactivity from 18 F-FMPEP-d 2 showed both hepatobiliary and urinary excretion. 11 C-MePPEP and 18 F-FMPEP-d 2 yield an effective dose similar to other PET radioligands labeled with either 11 C or 18 F. 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. (orig.)

  15. Recombinant human tripeptidyl peptidase-1 infusion to the monkey CNS: Safety, pharmacokinetics, and distribution

    Energy Technology Data Exchange (ETDEWEB)

    Vuillemenot, Brian R., E-mail: bvuillemenot@bmrn.com [BioMarin Pharmaceutical Inc., Novato, CA (United States); Kennedy, Derek [BioMarin Pharmaceutical Inc., Novato, CA (United States); Reed, Randall P.; Boyd, Robert B. [Northern Biomedical Research, Inc., Muskegon, MI (United States); Butt, Mark T. [Tox Path Specialists, LLC, Hagerstown, MD (United States); Musson, Donald G.; Keve, Steve; Cahayag, Rhea; Tsuruda, Laurie S.; O' Neill, Charles A. [BioMarin Pharmaceutical Inc., Novato, CA (United States)

    2014-05-15

    CLN2 disease is caused by deficiency in tripeptidyl peptidase-1 (TPP1), leading to neurodegeneration and death. The safety, pharmacokinetics (PK), and CNS distribution of recombinant human TPP1 (rhTPP1) were characterized following a single intracerebroventricular (ICV) or intrathecal-lumbar (IT-L) infusion to cynomolgus monkeys. Animals received 0, 5, 14, or 20 mg rhTPP1, ICV, or 14 mg IT-L, in artificial cerebrospinal fluid (aCSF) vehicle. Plasma and CSF were collected for PK analysis. Necropsies occurred at 3, 7, and 14 days post-infusion. CNS tissues were sampled for rhTPP1 distribution. TPP1 infusion was well tolerated and without effect on clinical observations or ECG. A mild increase in CSF white blood cells (WBCs) was detected transiently after ICV infusion. Isolated histological changes related to catheter placement and infusion were observed in ICV treated animals, including vehicle controls. The CSF and plasma exposure profiles were equivalent between animals that received an ICV or IT-L infusion. TPP1 levels peaked at the end of infusion, at which point the enzyme was present in plasma at 0.3% to 0.5% of CSF levels. TPP1 was detected in brain tissues with half-lives of 3–14 days. CNS distribution between ICV and IT-L administration was similar, although ICV resulted in distribution to deep brain structures including the thalamus, midbrain, and striatum. Direct CNS infusion of rhTPP1 was well tolerated with no drug related safety findings. The favorable nonclinical profile of ICV rhTPP1 supports the treatment of CLN2 by direct administration to the CNS. - Highlights: • TPP1 enzyme replacement therapy to the CNS is in development for CLN2 disease. • Toxicology, pharmacokinetics, and CNS distribution were assessed in monkeys. • TPP1 infusion directly to the brain did not result in any safety concerns. • A positive pharmacokinetic and distribution profile resulted from TPP1 infusion. • This study demonstrates the feasibility of ICV administered

  16. Recombinant human tripeptidyl peptidase-1 infusion to the monkey CNS: Safety, pharmacokinetics, and distribution

    International Nuclear Information System (INIS)

    Vuillemenot, Brian R.; Kennedy, Derek; Reed, Randall P.; Boyd, Robert B.; Butt, Mark T.; Musson, Donald G.; Keve, Steve; Cahayag, Rhea; Tsuruda, Laurie S.; O'Neill, Charles A.

    2014-01-01

    CLN2 disease is caused by deficiency in tripeptidyl peptidase-1 (TPP1), leading to neurodegeneration and death. The safety, pharmacokinetics (PK), and CNS distribution of recombinant human TPP1 (rhTPP1) were characterized following a single intracerebroventricular (ICV) or intrathecal-lumbar (IT-L) infusion to cynomolgus monkeys. Animals received 0, 5, 14, or 20 mg rhTPP1, ICV, or 14 mg IT-L, in artificial cerebrospinal fluid (aCSF) vehicle. Plasma and CSF were collected for PK analysis. Necropsies occurred at 3, 7, and 14 days post-infusion. CNS tissues were sampled for rhTPP1 distribution. TPP1 infusion was well tolerated and without effect on clinical observations or ECG. A mild increase in CSF white blood cells (WBCs) was detected transiently after ICV infusion. Isolated histological changes related to catheter placement and infusion were observed in ICV treated animals, including vehicle controls. The CSF and plasma exposure profiles were equivalent between animals that received an ICV or IT-L infusion. TPP1 levels peaked at the end of infusion, at which point the enzyme was present in plasma at 0.3% to 0.5% of CSF levels. TPP1 was detected in brain tissues with half-lives of 3–14 days. CNS distribution between ICV and IT-L administration was similar, although ICV resulted in distribution to deep brain structures including the thalamus, midbrain, and striatum. Direct CNS infusion of rhTPP1 was well tolerated with no drug related safety findings. The favorable nonclinical profile of ICV rhTPP1 supports the treatment of CLN2 by direct administration to the CNS. - Highlights: • TPP1 enzyme replacement therapy to the CNS is in development for CLN2 disease. • Toxicology, pharmacokinetics, and CNS distribution were assessed in monkeys. • TPP1 infusion directly to the brain did not result in any safety concerns. • A positive pharmacokinetic and distribution profile resulted from TPP1 infusion. • This study demonstrates the feasibility of ICV administered

  17. Plasma pharmacokinetics and synovial concentrations of S-flurbiprofen plaster in humans.

    Science.gov (United States)

    Yataba, Ikuko; Otsuka, Noboru; Matsushita, Isao; Kamezawa, Miho; Yamada, Ichimaro; Sasaki, Sigeru; Uebaba, Kazuo; Matsumoto, Hideo; Hoshino, Yuichi

    2016-01-01

    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. Study 1: SFPP tape-type patch (2-60 mg) was applied to the lower back for 24 h in healthy adult volunteers. S-flurbiprofen (SFP) plasma concentration was measured over time to examine SFP pharmacokinetics. Study 2: SFPP (20 mg) was applied for 12 h to the affected knee of osteoarthritis (OA) patients who were scheduled for total knee arthroplasty. 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. Study 1: The plasma concentration of SFP was sustained during 24-h topical application of the SFPP, showing a high percutaneous absorption ratio of 51.4-72.2 %. Cmax and AUC0-∞ were dose-proportional. Study 2: After application of the SFPP for 12 h, SFP concentrations in the synovial tissue and synovial fluid were 14.8-fold (p = 0.002) and 32.7-fold (p < 0.001) higher, respectively, than those achieved by the FP patch. Sustained plasma concentration of SFP and high percutaneous absorption ratio was observed after 24-h topical application of the SFPP. Compared to the FP patch, the SFPP showed superior percutaneous absorption and greater tissue penetration of SFP into the synovial tissue. Greater tissue penetration of the SFPP seemed to be primarily due to its formulation. Thus, SFPP is expected to show higher efficacy for the treatment of knee OA.

  18. Pharmacokinetics and tissue distribution of recombinant human tumor necrosis factor-alpha in mice

    International Nuclear Information System (INIS)

    Ferraiolo, B.L.; Moore, J.A.; Crase, D.; Gribling, P.; Wilking, H.; Baughman, R.A.

    1988-01-01

    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. After intravenous doses of 165 to 320 micrograms/kg, the clearance was 2.9-3.6 ml/hr, the initial volume of distribution was 1.4-1.6 ml (70-80 ml/kg), and the half-life was 18.5-19.2 min. Intramuscular administration of 320 micrograms/kg resulted in a peak serum concentration of 112 ng/ml. The time of the peak concentration was 1 hr, and the bioavailability of the intramuscular dose was 12%. The data suggest that the disposition of this protein may be biexponential. If this is the case, the terminal phase would appear to account for less than 1% of the total AUC. Since serum concentrations in the terminal phase are at the sensitivity limit of the assay, a single half-life is reported. 125I-Labeled and metabolically labeled 3H-rHuTNF were used to examine tissue distribution. After intravenous 125I-rHuTNF administration, the rank order of accumulation of the 125I-radiolabel in the major organs (per cent dose per organ over 1440 min) was: liver greater than kidney greater than lung greater than heart greater than spleen. This rank order of accumulation was confirmed by intravenous 3H-rHuTNF administration

  19. Strategies to distinguish new synthetic cannabinoid FUBIMINA (BIM-2201) intake from its isomer THJ-2201: metabolism of FUBIMINA in human hepatocytes.

    Science.gov (United States)

    Diao, Xingxing; Scheidweiler, Karl B; Wohlfarth, Ariane; Zhu, Mingshe; Pang, Shaokun; Huestis, Marilyn A

    Since 2013, a new drugs-of-abuse trend attempts to bypass drug legislation by marketing isomers of scheduled synthetic cannabinoids (SCs), e.g., FUBIMINA (BIM-2201) and THJ-2201. 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. Here, we investigated isomers FUBIMINA and THJ-2201 and propose strategies to distinguish their consumption. THJ-2201 was scheduled in the US, Japan, and Europe; however, FUBIMINA is easily available on the Internet. We previously investigated THJ-2201 metabolism in human hepatocytes, but human FUBIMINA metabolism is unknown. We aim to characterize FUBIMINA metabolism in human hepatocytes, recommend optimal metabolites to confirm its consumption, and propose strategies to distinguish between intakes of FUBIMINA and THJ-2201. FUBIMINA (10 μM) was incubated in human hepatocytes for 3 h, and metabolites were characterized with high-resolution mass spectrometry (HR-MS). We identified 35 metabolites generated by oxidative defluorination, further carboxylation, hydroxylation, dihydrodiol formation, glucuronidation, and their combinations. We recommend 5'-OH-BIM-018 (M34), BIM-018 pentanoic acid (M33), and BIM-018 pentanoic acid dihydrodiol (M7) as FUBIMINA specific metabolites. THJ-2201 produced specific metabolite markers 5'-OH-THJ-018 (F26), THJ-018 pentanoic acid (F25), and hydroxylated THJ-2201 (F13). 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-2201. Our HR-MS approach should be applicable for differentiating future isomeric SCs, which is especially important when different isomers have different legal status.

  20. What Are Synthetic Cannabinoids?

    Science.gov (United States)

    ... years, synthetic cannabinoid mixtures have been easy to buy in drug paraphernalia shops, novelty stores, gas stations, and over ... abuse, authorities have made it illegal to sell, buy, or possess some of ... use is that standard drug tests cannot easily detect many of the chemicals ...

  1. Anandamide induces matrix metalloproteinase-2 production through cannabinoid-1 receptor and transient receptor potential vanilloid-1 in human dental pulp cells in culture.

    Science.gov (United States)

    Miyashita, Keiko; Oyama, Tohru; Sakuta, Tetsuya; Tokuda, Masayuki; Torii, Mitsuo

    2012-06-01

    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. The aim of this study was to investigate the effect of AEA on matrix metalloproteinase (MMP)-2 induction in human dental pulp cells (HPC). We examined AEA-induced MMP-2 production and the expression of AEA receptors (cannabinoid [CB] receptor-1, CB2, and transient receptor potential vanilloid-1 [TRPV1]) in HPC by Western blot. MMP-2 concentrations in supernatants were determined by enzyme-linked immunosorbent assay. We then investigated the role of the AEA receptors and mitogen-activated protein kinase in AEA-induced MMP-2 production in HPC. AEA significantly induced MMP-2 production in HPC. HPC expressed all 3 types of AEA receptor (CB1, CB2, and TRPV1). AEA-induced MMP-2 production was blocked by CB1 or TRPV1 antagonists and by small interfering RNA for CB1 or TRPV1. Furthermore, c-Jun N-terminal kinase inhibitor also reduced MMP-2 production. We demonstrated for the first time that AEA induced MMP-2 production via CB1 and TRPV1 in HPC. Copyright © 2012 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  2. Chimeric mice transplanted with human hepatocytes as a model for prediction of human drug metabolism and pharmacokinetics.

    Science.gov (United States)

    Sanoh, Seigo; Ohta, Shigeru

    2014-03-01

    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 P450 (P450) 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 P450 and non-P450 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. Copyright © 2013 John Wiley & Sons, Ltd.

  3. Ocular pharmacokinetics of besifloxacin following topical administration to rabbits, monkeys, and humans.

    Science.gov (United States)

    Proksch, Joel W; Granvil, Camille P; Siou-Mermet, Raphaële; Comstock, Timothy L; Paterno, Michael R; Ward, Keith W

    2009-08-01

    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 (0.6%) was administered as a topical ocular instillation to pigmented rabbits, cynomolgus monkeys, and human subjects. At predetermined intervals after dosing, samples of ocular tissues and plasma were collected and analyzed for besifloxacin levels using HPLC/MS/MS methods. 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 6.43 microg/g, 2.10 microg/g, and 0.796 microg/mL, respectively, after a single topical dose, and concentrations declined in these tissues with an apparent half-life of 5-14 h. Following a single topical ocular administration to humans, the maximum besifloxacin concentration in tears was 610 microg/g with concentrations decreasing to approximately 1.6 microg/g at 24 h. The resulting pharmacokinetic parameters for besifloxacin in human tears were evaluated relative to the MIC(90) values (microg/mL) for besifloxacin against Streptococcus pneumoniae (0.125), Staphylococcus aureus (0.25), Staphylococcus epidermidis (0.5), and Haemophilus influenzae (0.06). Following a single topical administration, the C(max)/MIC(90) ratios for besifloxacin in human tears were > or =1,220, and the AUC((0-24))/MIC(90) ratios were > or =2,500 for these relevant ocular pathogens. 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 0.5 ng/mL, on average. Taken together, the results of the current investigation provide a PK/PD-based rationale that supports the

  4. A physiologically based pharmacokinetic model for ethylene oxide in mouse, rat, and human.

    Science.gov (United States)

    Fennell, T R; Brown, C D

    2001-06-15

    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 F344 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 200 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 2001 Academic Press.

  5. [Post-marketing re-evaluation about usage and dosage of Chinese medicine based on human population pharmacokinetics].

    Science.gov (United States)

    Jiang, Junjie; Xie, Yanming

    2011-10-01

    The usage and dosage of Chinese patent medicine are determined by rigorous evaluation which include four clinical trail stages: I, II, III. 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.

  6. Cannabinoids as modulators of cancer cell viability, neuronal differentiation, and embryonal development

    OpenAIRE

    Gustafsson, Sofia

    2012-01-01

    Cannabinoids (CBs) are compounds that activate the CB1 and CB2 receptors. 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 this thesis, the effects of cannabinoids on human colorectal carcinoma Caco-2 cells (Paper I) and mouse P19 embryonal carcinoma (EC) cells (Paper III) were studied.  In both cell lines, the compounds examined produced a concentr...

  7. [Cannabinoids in pain medicine].

    Science.gov (United States)

    Karst, M

    2018-06-07

    The endocannabinoid system (ECS) controls a large number of vital functions. 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.

  8. Estimated cancer risk of dioxins to humans using a bioassay and physiologically based pharmacokinetic model

    International Nuclear Information System (INIS)

    Maruyama, Wakae; Aoki, Yasunobu

    2006-01-01

    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 calculated REPs for TCDD, PeCDD, and PeCDF were 1.0, 0.34, and 0.05 for rats, respectively, and the REPs for humans were almost the same as those for rats. These values were different from the toxic equivalency factors (TEFs) presented previously (Van den Berg, M., Birnbaum, L., Bosveld, A.T.C., Brunstrom, B., Cook, P., Feeley, M., Giesy, J.P., Hanberg, A., Hasegawa, R., Kennedy, S.W., Kubiak, T., Larsen, J.C., Rolaf van Leeuwen, F.X., Liem, A.K.D., Nolt, C., Peterson, R.E., Poellinger. L., Safe, S., Schrenk, D., Tillitt, D, Tysklind, M., Younes, M., Waern, F., Zacharewski, T., 1998. Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environ. Health Perspect. 106, 775-792). The relative risk of excess liver cancer for Japanese people in general was 1.7-6.5 x 10 -7 by TCDD only, and 2.9-11 x 10 -7 by the three dioxins at the present level of contamination

  9. Bioavailability and pharmacokinetic profile of grape pomace phenolic compounds in humans.

    Science.gov (United States)

    Castello, Fabio; Costabile, Giuseppina; Bresciani, Letizia; Tassotti, Michele; Naviglio, Daniele; Luongo, Delia; Ciciola, Paola; Vitale, Marilena; Vetrani, Claudia; Galaverna, Gianni; Brighenti, Furio; Giacco, Rosalba; Del Rio, Daniele; Mena, Pedro

    2018-05-15

    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. The main circulating metabolites included phenyl-γ-valerolactones, hydroxybenzoic acids, simple phenols, hydroxyphenylpropionic acids, hydroxycinnamates, and (epi)catechin phase II conjugates. 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. Copyright © 2018 Elsevier Inc. All rights reserved.

  10. Metabolic and Pharmacokinetic Differentiation of STX209 and Racemic Baclofen in Humans

    Directory of Open Access Journals (Sweden)

    Raymundo Sanchez-Ponce

    2012-09-01

    Full Text Available STX209 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 STX209 are not. For potential clinical use, our findings suggest that STX209 has the advantage of being a biologically defined and active enantiomer.

  11. Pharmacokinetics and effects on serum cholinesterase activities of organophosphorus pesticides acephate and chlorpyrifos in chimeric mice transplanted with human hepatocytes.

    Science.gov (United States)

    Suemizu, Hiroshi; Sota, Shigeto; Kuronuma, Miyuki; Shimizu, Makiko; Yamazaki, Hiroshi

    2014-11-01

    Organophosphorus pesticides acephate and chlorpyrifos in foods have potential to impact human health. The aim of the current study was to investigate the pharmacokinetics of acephate and chlorpyrifos orally administered at lowest-observed-adverse-effect-level doses in chimeric mice transplanted with human hepatocytes. Absorbed acephate and its metabolite methamidophos were detected in serum from wild type mice and chimeric mice orally administered 150mg/kg. Approximately 70% inhibition of cholinesterase was evident in plasma of chimeric mice with humanized liver (which have higher serum cholinesterase activities than wild type mice) 1day after oral administrations of acephate. Adjusted animal biomonitoring equivalents from chimeric mice studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Estimated plasma concentrations of acephate and chlorpyrifos in humans were consistent with reported concentrations. Acephate cleared similarly in humans and chimeric mice but accidental/incidental overdose levels of chlorpyrifos cleared (dependent on liver metabolism) more slowly from plasma in humans than it did in mice. The data presented here illustrate how chimeric mice transplanted with human hepatocytes in combination with a simple PBPK model can assist evaluations of toxicological potential of organophosphorus pesticides. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. A Multi-Route Model of Nicotine-Cotinine Pharmacokinetics, Pharmacodynamics and Brain Nicotinic Acetylcholine Receptor Binding in Humans

    Energy Technology Data Exchange (ETDEWEB)

    Teeguarden, Justin G.; Housand, Conrad; Smith, Jordan N.; Hinderliter, Paul M.; Gunawan, Rudy; Timchalk, Charles

    2013-02-01

    The pharmacokinetics of nicotine, the pharmacologically active alkaloid in tobacco responsible for addiction, are well characterized in humans. We developed a physiologically based pharmacokinetic/pharmacodynamic model of nicotine pharmacokinetics, brain dosimetry and brain nicotinic acetylcholine receptor (nAChRs) occupancy. A Bayesian framework was applied to optimize model parameters against multiple human data sets. The resulting model was consistent with both calibration and test data sets, but in general underestimated variability. A pharmacodynamic model relating nicotine levels to increases in heart rate as a proxy for the pharmacological effects of nicotine accurately described the nicotine related changes in heart rate and the development and decay of tolerance to nicotine. The PBPK model was utilized to quantitatively capture the combined impact of variation in physiological and metabolic parameters, nicotine availability and smoking compensation on the change in number of cigarettes smoked and toxicant exposure in a population of 10,000 people presented with a reduced toxicant (50%), reduced nicotine (50%) cigarette Across the population, toxicant exposure is reduced in some but not all smokers. Reductions are not in proportion to reductions in toxicant yields, largely due to partial compensation in response to reduced nicotine yields. This framework can be used as a key element of a dosimetry-driven risk assessment strategy for cigarette smoke constituents.

  13. Metabolites of 5F-AKB-48, a synthetic cannabinoid receptor agonist, identified in human urine and liver microsomal preparations using liquid chromatography high-resolution mass spectrometry

    DEFF Research Database (Denmark)

    Holm, Niels Bjerre; Pedersen, Anders Just; Dalsgaard, Petur Weihe

    2015-01-01

    New types of synthetic cannabinoid designer drugs are constantly introduced to the illicit drug market to circumvent legislation. Recently, N-​(1-Adamant​yl)-​1-​(5-​fluoropentyl)-​1H-​indazole-​3-​carboxamide (5F-AKB-48), also known as 5F-APINACA, was identified as an adulterant in herbal products...

  14. A pilot study on the serum pharmacokinetics of nattokinase in humans following a single, oral, daily dose.

    Science.gov (United States)

    Ero, Michael Penfield; Ng, Connie M; Mihailovski, Tamara; Harvey, Nathaniel R; Lewis, Brad Howard

    2013-01-01

    Nattokinase is a serine protease and is derived from natto, a traditional Japanese, fermented, soybean food meal. Multiple authors have described the significant fibrinolytic, antithrombotic, and antihypertensive effects of natto. Nattokinase has been growing in popularity for use as a dietary supplement for the benefit of cardiovascular health. Little is known regarding the pharmacokinetic and pharmacodynamic properties of this enzyme, and the bioavailability of nattokinase is currently unknown. This study intended to (1) detect nattokinase directly and immunologically, (2) show that nattokinase and/or its metabolites were detectable in human blood following ingestion of a commercial preparation, and (3) chart a pharmacokinetic dosing effect for nattokinase. The research team designed the pilot study as an in vivo, human clinical trial. Healthy human subjects responded to an advertisement and were screened. Subjects who satisfied both inclusion and exclusion criteria were enrolled into the study. Subjects were then instructed to orally ingest a single capsule containing a known concentration of nattokinase immediately following a baseline blood draw. Subsequent blood draws occurred over a 24-h period. This study was conducted in Oakland, California, at a clinical reference laboratory and was performed with the approval of an institutional review board (IRB) to ensure that appropriate ethical standards were met. Eleven healthy participants (five male, six female, ages 21-65), who met eligibility criteria, were enrolled. Administration of nattokinase occurred orally with the ingestion of a single daily dose (2000 FU) of nattokinase. Capsules, each containing approximately 100 mg of nattokinase, in softgel form (NSK-SD, Japan Bio Science Laboratory, Osaka, Japan), were used in the study. Baseline blood samples were collected, and participants were observed swallowing a single capsule of the nattokinase supplement before returning at 2, 4, 8, 12, 24, and 48 h post

  15. Pharmacokinetics and pharmacokinetic/pharmacodynamic associations of ofatumumab, a human monoclonal CD20 antibody, in patients with relapsed or refractory chronic lymphocytic leukaemia: a phase 1-2 study

    DEFF Research Database (Denmark)

    Coiffier, Bertrand; Losic, Nedjad; Rønn, Birgitte Biilmann

    2010-01-01

    The purpose of this phase 1-2 study was to investigate the association between the pharmacokinetic properties of ofatumumab, a human monoclonal CD20 antibody, and outcomes in 33 patients with relapsed/refractory chronic lymphocytic leukaemia receiving 4 weekly infusions of ofatumumab. The ofatumu...

  16. Effects of chlorophyll and chlorophyllin on low-dose aflatoxin B1 pharmacokinetics in human volunteers: A pilot study

    Energy Technology Data Exchange (ETDEWEB)

    Jubert, C; Mata, J; Bench, G; Dashwood, R; Pereira, C; Tracewell, W; Turteltaub, K; Williams, D; Bailey, G

    2009-04-20

    Chlorophyll (Chla) and chlorophyllin (CHL) were shown previously to reduce carcinogen bioavailability, biomarker damage, and tumorigenicity in trout and rats. These findings were partially extended to humans (Proc Natl Acad Sci USA 98, 14601-14606 (2001)), where CHL reduced excretion of aflatoxin B{sub 1} (AFB{sub 1})-DNA repair products in Chinese unavoidably exposed to dietary AFB{sub 1}. However, neither AFB{sub 1} pharmacokinetics nor Chla effects were examined. We conducted a small unblinded crossover study to establish AFB{sub 1} pharmacokinetic parameters in human volunteers, and to explore possible effects of CHL or Chla co-treatment on those parameters. For protocol 1, fasted subjects received an IRB-approved dose of 14C-AFB{sub 1} (30 ng, 5 nCi) by capsule with 100 ml water, followed by normal eating and drinking after hr 2. Blood and cumulative urine samples were collected over 72 hr, and {sup 14}C-AFB{sub 1} equivalents were determined by Accelerator Mass Spectrometry. Protocols 2 and 3 were similar except capsules also contained 150 mg of purified Chla, or CHL, respectively. All protocols were repeated 3 times for each of three volunteers. The study revealed rapid human AFB{sub 1} uptake (plasma ka 5.05 {+-} 1.10 hr-1, Tmax 1.0 hr) and urinary elimination (95% complete by 24 hr) kinetics. Chla and CHL treatment each significantly impeded AFB{sub 1} absorption and reduced Cmax and AUC's (plasma and urine) in one or more subjects. These initial results provide AFB{sub 1} pharmacokinetic parameters previously unavailable for humans, and suggest that Chla or CHL co-consumption may limit the bioavailability of ingested aflatoxin in humans, as they do in animal models.

  17. Milk decreases urinary excretion but not plasma pharmacokinetics of cocoa flavan-3-ol metabolites in humans.

    Science.gov (United States)

    Mullen, William; Borges, Gina; Donovan, Jennifer L; Edwards, Christine A; Serafini, Mauro; Lean, Michael E J; Crozier, Alan

    2009-06-01

    Cocoa drinks containing flavan-3-ols are associated with many health benefits, and conflicting evidence exists as to whether milk adversely affects the bioavailability of flavan-3-ols. The objective was to determine the effect of milk on the bioavailability of cocoa flavan-3-ol metabolites. Nine human volunteers followed a low-flavonoid diet for 2 d before drinking 250 mL of a cocoa beverage, made with water or milk, that contained 45 micromol (-)-epicatechin and (-)-catechin. Plasma and urine samples were collected for 24 h, and flavan-3-ol metabolites were analyzed by HPLC with photodiode array and mass spectrometric detection. Milk affected neither gastric emptying nor the transit time through the small intestine. Two flavan-3-ol metabolites were detected in plasma and 4 in urine. Milk had only minor effects on the plasma pharmacokinetics of an (epi)catechin-O-sulfate and had no effect on an O-methyl-(epi)catechin-O-sulfate. However, milk significantly lowered the excretion of 4 urinary flavan-3-ol metabolites from 18.3% to 10.5% of the ingested dose (P = 0.016). Studies that showed protective effects of cocoa and those that showed no effect of milk on bioavailability used products that have a much higher flavan-3-ol content than does the commercial cocoa used in the present study. Most studies of the protective effects of cocoa have used drinks with a very high flavan-3-ol content. Whether similar protective effects are associated with the consumption of many commercial chocolate and cocoa products containing substantially lower amounts of flavan-3-ols, especially when absorption at lower doses is obstructed by milk, remains to be determined.

  18. The pharmacokinetic profile of crocetin in healthy adult human volunteers after a single oral administration.

    Science.gov (United States)

    Umigai, N; Murakami, K; Ulit, M V; Antonio, L S; Shirotori, M; Morikawa, H; Nakano, T

    2011-05-15

    Crocetin, a unique carotenoid with a short carbon chain length, is an active compound of saffron and Gardenia jasminoides Ellis used as traditional herbal medicine. The present study was undertaken to investigate the pharmacokinetic profiles of crocetin in healthy adult subjects. The study was conducted as an open-label, single dose escalation with 10 Filipino volunteers (5 men and 5 women). The subjects received a single dose of crocetin at three doses (7.5, 15 and 22.5 mg) in one week interval. Blood samples were collected from the brachial vein before and at 1, 2, 4, 6, 8, 10 and 24 h after administration. Plasma concentrations of crocetin were determined by high-performance liquid chromatography (HPLC). Crocetin was rapidly absorbed and detected within an hour of administration with a mean time to reach maximum concentration (T(max)) of crocetin ranging from 4.0 to 4.8 h. The mean values of C(max) and AUC(0-24h) ranged from 100.9 to 279.7 ng/ml and 556.5 to 1720.8 ng. h/ml respectively. C(max) and AUC values increased with dose proportional manner. Crocetin was eliminated from human plasma with a mean elimination half life (T(½) of 6.1 to 7.5 h. In summary, there were no serious adverse events up to 22.5 mg dose of crocetin while crocetin was found to be absorbed more quickly than the other carotenoids such as β-carotene, lutein and lycopene. Copyright © 2010 Elsevier GmbH. All rights reserved.

  19. Pharmacokinetic modeling of a gel-delivered dapivirine microbicide in humans.

    Science.gov (United States)

    Halwes, Michael E; Steinbach-Rankins, Jill M; Frieboes, Hermann B

    2016-10-10

    Although a number of drugs have been developed for the treatment and prevention of human immunodeficiency virus (HIV) infection, it has proven difficult to optimize the drug and dosage parameters. The vaginal tissue, comprised of epithelial, stromal and blood compartments presents a complex system which challenges evaluation of drug kinetics solely through empirical effort. To provide insight into the underlying processes, mathematical modeling and computational simulation have been applied to the study of retroviral microbicide pharmacokinetics. Building upon previous pioneering work that modeled the delivery of Tenofovir (TFV) via topical delivery to the vaginal environment, here we computationally evaluate the performance of the retroviral inhibitor dapivirine released from a microbicide gel. We adapt the TFV model to simulate the multicompartmental diffusion and uptake of dapivirine into the blood plasma and vaginal compartments. The results show that dapivirine is expected to accumulate at the interface between the gel and epithelium compartments due to its hydrophobic characteristics. Hydrophobicity also results in decreased diffusivity, which may impact distribution by up to 2 orders of magnitude compared to TFV. Maximum concentrations of dapivirine in the epithelium, stroma, and blood were 9.9e7, 2.45e6, and 119pg/mL, respectively. This suggests that greater initial doses or longer time frames are required to obtain higher drug concentrations in the epithelium. These observations may have important ramifications if a specific time frame is required for efficacy, or if a minimum/maximum concentration is needed in the mucus, epithelium, or stroma based on combined efficacy and safety data. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. The multidrug transporter ABCG2 (BCRP) is inhibited by plant-derived cannabinoids.

    Science.gov (United States)

    Holland, M L; Lau, D T T; Allen, J D; Arnold, J C

    2007-11-01

    Cannabinoids are used therapeutically for the palliation of the adverse side effects associated with cancer chemotherapy. However, cannabinoids also inhibit both the activity and expression of the multidrug transporter, P-glycoprotein in vitro. Here we address the interaction of cannabinol (CBN), cannabidiol (CBD) and delta 9-tetrahydrocannabinol (THC) with the related multidrug transporter, ABCG2. Cannabinoid inhibition of Abcg2/ABCG2 was assessed using flow cytometric analysis of substrate accumulation and ATPase activity assays. The cytotoxicity and chemosensitization by cannabinoids was determined with cell viability assays. Expression of cannabinoid and vanilloid receptors was assessed using reverse transcriptase polymerase chain reaction, and cannabinoid modulation of ABCG2 expression was examined using immunoblotting. CBN, CBD and THC increased the intracellular accumulation of the Abcg2/ABCG2 substrate, mitoxantrone, in an over-expressing cell line. The THC metabolite, (-)-11-nor-9-carboxy-delta 9-THC was much less potent. The plant cannabinoids inhibited both basal and substrate stimulated ATPase activity of human ABCG2. Cannabinoid cytotoxicity occurred in the absence of known cannabinoid cell surface receptors, and only at concentrations higher than those required for Abcg2/ABCG2 inhibition. Sub-toxic concentrations of the cannabinoids resensitized the overexpressing cell line to the cytotoxic effect of Abcg2/ABCG2 substrates, mitoxantrone and topotecan. This occurred in the absence of any effect on ABCG2 expression. Cannabinoids are novel Abcg2/ABCG2 inhibitors, reversing the Abcg2-mediated multidrug-resistant phenotype in vitro. This finding may have implications for the co-administration of cannabinoids with pharmaceuticals that are ABCG2 substrates.

  1. Cannabis, cannabinoids, and health.

    Science.gov (United States)

    Lafaye, Genevieve; Karila, Laurent; Blecha, Lisa; Benyamina, Amine

    2017-09-01

    Cannabis (also known as marijuana) is the most frequently used illicit psychoactive substance in the world. Though it was long considered to be a "soft" drug, studies have proven the harmful psychiatric and addictive effects associated with its use. A number of elements are responsible for the increased complications of cannabis use, including the increase in the potency of cannabis and an evolution in the ratio between the two primary components, Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and cannabidiol (toward a higher proportion of Δ 9 -THC), Synthetic cannabinoid (SC) use has rapidly progressed over the last few years, primarily among frequent cannabis users, because SCs provide similar psychoactive effects to cannabis. However, their composition and pharmacological properties make them dangerous substances. Cannabis does have therapeutic properties for certain indications. These therapeutic applications pertain only to certain cannabinoids and their synthetic derivatives. The objective of this article is to summarize current developments concerning cannabis and the spread of SCs. Future studies must further explore the benefit-risk profile of medical cannabis use.

  2. Potent human uric acid transporter 1 inhibitors: in vitro and in vivo metabolism and pharmacokinetic studies

    Directory of Open Access Journals (Sweden)

    Wempe MF

    2012-11-01

    Full Text Available Michael F Wempe,1 Janet W Lightner,2 Bettina Miller,1 Timothy J Iwen,1 Peter J Rice,1 Shin Wakui,3 Naohiko Anzai,4 Promsuk Jutabha,4 Hitoshi Endou51Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; 2Department of Pharmacology, East Tennessee State University, Johnson City, TN, USA; 3Department of Toxicology, Azabu University School of Veterinary Medicine, Chuo Sagamihara, Kanagawa, Japan; 4Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Mibu, Shimotsuga, Tochigi, Japan; 5Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Mitaka, Tokyo, JapanAbstract: Human uric acid transporter 1 (hURAT1; SLC22A12 is a very important urate anion exchanger. Elevated urate levels are known to play a pivotal role in cardiovascular diseases, chronic renal disease, diabetes, and hypertension. Therefore, the development of potent uric acid transport inhibitors may lead to novel therapeutic agents to combat these human diseases. The current study investigates small molecular weight compounds and their ability to inhibit 14C-urate uptake in oocytes expressing hURAT1. Using the most promising drug candidates generated from our structure–activity relationship findings, we subsequently conducted in vitro hepatic metabolism and pharmacokinetic (PK studies in male Sprague-Dawley rats. Compounds were incubated with rat liver microsomes containing cofactors nicotinamide adenine dinucleotide phosphate and uridine 5'-diphosphoglucuronic acid. In vitro metabolism and PK samples were analyzed using liquid chromatography/mass spectrometry-mass spectrometry methods. Independently, six different inhibitors were orally (capsule dosing or intravenously (orbital sinus administered to fasting male Sprague-Dawley rats. Blood samples were collected and analyzed; these data were used to compare in vitro and in vivo metabolism and to

  3. Strategies to distinguish new synthetic cannabinoid FUBIMINA (BIM-2201) intake from its isomer THJ-2201: metabolism of FUBIMINA in human hepatocytes

    OpenAIRE

    Diao, Xingxing; Scheidweiler, Karl B.; Wohlfarth, Ariane; Zhu, Mingshe; Pang, Shaokun; Huestis, Marilyn A.

    2016-01-01

    Since 2013, a new drugs-of-abuse trend attempts to bypass drug legislation by marketing isomers of scheduled synthetic cannabinoids (SCs), e.g., FUBIMINA (BIM-2201) and THJ-2201. 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. Here, we investigated isomers FUBIMINA and THJ-2201 and propose strategies to dist...

  4. Pharmacokinetics and pharmacodynamics of eltanolone (pregnanolone), a new steroid intravenous anaesthetic, in humans

    DEFF Research Database (Denmark)

    Carl, Peder; Høgskilde, S; Lang-Jensen, T

    1994-01-01

    Eltanolone, a new intravenous steroid anaesthetic agent was administered intravenously in a dose of 0.6 mg.kg-1 over 45 s to eight healthy male volunteers to evaluate some of its pharmacokinetic and pharmacodynamic effects. Drug concentration-time data were analysed by PCNONLIN, a non...

  5. Population Pharmacokinetic Modelling of FE 999049, a Recombinant Human Follicle-Stimulating Hormone, in Healthy Women After Single Ascending Doses

    DEFF Research Database (Denmark)

    Rose, Trine Høyer; Röshammar, Daniel; Erichsen, Lars

    2016-01-01

    reproductive technologies. Methods: Serum FSH levels were measured following a single subcutaneous FE 999049 injection of 37.5, 75, 150, 225 or 450 IU in 27 pituitary-suppressed healthy female subjects participating in this first-in-human single ascending dose trial. Data was analysed by nonlinear mixed...... volume of distribution (V/F) estimates were found to increase with body weight. Body weight was included as an allometrically scaled covariate with a power exponent of 0.75 for CL/F and 1 for V/F. Conclusions: The single-dose pharmacokinetics of FE 999049 were adequately described by a population...

  6. Pharmacokinetic-Pharmacodynamic Modelling of the Analgesic and Antihyperalgesic Effects of Morphine after Intravenous Infusion in Human Volunteers

    DEFF Research Database (Denmark)

    Ravn, Pernille; Foster, David J. R.; Kreilgaard, Mads

    2014-01-01

    Using a modelling approach, this study aimed to (i) examine whether the pharmacodynamics of the analgesic and antihyperalgesic effects of morphine differ; (ii) investigate the influence of demographic, pain sensitivity and genetic (OPRM1) variables on between-subject variability of morphine...... pharmacokinetics and pharmacodynamics in human experimental pain models. The study was a randomized, double-blind, 5-arm, cross-over, placebo-controlled study. The psychophysical cutaneous pain tests, electrical pain tolerance (EPTo) and secondary hyperalgesia areas (2HA) were studied in 28 healthy individuals (15...

  7. Pharmacokinetic modeling: Prediction and evaluation of route dependent dosimetry of bisphenol A in monkeys with extrapolation to humans

    International Nuclear Information System (INIS)

    Fisher, Jeffrey W.; Twaddle, Nathan C.; Vanlandingham, Michelle; Doerge, Daniel R.

    2011-01-01

    A physiologically based pharmacokinetic (PBPK) model was developed for bisphenol A (BPA) in adult rhesus monkeys using intravenous (iv) and oral bolus doses of 100 μg d6-BPA/kg (). This calibrated PBPK adult monkey model for BPA was then evaluated against published monkey kinetic studies with BPA. Using two versions of the adult monkey model based on monkey BPA kinetic data from and , the aglycone BPA pharmacokinetics were simulated for human oral ingestion of 5 mg d16-BPA per person (Völkel et al., 2002). Völkel et al. were unable to detect the aglycone BPA in plasma, but were able to detect BPA metabolites. These human model predictions of the aglycone BPA in plasma were then compared to previously published PBPK model predictions obtained by simulating the Völkel et al. kinetic study. Our BPA human model, using two parameter sets reflecting two adult monkey studies, both predicted lower aglycone levels in human serum than the previous human BPA PBPK model predictions. BPA was metabolized at all ages of monkey (PND 5 to adult) by the gut wall and liver. However, the hepatic metabolism of BPA and systemic clearance of its phase II metabolites appear to be slower in younger monkeys than adults. The use of the current non-human primate BPA model parameters provides more confidence in predicting the aglycone BPA in serum levels in humans after oral ingestion of BPA. -- Highlights: ► A bisphenol A (BPA) PBPK model for the infant and adult monkey was constructed. ► The hepatic metabolic rate of BPA increased with age of the monkey. ► The systemic clearance rate of metabolites increased with age of the monkey. ► Gut wall metabolism of orally administered BPA was substantial across all ages of monkeys. ► Aglycone BPA plasma concentrations were predicted in humans orally given oral doses of deuterated BPA.

  8. Cannabinoid Receptors: A Novel Target for Therapy of Prostate Cancer

    National Research Council Canada - National Science Library

    Mukhtar, Hasan; Afaq, Farrukh; Sarfaraz, Sami

    2005-01-01

    .... Here we show that expression levels of both cannabinoid receptors CB(sub 1) and CB(sub 2) are significantly higher in CA-HPV-10 and other human prostate cells LNCaP, DUI45, PC3, and CWR22RV1 than in human prostate epithelial and PZ-HPV-7 cells...

  9. Pharmacokinetics and Concentration-Effect Relationship of Oral LSD in Humans.

    Science.gov (United States)

    Dolder, Patrick C; Schmid, Yasmin; Haschke, Manuel; Rentsch, Katharina M; Liechti, Matthias E

    2015-06-24

    The pharmacokinetics of oral lysergic acid diethylamide are unknown despite its common recreational use and renewed interest in its use in psychiatric research and practice. We characterized the pharmacokinetic profile, pharmacokinetic-pharmacodynamic relationship, and urine recovery of lysergic acid diethylamide and its main metabolite after administration of a single oral dose of lysergic acid diethylamide (200 μg) in 8 male and 8 female healthy subjects. Plasma lysergic acid diethylamide concentrations were quantifiable (>0.1 ng/mL) in all the subjects up to 12 hours after administration. Maximal concentrations of lysergic acid diethylamide (mean±SD: 4.5±1.4 ng/mL) were reached (median, range) 1.5 (0.5-4) hours after administration. Concentrations then decreased following first-order kinetics with a half-life of 3.6±0.9 hours up to 12 hours and slower elimination thereafter with a terminal half-life of 8.9±5.9 hours. One percent of the orally administered lysergic acid diethylamide was eliminated in urine as lysergic acid diethylamide, and 13% was eliminated as 2-oxo-3-hydroxy-lysergic acid diethylamide within 24 hours. No sex differences were observed in the pharmacokinetic profiles of lysergic acid diethylamide. The acute subjective and sympathomimetic responses to lysergic acid diethylamide lasted up to 12 hours and were closely associated with the concentrations in plasma over time and exhibited no acute tolerance. These first data on the pharmacokinetics and concentration-effect relationship of oral lysergic acid diethylamide are relevant for further clinical studies and serve as a reference for the assessment of intoxication with lysergic acid diethylamide. © The Author 2015. Published by Oxford University Press on behalf of CINP.

  10. Assessment of chimeric mice with humanized livers in new drug development: generation of pharmacokinetics, metabolism and toxicity data for selecting the final candidate compound.

    Science.gov (United States)

    Kamimura, Hidetaka; Ito, Satoshi

    2016-01-01

    1. Chimeric mice with humanized livers are expected to be a novel tool for new drug development. This review discusses four applications where these animals can be used efficiently to collect supportive data for selecting the best compound in the final stage of drug discovery. 2. The first application is selection of the final compound based on estimated pharmacokinetic parameters in humans. Since chimeric mouse livers are highly repopulated with human hepatocytes, hepatic clearance values in vivo could be used preferentially to estimate pharmacokinetic profiles for humans. 3. The second is prediction of human-specific or disproportionate metabolites. Chimeric mice reproduce human-specific metabolites of drugs under development to conform to ICH guidance M3(R2), except for compounds that were extensively eliminated by co-existing mouse hepatocytes. 4. The third is identifying metabolites with distinct pharmacokinetic profiles in humans. Slow metabolite elimination specifically in humans increases its exposure level, but if its elimination is faster in laboratory animals, the animal exposure level might not satisfy ICH guidance M3(R2). 5. Finally, two examples of reproducing acute liver toxicity in chimeric mice are introduced. Integrated pharmacokinetics, metabolism and toxicity information are expected to assist pharmaceutical scientists in selecting the best candidate compound in new drug development.

  11. Pharmacokinetics of Snake Venom

    OpenAIRE

    Suchaya Sanhajariya; Stephen B. Duffull; Geoffrey K. Isbister

    2018-01-01

    Understanding snake venom pharmacokinetics is essential for developing risk assessment strategies and determining the optimal dose and timing of antivenom required to bind all venom in snakebite patients. This review aims to explore the current knowledge of snake venom pharmacokinetics in animals and humans. Literature searches were conducted using EMBASE (1974–present) and Medline (1946–present). For animals, 12 out of 520 initially identified studies met the inclusion criteria. In general, ...

  12. A first-generation physiologically based pharmacokinetic (PBPK) model of alpha-tocopherol in human influenza vaccine adjuvant.

    Science.gov (United States)

    Tegenge, Million A; Mitkus, Robert J

    2015-04-01

    Alpha (α)-tocopherol is a component of a new generation of squalene-containing oil-in-water (SQ/W) emulsion adjuvants that have been licensed for use in certain influenza vaccines. Since regulatory pharmacokinetic studies are not routinely required for influenza vaccines, the in vivo fate of this vaccine constituent is largely unknown. In this study, we constructed a physiologically based pharmacokinetic (PBPK) model for emulsified α-tocopherol in human adults and infants. An independent sheep PBPK model was also developed to inform the local preferential lymphatic transfer and for the purpose of model evaluation. The PBPK model predicts that α-tocopherol will be removed from the injection site within 24h and rapidly transfer predominantly into draining lymph nodes. A much lower concentration of α-tocopherol was estimated to peak in plasma within 8h. Any systemically absorbed α-tocopherol was predicted to accumulate slowly in adipose tissue, but not in other tissues. Model evaluation and uncertainty analyses indicated acceptable fit, with the fraction of dose taken up into the lymphatics as most influential on plasma concentration. In summary, this study estimates the in vivo fate of α-tocopherol in adjuvanted influenza vaccine, may be relevant in explaining its immunodynamics in humans, and informs current regulatory risk-benefit analyses. Published by Elsevier Inc.

  13. Tumor trapping of 5-fluorouracil: In vivo 19F NMR spectroscopic pharmacokinetics in tumor-bearing humans and rabbits

    International Nuclear Information System (INIS)

    Wolf, W.; Servis, K.L.; El-Tahtawy, A.; Singh, M.; Ray, M.; Shani, J.; Presant, C.A.; King, M.; Wiseman, C.; Blayney, D.; Albright, M.J.; Atkinson, D.; Ong, R.; Barker, P.B.; Ring, R. III

    1990-01-01

    The pharmacokinetics of 5-fluorouracil (5FU) were studied in vivo in patients with discrete tumors and in rabbits bearing VX2 tumors by using 19 F NMR spectroscopy. Free 5FU was detected in the tumors of four of the six patients and in all VX2 tumors but not in normal rabbit tissues. No other metabolites were seen in these tumors, contrary to the extensive catabolism previously documented using 19 F NMR spectroscopy in both human and animal livers. The tumor pool of free 5FU in those human tumors that trapped 5FU was determined to have a half-life of 0.4-2.1 hr, much longer than expected and significantly longer than the half-life of 5FU in blood (5-15 min), whereas the half-life of trapped 5FU in the VX2 tumors ranged from 1.05 to 1.22 hr. These studies document that NMR spectroscopy is clinically feasible in vivo, allows noninvasive pharmacokinetic analyses at a drug-target tissue in real time, and may produce therapeutically important information at the time of drug administration. Demonstration of the trapping of 5FU in tumors provides both a model for studying metabolic modulation in experimental tumors (in animals) and a method for testing modulation strategies clinically (in patients)

  14. Metabolism of the synthetic cannabinoid 5F-PY-PICA by human and rat hepatocytes and identification of biliary analytical targets by directional efflux in sandwich-cultured rat hepatocytes using UHPLC-HR-MS/MS

    DEFF Research Database (Denmark)

    Mardal, Marie; Annaert, Pieter; Noble, Carolina

    2018-01-01

    Analytical strategies for detecting drugs in biological samples rely on information on metabolism and elimination. 5F-PY-PICA belongs to the group of synthetic cannabinoids that are known to undergo excretion into the bile. The aims of this study were the in vitro identification of metabolites of 5......F-PY-PICA and to determine which analytical targets are excreted into the bile and urine. Metabolites identified after incubation of 5F-PY-PICA with pooled human liver microsomes (pHLM), pooled human hepatocytes (pHH), or suspended and sandwich-cultured rat hepatocytes (SCRH). Rat hepatocytes were......-PY-PICA, M4, and M22 are proposed as analytical targets for bile analysis in forensic screening protocols, whereas M6 should be one of the main urinary targets for 5F-PY-PICA analysis....

  15. A Physiologically Based Pharmacokinetic Model for the Oxime TMB-4: Simulation of Rodent and Human Data

    Science.gov (United States)

    2013-01-13

    later, Garrigue and other colleagues (Maurizis et al. 1992) pub- lished an in vitro binding study of TMB-4 with rabbit cartilaginous tissue cultures...as well as fat, kidney, liver, rapidly perfused tissues and slowly perfused tissues . All tissue compartments are diffusion limited. Model...pharmacokinetic data from the literature. The model was parameterized using rat plasma, tissue and urine time course data from intramuscular administration, as

  16. Pharmacokinetic Analysis of 64Cu-ATSM Dynamic PET in Human Xenograft Tumors in Mice

    DEFF Research Database (Denmark)

    Li, Fan; Jørgensen, Jesper Tranekjær; Madsen, Jacob

    2015-01-01

    The aim of this study was to evaluate the feasibility to perform voxel-wise kinetic modeling on datasets obtained from tumor-bearing mice that underwent dynamic PET scans with 64Cu-ATSM and extract useful physiological parameters.METHODS: Tumor-bearing mice underwent 90-min dynamic PET scans...... relevant parameters from voxel-wise pharmacokinetic analysis to be used for preclinical validation of 64Cu-ATSM as a hypoxia-specific PET tracer....

  17. Quantitative determination of metaxalone in human plasma by LC-MS and its application in a pharmacokinetic study

    Directory of Open Access Journals (Sweden)

    Lanting Zhao

    2016-10-01

    Full Text Available A simple and rapid method using liquid chromatography–mass spectrometry (LC-MS for the determination of metaxalone in human plasma has been developed and validated. Letrozole was used as the internal standard (IS. The plasma samples were simply treated with acetonitrile which allowed the precipitation of plasma proteins. The chromatographic separation was achieved on a Sapphire C18 (2.1 mm × 150 mm, 5 µm, Newark, USA column using the mobile phase (5 mM ammonium acetate containing 0.01% formic acid: acetonitrile (45:55, v/v at a flow rate of 0.3 ml/min. The selected ion monitoring (SIM in the positive mode was used for the determination of [M + H]+ m/z 222.1 and 286.1 for metaxalone and letrozole, respectively. The standard curve obtained was linear (r2 ≥ 0.99 over the concentration range of 30.24−5040 ng/ml. Meanwhile, no interfering peaks or matrix effect was observed. The method established was simple and successfully applied to a pharmacokinetic study of metaxalone in healthy Chinese volunteers after a single oral dose administration of 800 mg metaxalone. The main pharmacokinetic parameters of metaxalone were as follow: Cmax, (1664 ± 1208 ng/ml and (2063 ± 907 ng/ml; AUC0−36, (13925 ± 6590 ng/ml h and (18620 ± 5717 ng/ml h; t1/2, (13.6 ± 7.7 h and (20.3 ± 7.7 h for the reference and test tablets, respectively. These pharmacokinetic parameters of metaxalone in healthy Chinese volunteers were reported for the first time.

  18. Single-dose and steady-state pharmacokinetics of tenofovir disoproxil fumarate in human immunodeficiency virus-infected children.

    Science.gov (United States)

    Hazra, Rohan; Balis, Frank M; Tullio, Antonella N; DeCarlo, Ellen; Worrell, Carol J; Steinberg, Seth M; Flaherty, John F; Yale, Kitty; Poblenz, Marianne; Kearney, Brian P; Zhong, Lijie; Coakley, Dion F; Blanche, Stephane; Bresson, Jean Louis; Zuckerman, Judith A; Zeichner, Steven L

    2004-01-01

    Tenofovir disoproxil fumarate (DF) is a potent nucleotide analog reverse transcriptase inhibitor approved for the treatment of human immunodeficiency virus (HIV)-infected adults. The single-dose and steady-state pharmacokinetics of tenofovir were evaluated following administration of tenofovir DF in treatment-experienced HIV-infected children requiring a change in antiretroviral therapy. Using increments of tenofovir DF 75-mg tablets, the target dose was 175 mg/m(2); the median administered dose was 208 mg/m(2). Single-dose pharmacokinetics were evaluated in 18 subjects, and the geometric mean area under the concentration-time curve from 0 h to infinity (AUC(0- infinity )) was 2,150 ng. h/ml and the geometric mean maximum concentration (C(max)) was 266 ng/ml. Subsequently, other antiretrovirals were added to each patient's regimen based upon treatment history and baseline viral resistance results. Steady-state pharmacokinetics were evaluated in 16 subjects at week 4. The steady-state, geometric mean AUC for the 24-h dosing interval was 2,920 ng. h/ml and was significantly higher than the AUC(0- infinity ) after the first dose (P = 0.0004). The geometric mean C(max) at steady state was 302 ng/ml. Tenofovir DF was generally very well tolerated. Steady-state tenofovir exposures in children receiving tenofovir DF-containing combination antiretroviral therapy approached values seen in HIV-infected adults (AUC, approximately 3,000 ng. h/ml; C(max), approximately 300 ng/ml) treated with tenofovir DF at 300 mg.

  19. Cannabis, Cannabinoids, and Cerebral Metabolism: Potential Applications in Stroke and Disorders of the Central Nervous System.

    Science.gov (United States)

    Latorre, Julius Gene S; Schmidt, Elena B

    2015-09-01

    No compound has generated more attention in both the scientific and recently in the political arena as much as cannabinoids. These diverse groups of compounds referred collectively as cannabinoids have both been vilified due to its dramatic and potentially harmful psychotropic effects and glorified due to its equally dramatic and potential application in a number of acute and chronic neurological conditions. Previously illegal to possess, cannabis, the plant where natural form of cannabinoids are derived, is now accepted in a growing number of states for medicinal purpose, and some even for recreational use, increasing opportunities for more scientific experimentation. The purpose of this review is to summarize the growing body of literature on cannabinoids and to present an overview of our current state of knowledge of the human endocannabinoid system in the hope of defining the future of cannabinoids and its potential applications in disorders of the central nervous system, focusing on stroke.

  20. Cannabinoids reduce markers of inflammation and fibrosis in pancreatic stellate cells.

    Directory of Open Access Journals (Sweden)

    Christoph W Michalski

    2008-02-01

    Full Text Available While cannabinoids have been shown to ameliorate liver fibrosis, their effects in chronic pancreatitis and on pancreatic stellate cells (PSC are unknown.The activity of the endocannabinoid system was evaluated in human chronic pancreatitis (CP tissues. In vitro, effects of blockade and activation of cannabinoid receptors on pancreatic stellate cells were characterized. In CP, cannabinoid receptors were detected predominantly in areas with inflammatory changes, stellate cells and nerves. Levels of endocannabinoids were decreased compared with normal pancreas. Cannabinoid-receptor-1 antagonism effectuated a small PSC phenotype and a trend toward increased invasiveness. Activation of cannabinoid receptors, however, induced de-activation of PSC and dose-dependently inhibited growth and decreased IL-6 and MCP-1 secretion as well as fibronectin, collagen1 and alphaSMA levels. De-activation of PSC was partially reversible using a combination of cannabinoid-receptor-1 and -2 antagonists. Concomitantly, cannabinoid receptor activation specifically decreased invasiveness of PSC, MMP-2 secretion and led to changes in PSC phenotype accompanied by a reduction of intracellular stress fibres.Augmentation of the endocannabinoid system via exogenously administered cannabinoid receptor agonists specifically induces a functionally and metabolically quiescent pancreatic stellate cell phenotype and may thus constitute an option to treat inflammation and fibrosis in chronic pancreatitis.

  1. Studies of the brain cannabinoid system using positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Gatley, S.J.; Volkow, N.D.

    1995-10-01

    Studies using radiolabeled psychoactive drugs in conjunction with positron emission tomography (PET) have permitted the imaging of binding sites in the human brain. Similar studies of marijuana have been hampered by the unsuitability of radiolabeled THC for PET studies, and the current unavailability of other in vivo imaging agents for cannabinoid receptors. Recent developments in medicinal chemistry suggest that a PET radiotracer for cannabinoid receptors will soon become available. This chapter briefly reviews these developments, together with the results of PET studies of the effects of marijuana and other abused drugs on brain metabolism. It also reviews PET studies of cocaine binding sites, to demonstrate the kind of investigations that will be possible when a cannabinoid receptor PET radioligand becomes available.

  2. Studies of the brain cannabinoid system using positron emission tomography

    International Nuclear Information System (INIS)

    Gatley, S.J.; Volkow, N.D.

    1995-01-01

    Studies using radiolabeled psychoactive drugs in conjunction with positron emission tomography (PET) have permitted the imaging of binding sites in the human brain. Similar studies of marijuana have been hampered by the unsuitability of radiolabeled THC for PET studies, and the current unavailability of other in vivo imaging agents for cannabinoid receptors. Recent developments in medicinal chemistry suggest that a PET radiotracer for cannabinoid receptors will soon become available. This chapter briefly reviews these developments, together with the results of PET studies of the effects of marijuana and other abused drugs on brain metabolism. It also reviews PET studies of cocaine binding sites, to demonstrate the kind of investigations that will be possible when a cannabinoid receptor PET radioligand becomes available

  3. Pharmacokinetic study of isocorynoxeine metabolites mediated by cytochrome P450 enzymes in rat and human liver microsomes.

    Science.gov (United States)

    Zhao, Lizhu; Zang, Bin; Qi, Wen; Chen, Fangfang; Wang, Haibo; Kano, Yoshihiro; Yuan, Dan

    2016-06-01

    Isocorynoxeine (ICN) is one of the major bioactive tetracyclic oxindole alkaloids found in Uncaria rhynchophylla (Miq.) Jacks. that is widely used for the treatment of hypertension, vascular dementia, and stroke. The present study was undertaken to assess the plasma pharmacokinetic characteristics of major ICN metabolites, and the role of simulated gastric and intestinal fluid (SGF and SIF), human and rat liver microsomes (HLMs and RLMs), and seven recombinant human CYP enzymes in the major metabolic pathway of ICN. A rapid, sensitive and accurate UHPLC/Q-TOF MS method was validated for the simultaneous determination of ICN and its seven metabolites in rat plasma after oral administration of ICN at 40mg/kg. It was found that 18.19-dehydrocorynoxinic acid (DCA) and 5-oxoisocorynoxeinic acid (5-O-ICA) were both key and predominant metabolites, rather than ICN itself, due to the rapid and extensive metabolism of ICN in vivo. The further study indicated that ICN was mainly metabolized in human or rat liver, and CYPs 2C19, 3A4 and 2D6 were the major enzymes responsible for the biotransformation of ICN to DCA and 5-O-ICA in human. These findings are of significance in understanding of the pharmacokinetic nature of tetracyclic oxindole alkaloids, and provide helpful information for the clinical co-administration of the herbal preparations containing U. rhynchophylla with antihypertensive drugs that are mainly metabolized by CYP3A4 and CYP2C19. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Pharmacokinetic evaluation of UK-49,858, a metabolically stable triazole antifungal drug, in animals and humans.

    Science.gov (United States)

    Humphrey, M J; Jevons, S; Tarbit, M H

    1985-11-01

    The pharmacokinetic profile of UK-49,858 (fluconazole), a novel triazole antifungal agent which is being developed for oral and intravenous use, was determined in mice, rats, dogs, and humans. Comparative data following oral and intravenous administration showed that bioavailability was essentially complete in all four species. Peak concentrations in plasma of drug normalized to a 1-mg/kg dose level following oral administration, were relatively high: 0.7, 0.6, 1.1, and 1.4 micrograms/ml in mice, rats, dogs, and humans, respectively. The volumes of distribution ranged between 1.1 liter/kg in mice and 0.7 liter/kg in humans, which are approximate to the values for total body water. Whole body autoradiography studies in mice following intravenous administration of [14C]UK-49,858 demonstrated that the drug was evenly distributed throughout the tissues, including the central nervous system and the gastrointestinal tract. Plasma protein binding was low (11 to 12%) in all species. Marked species differences were observed in elimination half-lives, with mean values of 4.8, 4.0, 14, and 22 h in mice, rats, dogs, and humans, respectively. The major route of elimination of the drug was renal clearance, with about 70% of the dose being excreted unchanged in the urine in each species. Studies with [14C]UK-49,858 on metabolism and excretion (intravenous and oral) in mice and dogs showed that about 90% of the dose was recovered as unchanged drug in urine and feces, confirming the metabolic stability of the drug. This pharmacokinetic profile is markedly different from that of imidazole antifungal drugs and undoubtedly contributes to the excellent efficacy of UK-49,858 in vivo.

  5. [Determination of ferulic acid absorbed into human serum from oral decoction of rhizoma chuanxiong and pharmacokinetic study of ferulic acid].

    Science.gov (United States)

    Sun, S; Huang, X; Zhang, L; Ren, P; Chang, Z

    2001-10-01

    To improve the HPLC method for determining ferulic acid(FA) in the human serum and to research FA clinical pharmacokinetics. Serum concentrations of FA were determined by HPLC using methanol-water-acetic acid (40:59.7:0.3, v/v) as the mobile phase and the column packed with ODS (150 mm x 4.6 mm, 5 microns) as a fixed phase and the flow rate was 1.0 ml/min. FA was detected at 320 nm wave length. The internal standard was coumarin. The serum samples were treated by the water-boiling method. Peak of FA in serum was recognized by photodiode-array detection. FA and internal standard were separated completely under the condition described as above. FA was linear in the range of (40.16-8032 ng/ml) (r = 0.9975). The CV was less than 10%, the average recovery was 100.3%, and the limit concentration in serum was 25.1 ng/ml. PK was in accordance with open bicameral model. This method can be applied to clinical pharmacokinetic study of FA.

  6. Cannabinoids for epilepsy.

    Science.gov (United States)

    Gloss, David; Vickrey, Barbara

    2014-03-05

    Marijuana appears to have anti-epileptic effects in animals. It is not currently known if it is effective in patients with epilepsy. Some states in the United States of America have explicitly approved its use for epilepsy. To assess the efficacy and safety of cannabinoids when used as monotherapy or add-on treatment for people with epilepsy. We searched the Cochrane Epilepsy Group Specialized Register (9 September 2013), Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 8), MEDLINE (Ovid) (9 September 2013), ISI Web of Knowledge (9 September 2013), CINAHL (EBSCOhost) (9 September 2013), and ClinicalTrials.gov (9 September 2013). In addition, we included studies we personally knew about that were not found by the searches, as well as searched the references in the identified studies. Randomized controlled trials (RCTs) whether blinded or not. Two authors independently selected trials for inclusion and extracted the data. The primary outcome investigated was seizure freedom at one year or more, or three times the longest interseizure interval. Secondary outcomes included responder rate at six months or more, objective quality of life data, and adverse events. We found four randomized trial reports that included a total of 48 patients, each of which used cannabidiol as the treatment agent. One report was an abstract and another was a letter to the editor. Anti-epileptic drugs were continued in all studies. Details of randomisation were not included in any study report. There was no investigation of whether the control and treatment participant groups were the same or different. All the reports were low quality.The four reports only answered the secondary outcome about adverse effects. None of the patients in the treatment groups suffered adverse effects. No reliable conclusions can be drawn at present regarding the efficacy of cannabinoids as a treatment for epilepsy. The dose of 200 to 300 mg daily of cannabidiol was

  7. Cannabinoid Receptors: A Novel Target for Therapy for Prostate Cancer

    National Research Council Canada - National Science Library

    Mukhtar, Hasan; Afaq, Farrukh; Sarfaraz, Sami

    2008-01-01

    We have shown that the expression levels of both cannabinoid receptors CB1 and CB2 are higher in human prostate cancer cells than in normal prostate epithelial cells and treatment of LNCaP cells with WIN-55,212-2 (WIN...

  8. Cannabinoid Receptors: A Novel Target for Treating Prostate Cancer

    National Research Council Canada - National Science Library

    Mukhtar, Hasan; Afaq, Farrukh; Sarfaraz, Sami

    2006-01-01

    Recently we have shown that expression levels of both cannabinoid receptors CB and CB12 are higher in human prostate cancer cells than in normal prostate epithelial cells and treatment of LNCaP cells with WIN-55,212-2...

  9. Cannabinoid Receptors: A Novel Target for Therapy of Prostate Cancer

    National Research Council Canada - National Science Library

    Mukhtar, Hasan; Afaq, Farrukh; Sarfaraz, Sami

    2007-01-01

    .... We have shown that the expression levels of both cannabinoid receptors CB1 and CB2 are higher in human prostate cancer cells than in normal prostate epithelial cells and treatment of LNCaP cells with WIN-55,212-2 (WIN...

  10. Enzyme-linked immunosorbent assay (ELISA) for the detection of use of the synthetic cannabinoid agonists UR-144 and XLR-11 in human urine.

    Science.gov (United States)

    Mohr, Amanda L A; Ofsa, Bill; Keil, Alyssa Marie; Simon, John R; McMullin, Matthew; Logan, Barry K

    2014-09-01

    Ongoing changes in the synthetic cannabinoid drug market create the need for relevant targeted immunoassays for rapid screening of biological samples. We describe the validation and performance characteristics of an enzyme-linked immunosorbent assay designed to detect use of one of the most prevalent synthetic cannabinoids in urine, UR-144, by targeting its pentanoic acid metabolite. Fluorinated UR-144 (XLR-11) has been demonstrated to metabolize to this common product. The assay has significant cross-reactivity with UR-144-5-OH, UR-144-4-OH and XLR-11-4-OH metabolites, but assay's cutoff is 5 ng/mL relative to the pentanoic acid metabolite of UR-144, which is used as the calibrator. The method was validated with 90 positive and negative control urine samples for UR-144, XLR-11 and its metabolites tested versus liquid chromatography-tandem mass spectrometry. The accuracy, sensitivity and specificity were determined to be 100% for the assay at the specified cutoff. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  11. Distribution and Metabolism of Lipocurc™ (Liposomal Curcumin) in Dog and Human Blood Cells: Species Selectivity and Pharmacokinetic Relevance.

    Science.gov (United States)

    Bolger, Gordon T; Licollari, Albert; Tan, Aimin; Greil, Richard; Vcelar, Brigitta; Majeed, Muhammad; Helson, Lawrence

    2017-07-01

    The aim of this study was to investigate the distribution of curcumin (in the form of Lipocurc™) and its major metabolite tetrahydrocurcumin (THC) in Beagle dog and human red blood cells, peripheral blood mononuclear cells (PBMC) and hepatocytes. Lipocurc™ was used as the source of curcumin for the cell distribution assays. In vitro findings with red blood cells were also compared to in vivo pharmacokinetic data available from preclinical studies in dogs and phase I clinical studies in humans. High levels of curcumin were measured in PBMCs (625.5 ng/g w.w. cell pellet or 7,297 pg/10 6 cells in dog and 353.7 ng/g w.w. cell pellet or 6,809 pg/10 6 cells in human) and in hepatocytes (414.5 ng/g w.w. cell pellet or 14,005 pg/10 6 cells in dog and 813.5 ng/g w.w. cell pellet or 13,780 pg/10 6 cells in human). Lower curcumin levels were measured in red blood cells (dog: 78.4 ng/g w.w. cell pellet or 7.2 pg/10 6 cells, human: 201.5 ng/g w.w. cell pellet or 18.6 pg/10 6 cells). A decrease in the medium concentration of curcumin was observed in red blood cells and hepatocytes, but not in PBMCs. Red blood cell levels of THC were ~5-fold higher in dog compared to human and similar between dog and human for hepatocytes and PBMCs. The ratio of THC to curcumin found in the red blood cell medium following incubation was 6.3 for dog compared to 0.006 for human, while for PBMCs and hepatocytes the ratio of THC to curcumin in the medium did not display such marked species differences. There was an excellent correlation between the in vitro disposition of curcumin and THC following incubation with red blood cells and in vivo plasma levels of curcumin and THC in dog and human following intravenous infusion. The disposition of curcumin in blood cells is, therefore, species-dependent and of pharmacokinetic relevance. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  12. Modulation of limbic noradrenergic circuits by cannabinoids

    OpenAIRE

    Carvalho, Ana Raquel Franky Gomes

    2010-01-01

    Tese de doutoramento Medicina The endocannabinoid system has been implicated in the regulation of several physiological functions. The widespread distribution of the endocannabinoid system in the central nervous system (CNS) accounts for many effects attributed to cannabinoids. Importantly, cannabinoids have been shown to modulate mood, cognition and memory. There is growing evidence suggesting that cannabinoids can interact with the noradrenergic system. Noradrenergic trans...

  13. Plant cannabinoids: a neglected pharmacological treasure trove.

    Science.gov (United States)

    Mechoulam, Raphael

    2005-12-01

    Most of the cannabinoids in Cannabis sativa L. have not been fully evaluated for their pharmacological activity. A publication in this issue presents evidence that a plant cannabinoid, Delta(9)-tetrahydrocannabivarin is a potent antagonist of anandamide, a major endogenous cannabinoid. It seems possible that many of the non-psychoactive constituents of this plant will be of biological interest.

  14. Pharmacokinetic and bioavailability studies of commercially available simvastatin tablets in healthy and moderately hyperlipidaemic human subjects

    International Nuclear Information System (INIS)

    Ahmed, M.; Qamar-uz-Zaman, M.; Madni, A.; Usman, M.; Atif, M.; Akhtar, N.; Murtaza, G.

    2011-01-01

    Simvastatin, an analogue of Lovostatin, is a HMG.CoA reductase inhibitor. It is widely used in the treatment of hyperlipidaemia and coronary heart disease (CHD) with low incidence of myopathy and rhabdomyolysis. As these diseases may alter the pharmacokinetics of drugs, the present study was aimed to elaborate the variation in the pharmacokinetics and bioavailability of simvastatin in local healthy and moderately hyperlipidaemic population. Open, single dose and parallel design was applied to study. A total of 36 male volunteers were used for healthy and moderately hyperlipidaemic groups (n 18 for each) in this study on the basis of screening procedures, body chemistry and physical examination. Simvastatin 40 mg tablets (Saista 40, Bosch, Pakistan) were administered to over-night fasted volunteers. Blood samples were collected before dosing (zero time) and at regular intervals of time. The plasma samples were processed through a liquid-liquid extraction procedure and assayed by using HPLC consisting reversed phase C/sub 18/ column (ZORBAX, 4.6 x 150 mm, 5 mu m), UV detector set at 238 nm. The mobile phase consisted of the mixture of 0.025 M sodium dihydrogen phosphate (pH 4.5): acetonitrile (35: 65, v/v) which was pumped at a flow rate of 1.5 mL.min/sup -1/. The retention time of simvastatin was 7.5 minutes. The plasma drug concentration-time profiles of both groups were found significantly (P 0.05) difference between the values of following pharmacokinetic parameters in healthy and hyperlipidaemic volunteers i.e. C/sub max/, t/sub max/, AUC/sub 0-fi), AUMC/sub 0-enfinity), MRT, t/sub 1/2/, Cl/sub t /and K/sub e/. This study confirmed no significant (P > 0.05) difference in pharmacokinetics and bioavailability parameters after the administration of a single oral dose of 40 mg simvastatin (cholesterol lowering drug) to healthy and moderately hyperlipidaemic volunteers. (author)

  15. The Analgesic Potential of Cannabinoids

    Science.gov (United States)

    Elikottil, Jaseena; Gupta, Pankaj; Gupta, Kalpna

    2013-01-01

    Historically and anecdotally cannabinoids have been used as analgesic agents. In recent years, there has been an escalating interest in developing cannabis-derived medications to treat severe pain. This review provides an overview of the history of cannabis use in medicine, cannabinoid signaling pathways, and current data from preclinical as well as clinical studies on using cannabinoids as potential analgesic agents. Clinical and experimental studies show that cannabis-derived compounds act as anti-emetic, appetite modulating and analgesic agents. However, the efficacy of individual products is variable and dependent upon the route of administration. Since opioids are the only therapy for severe pain, analgesic ability of cannabinoids may provide a much-needed alternative to opioids. Moreover, cannabinoids act synergistically with opioids and act as opioid sparing agents, allowing lower doses and fewer side effects from chronic opioid therapy. Thus, rational use of cannabis based medications deserves serious consideration to alleviate the suffering of patients due to severe pain. PMID:20073408

  16. Modeling of pharmacokinetics of cocaine in human reveals the feasibility for development of enzyme therapies for drugs of abuse.

    Directory of Open Access Journals (Sweden)

    Fang Zheng

    Full Text Available A promising strategy for drug abuse treatment is to accelerate the drug metabolism by administration of a drug-metabolizing enzyme. The question is how effectively an enzyme can actually prevent the drug from entering brain and producing physiological effects. In the present study, we have developed a pharmacokinetic model through a combined use of in vitro kinetic parameters and positron emission tomography data in human to examine the effects of a cocaine-metabolizing enzyme in plasma on the time course of cocaine in plasma and brain of human. Without an exogenous enzyme, cocaine half-lives in both brain and plasma are almost linearly dependent on the initial cocaine concentration in plasma. The threshold concentration of cocaine in brain required to produce physiological effects has been estimated to be 0.22±0.07 µM, and the threshold area under the cocaine concentration versus time curve (AUC value in brain (denoted by AUC2(∞ required to produce physiological effects has been estimated to be 7.9±2.7 µM·min. It has been demonstrated that administration of a cocaine hydrolase/esterase (CocH/CocE can considerably decrease the cocaine half-lives in both brain and plasma, the peak cocaine concentration in brain, and the AUC2(∞. The estimated maximum cocaine plasma concentration which a given concentration of drug-metabolizing enzyme can effectively prevent from entering brain and producing physiological effects can be used to guide future preclinical/clinical studies on cocaine-metabolizing enzymes. Understanding of drug-metabolizing enzymes is key to the science of pharmacokinetics. The general insights into the effects of a drug-metabolizing enzyme on drug kinetics in human should be valuable also in future development of enzyme therapies for other drugs of abuse.

  17. Modeling of pharmacokinetics of cocaine in human reveals the feasibility for development of enzyme therapies for drugs of abuse.

    Science.gov (United States)

    Zheng, Fang; Zhan, Chang-Guo

    2012-01-01

    A promising strategy for drug abuse treatment is to accelerate the drug metabolism by administration of a drug-metabolizing enzyme. The question is how effectively an enzyme can actually prevent the drug from entering brain and producing physiological effects. In the present study, we have developed a pharmacokinetic model through a combined use of in vitro kinetic parameters and positron emission tomography data in human to examine the effects of a cocaine-metabolizing enzyme in plasma on the time course of cocaine in plasma and brain of human. Without an exogenous enzyme, cocaine half-lives in both brain and plasma are almost linearly dependent on the initial cocaine concentration in plasma. The threshold concentration of cocaine in brain required to produce physiological effects has been estimated to be 0.22±0.07 µM, and the threshold area under the cocaine concentration versus time curve (AUC) value in brain (denoted by AUC2(∞)) required to produce physiological effects has been estimated to be 7.9±2.7 µM·min. It has been demonstrated that administration of a cocaine hydrolase/esterase (CocH/CocE) can considerably decrease the cocaine half-lives in both brain and plasma, the peak cocaine concentration in brain, and the AUC2(∞). The estimated maximum cocaine plasma concentration which a given concentration of drug-metabolizing enzyme can effectively prevent from entering brain and producing physiological effects can be used to guide future preclinical/clinical studies on cocaine-metabolizing enzymes. Understanding of drug-metabolizing enzymes is key to the science of pharmacokinetics. The general insights into the effects of a drug-metabolizing enzyme on drug kinetics in human should be valuable also in future development of enzyme therapies for other drugs of abuse.

  18. Safety, Pharmacokinetics, Immunogenicity, and Biodistribution of (186)Re-Labeled Humanized Monoclonal Antibody BIWA 4 (Bivatuzumab( in Patients with Early-Stage Breast Cancer.

    NARCIS (Netherlands)

    Koppe, M.; Schaijk, F. van; Roos, J.C.; Leeuwen, P.; Heider, K.H.; Kuthan, H.; Bleichrodt, R.P.

    2004-01-01

    The aim of this prospective study was to evaluate the safety, pharmacokinetics, immunogenicity, and biodistribution of (186)Re-labeled humanized anti-CD44v6 monoclonal antibody (MAb( BIWA 4 (Bivatuzumab( in 9 patients with early-stage breast cancer. Radioimmunoscintigraphy (RIS( was performed within

  19. Cannabinoids for fibromyalgia.

    Science.gov (United States)

    Walitt, Brian; Klose, Petra; Fitzcharles, Mary-Ann; Phillips, Tudor; Häuser, Winfried

    2016-07-18

    This review is one of a series on drugs used to treat fibromyalgia. Fibromyalgia is a clinically well-defined chronic condition of unknown aetiology characterised by chronic widespread pain that often co-exists with sleep problems and fatigue affecting approximately 2% of the general population. People often report high disability levels and poor health-related quality of life (HRQoL). Drug therapy focuses on reducing key symptoms and disability, and improving HRQoL. Cannabis has been used for millennia to reduce pain and other somatic and psychological symptoms. To assess the efficacy, tolerability and safety of cannabinoids for fibromyalgia symptoms in adults. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE to April 2016, together with reference lists of retrieved papers and reviews, three clinical trial registries, and contact with trial authors. We selected randomised controlled trials of at least four weeks' duration of any formulation of cannabis products used for the treatment of adults with fibromyalgia. Two review authors independently extracted the data of all included studies and assessed risk of bias. We resolved discrepancies by discussion. We performed analysis using three tiers of evidence. First tier evidence was derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for drop-outs; at least 200 participants in the comparison, eight to 12 weeks' duration, parallel design), second tier evidence from data that did not meet one or more of these criteria and were considered at some risk of bias but with adequate numbers (i.e. data from at least 200 participants) in the comparison, and third tier evidence from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both. We assessed the

  20. [Cannabinoid hyperemesis syndrome].

    Science.gov (United States)

    Stuijvenberg, Marleen P; Ramaekers, Guy M G I; Bijpost, Yan

    2011-01-01

    A 22-year-old man was referred to our clinic with a 7-year history of episodes of severe vomiting interspersed with symptom-free periods. We saw another patient, a 22-year-old woman, after she had been admitted for the second time with dehydration and hypokalaemia following severe vomiting. We saw a third patient, a 25-year-old woman with a personality disorder and cannabis addiction, after she had gone to the casualty department following several days of persistent excessive vomiting. All three patients seemed to be suffering from cannabinoid hyperemesis syndrome. This is a rarely described syndrome, characterised by the triad of chronic cannabis abuse, unexplained cyclical excessive vomiting and compulsive taking of hot baths for symptom relief. A subgroup of chronic frequent cannabis users suffer from this syndrome, which can appear for the first time several years after initial cannabis use. The exact mechanism of origin is unknown, though various theories exist. In the case of unexplained chronic symptoms of nausea and vomiting our advice is always to question the patient about substance misuse, and showering and bathing habits.

  1. Human plasma metabolic profiles of benzydamine, a flavin-containing monooxygenase probe substrate, simulated with pharmacokinetic data from control and humanized-liver mice.

    Science.gov (United States)

    Yamazaki-Nishioka, Miho; Shimizu, Makiko; Suemizu, Hiroshi; Nishiwaki, Megumi; Mitsui, Marina; Yamazaki, Hiroshi

    2018-02-01

    1. Benzydamine is used clinically as a nonsteroidal anti-inflammatory drug in oral rinses and is employed in preclinical research as a flavin-containing monooxygenase (FMO) probe substrate. In this study, plasma concentrations of benzydamine and its primary N-oxide and N-demethylated metabolites were investigated in control TK-NOG mice, in humanized-liver mice, and in mice whose liver cells had been ablated with ganciclovir. 2. Following oral administration of benzydamine (10 mg/kg) in humanized-liver TK-NOG mice, plasma concentrations of benzydamine N-oxide were slightly higher than those of demethyl benzydamine. In contrast, in control and ganciclovir-treated TK-NOG mice, concentrations of demethyl benzydamine were slightly higher than those of benzydamine N-oxide. 3. Simulations of human plasma concentrations of benzydamine and its N-oxide were achieved using simplified physiologically based pharmacokinetic models based on data from control TK-NOG mice and from reported benzydamine concentrations after low-dose administration in humans. Estimated clearance rates based on data from humanized-liver and ganciclovir-treated TK-NOG mice were two orders magnitude high. 4. The pharmacokinetic profiles of benzydamine were different for control and humanized-liver TK-NOG mice. Humanized-liver mice are generally accepted human models; however, drug oxidation in mouse kidney might need to be considered when probe substrates undergo FMO-dependent drug oxidation in mouse liver and kidney.

  2. A validated bioanalytical HPLC method for pharmacokinetic evaluation of 2-deoxyglucose in human plasma.

    Science.gov (United States)

    Gounder, Murugesan K; Lin, Hongxia; Stein, Mark; Goodin, Susan; Bertino, Joseph R; Kong, Ah-Ng Tony; DiPaola, Robert S

    2012-05-01

    2-Deoxyglucose (2-DG), an analog of glucose, is widely used to interfere with glycolysis in tumor cells and studied as a therapeutic approach in clinical trials. To evaluate the pharmacokinetics of 2-DG, we describe the development and validation of a sensitive HPLC fluorescent method for the quantitation of 2-DG in plasma. Plasma samples were deproteinized with methanol and the supernatant was dried at 45°C. The residues were dissolved in methanolic sodium acetate-boric acid solution. 2-DG and other monosaccharides were derivatized to 2-aminobenzoic acid derivatives in a single step in the presence of sodium cyanoborohydride at 80°C for 45 min. The analytes were separated on a YMC ODS C₁₈ reversed-phase column using gradient elution. The excitation and emission wavelengths were set at 360 and 425 nm. The 2-DG calibration curves were linear over the range of 0.63-300 µg/mL with a limit of detection of 0.5 µg/mL. The assay provided satisfactory intra-day and inter-day precision with RSD less than 9.8%, and the accuracy ranged from 86.8 to 110.0%. The HPLC method is reproducible and suitable for the quantitation of 2-DG in plasma. The method was successfully applied to characterize the pharmacokinetics profile of 2-DG in patients with advanced solid tumors. Copyright © 2011 John Wiley & Sons, Ltd.

  3. Rifampin pharmacokinetics in children, with and without human immunodeficiency virus infection, hospitalized for the management of severe forms of tuberculosis

    Directory of Open Access Journals (Sweden)

    McIlleron Helen

    2009-04-01

    Full Text Available Abstract Background Rifampin is a key drug in antituberculosis chemotherapy because it rapidly kills the majority of bacilli in tuberculosis lesions, prevents relapse and thus enables 6-month short-course chemotherapy. Little is known about the pharmacokinetics of rifampin in children. The objective of this study was to evaluate the pharmacokinetics of rifampin in children with tuberculosis, both human immunodeficiency virus type-1-infected and human immunodeficiency virus-uninfected. Methods Fifty-four children, 21 human immunodeficiency virus-infected and 33 human immunodeficiency virus-uninfected, mean ages 3.73 and 4.05 years (P = 0.68, respectively, admitted to a tuberculosis hospital in Cape Town, South Africa with severe forms of tuberculosis were studied approximately 1 month and 4 months after commencing antituberculosis treatment. Blood specimens for analysis were drawn in the morning, 45 minutes, 1.5, 3.0, 4.0 and 6.0 hours after dosing. Rifampin concentrations were determined by liquid chromatography tandem mass spectrometry. For two sample comparisons of means, the Welch version of the t-test was used; associations between variables were examined by Pearson correlation and by multiple linear regression. Results The children received a mean rifampin dosage of 9.61 mg/kg (6.47 to 15.58 body weight at 1 month and 9.63 mg/kg (4.63 to 17.8 at 4 months after commencing treatment administered as part of a fixed-dose formulation designed for paediatric use. The mean rifampin area under the curve 0 to 6 hours after dosing was 14.9 and 18.1 μg/hour/ml (P = 0.25 1 month after starting treatment in human immunodeficiency virus-infected and human immunodeficiency virus-uninfected children, respectively, and 16.52 and 17.94 μg/hour/ml (P = 0.59 after 4 months of treatment. The mean calculated 2-hour rifampin concentrations in these human immunodeficiency virus-infected and human immunodeficiency virus-uninfected children were 3.9 and 4.8

  4. Cannabinoids enhance gastric X/A-like cells activity.

    Directory of Open Access Journals (Sweden)

    Bogusław Sawicki

    2008-06-01

    Full Text Available It has been reported that cannabinoids may cause overeating in humans and in laboratory animals. Although, endogenous cannabinoids and their receptors (CB1 have been found in the hypothalamus, and recently also in gastrointestinal tract, the precise mechanism of appetite control by cannabinoids remains unknown. Recently, ghrelin--a hormone secreted mainly from the stomach X/A-like cells was proposed to be an appetite stimulating agent. The aim of this study was the evaluation of the influence of a single ip injection of a stable analogue of endogenous cannabinoid--anandamide, R-(+-methanandamide (2.5 mg/kg and CP 55,940 (0.25 mg/kg, an exogenous agonist of CB1 receptors, on ghrelin plasma concentration and on ghrelin immunoreactivity in the gastric mucosa of male Wistar rats. Four hours after a single injection of both cannabinoids or vehicle, the animals were anaesthetized and blood was taken from the abdominal aorta to determinate plasma ghrelin concentration by RIA. Subsequently, the animals underwent resection of distal part of stomach. Immunohistochemical study of gastric mucosa, using the EnVision method and specific monoclonal antibodies against ghrelin was performed. The intensity of ghrelin immunoreactivity in X/A-like cells was analyzed using Olympus Cell D image analysis system. The attenuation of ghrelin-immunoreactivity of gastric mucosa, after a single injection of R-(+-methanandamide and CP 55,940 was accompanied by a significant increase of ghrelin plasma concentration. These results indicate that stimulation of appetite exerted by cannabinoids may be connected with an increase of ghrelin secretion from gastric X/A-like cells.

  5. Mass balance, metabolic disposition, and pharmacokinetics of a single oral dose of regorafenib in healthy human subjects.

    Science.gov (United States)

    Gerisch, Michael; Hafner, Frank-Thorsten; Lang, Dieter; Radtke, Martin; Diefenbach, Konstanze; Cleton, Adriaan; Lettieri, John

    2018-01-01

    To evaluate the mass balance, metabolic disposition, and pharmacokinetics of a single dose of regorafenib in healthy volunteers. In addition, in vitro metabolism of regorafenib in human hepatocytes was investigated. Four healthy male subjects received one 120 mg oral dose of regorafenib containing approximately 100 µCi (3.7 MBq) [ 14 C]regorafenib. Plasma concentrations of parent drug were derived from HPLC-MS/MS analysis and total radioactivity from liquid scintillation counting (LSC). Radiocarbon analyses used HPLC with fraction collection followed by LSC for all urine samples, plasma, and fecal homogenate extracts. For the in vitro study, [ 14 C]regorafenib was incubated with human hepatocytes and analyzed using HPLC-LSC and HPLC-HRMS/MS. Regorafenib was the major component in plasma, while metabolite M-2 (pyridine N-oxide) was the most prominent metabolite. Metabolites M-5 (demethylated pyridine N-oxide) and M-7 (N-glucuronide) were identified as minor plasma components. The mean concentration of total radioactivity in plasma/whole blood appeared to plateau at 1-4 h and again at 6-24 h post-dose. In total, 90.5% of administered radioactivity was recovered in the excreta within a collection interval of 12 days, most of which (71.2%) was eliminated in feces, while excretion via urine accounted for 19.3%. Regorafenib (47.2%) was the most prominent component in feces and was not excreted into urine. Excreted metabolites resulted from oxidative metabolism and glucuronidation. Regorafenib was eliminated predominantly in feces as well as by hepatic biotransformation. The multiple biotransformation pathways of regorafenib decrease the risk of pharmacokinetic drug-drug interactions.

  6. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers.

    Science.gov (United States)

    Hirvonen, J; Goodwin, R S; Li, C-T; Terry, G E; Zoghbi, S S; Morse, C; Pike, V W; Volkow, N D; Huestis, M A; Innis, R B

    2012-06-01

    Chronic cannabis (marijuana, hashish) smoking can result in dependence. Rodent studies show reversible downregulation of brain cannabinoid CB(1) (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 CB(1) receptors in human subjects who chronically smoke cannabis. Downregulation correlated with years of cannabis smoking and was selective to cortical brain regions. After ∼4 weeks of continuously monitored abstinence from cannabis on a secure research unit, CB(1) receptor density returned to normal levels. This is the first direct demonstration of cortical cannabinoid CB(1) receptor downregulation as a neuroadaptation that may promote cannabis dependence in human brain.

  7. Phase I safety, tolerability and pharmacokinetic study of recombinant human mannan-binding lectin

    DEFF Research Database (Denmark)

    Petersen, K.A.; Matthiesen, F.; Agger, T.

    2006-01-01

    (rhMBL) is in development as a novel therapeutic approach. To assess the safety, tolerability, and pharmacokinetics of rhMBL, a placebo-controlled double-blinded study was performed in MBL-deficient healthy male subjects. rhMBL was administered as both single intravenous (i.v.) infusions (0.01, 0...... mild and no serious adverse events were recorded. There were no clinically significant changes in laboratory evaluations, ECG or vital signs, and no anti-MBL antibodies were detected following rhMBL administration. After single i.v. doses of rhMBL the maximal plasma levels increased in a dose...... of the complement system without non-specific activation of the complement cascade.In conclusion, no safety or tolerability concern was raised following rhMBL administration no signs of immunogenicity detected, and an rhMBL plasma level judged sufficient to achieve therapeutic benefit (>1000 ng/mL) can be achieved....

  8. Chiral Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine and its Phase I and II Metabolites following Controlled Administration to Humans.

    OpenAIRE

    Steuer Andrea E; Schmidhauser Corina; Schmid Yasmin; Rickli Anna; Liechti Matthias E; Kraemer Thomas

    2015-01-01

    Generally, pharmacokinetic studies on 3,4-methylenedioxymethamphetamine (MDMA) in blood have been performed after conjugate cleavage, without taking into account that phase II metabolites represent distinct chemical entities with their own effects and stereoselective pharmacokinetics. The aim of the present study was to stereoselectively investigate the pharmacokinetics of intact glucuronide and sulfate metabolites of MDMA in blood plasma after a controlled single MDMA dose. Plasma samples fr...

  9. The influence of cannabinoids on learning and memory processes of the dorsal striatum.

    Science.gov (United States)

    Goodman, Jarid; Packard, Mark G

    2015-11-01

    Extensive evidence indicates that the mammalian endocannabinoid system plays an integral role in learning and memory. Our understanding of how cannabinoids influence memory comes predominantly from studies examining cognitive and emotional memory systems mediated by the hippocampus and amygdala, respectively. However, recent evidence suggests that cannabinoids also affect habit or stimulus-response (S-R) memory mediated by the dorsal striatum. Studies implementing a variety of maze tasks in rats indicate that systemic or intra-dorsolateral striatum infusions of cannabinoid receptor agonists or antagonists impair habit memory. In mice, cannabinoid 1 (CB1) receptor knockdown can enhance or impair habit formation, whereas Δ(9)THC tolerance enhances habit formation. Studies in human cannabis users also suggest an enhancement of S-R/habit memory. A tentative conclusion based on the available data is that acute disruption of the endocannabinoid system with either agonists or antagonists impairs, whereas chronic cannabinoid exposure enhances, dorsal striatum-dependent S-R/habit memory. CB1 receptors are required for multiple forms of striatal synaptic plasticity implicated in memory, including short-term and long-term depression. Interactions with the hippocampus-dependent memory system may also have a role in some of the observed effects of cannabinoids on habit memory. The impairing effect often observed with acute cannabinoid administration argues for cannabinoid-based treatments for human psychopathologies associated with a dysfunctional habit memory system (e.g. post-traumatic stress disorder and drug addiction/relapse). In addition, the enhancing effect of repeated cannabinoid exposure on habit memory suggests a novel neurobehavioral mechanism for marijuana addiction involving the dorsal striatum-dependent memory system. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Pharmacokinetics, biodistribution and dosimetry of {sup 99m}Tc-labeled anti-human epidermal growth factor receptor humanized monoclonal antibody R3 in rats

    Energy Technology Data Exchange (ETDEWEB)

    Escobar, Normando Iznaga; Morales, Alejo Morales; Duconge, Jorge; Torres, Idania Caballero; Fernandez, Eduardo; Gomez, Jose A

    1998-01-01

    The pharmacokinetics, biodistribution and dosimetry of {sup 99m}Tc-labeled anti-human epidermal growth factor receptor (anti-hEGF-r) humanized monoclonal antibody (MAb) R3 was investigated following intravenous injection in normal Wistar rats. Serum disappearance curves were best fit by a two-compartment model having a mean distribution half-life (t{sub (1(2{alpha}}{sub ))}) of 0.250 h and a mean elimination (t{sub (1(2{beta}}{sub ))}) of 13.89 h. Among the various organs, a little accumulation of the radiolabeled antibody was found only in kidneys. Biodistribution and dosimetry studies in humans were performed by extrapolation of the animal data to humans. Absorbed dose to normal organs and the remainder of the whole body were estimated using the medical internal radiation dose formula, and dose contributions from radioactivity in transit through the gastrointestinal tract were estimated using a compartment model. Extrapolated values of radiation absorbed dose to normal organs in rads per millicurie administered were whole body, 0.0085; lower large intestine wall, 0.0898; small intestine, 0.0530; upper large intestine wall, 0.0731; and kidneys, 0.0455. The effective dose equivalent predicted was 0.0162 rem/mCi and the effective dose was found to be 0.015 rem/mCi. On the basis of the pharmacokinetics, biodistribution and internal radiation dosimetry information obtained in this study, a diagnostic phase I clinical trial with {sup 99m}Tc-labeled humanized MAb R3 conjugate in patients should be supported.

  11. Pharmacokinetics, biodistribution and dosimetry of 99mTc-labeled anti-human epidermal growth factor receptor humanized monoclonal antibody R3 in rats

    International Nuclear Information System (INIS)

    Escobar, Normando Iznaga; Morales, Alejo Morales; Duconge, Jorge; Torres, Idania Caballero; Fernandez, Eduardo; Gomez, Jose A.

    1998-01-01

    The pharmacokinetics, biodistribution and dosimetry of 99m Tc-labeled anti-human epidermal growth factor receptor (anti-hEGF-r) humanized monoclonal antibody (MAb) R3 was investigated following intravenous injection in normal Wistar rats. Serum disappearance curves were best fit by a two-compartment model having a mean distribution half-life (t (1(2α)) ) of 0.250 h and a mean elimination (t (1(2β)) ) of 13.89 h. Among the various organs, a little accumulation of the radiolabeled antibody was found only in kidneys. Biodistribution and dosimetry studies in humans were performed by extrapolation of the animal data to humans. Absorbed dose to normal organs and the remainder of the whole body were estimated using the medical internal radiation dose formula, and dose contributions from radioactivity in transit through the gastrointestinal tract were estimated using a compartment model. Extrapolated values of radiation absorbed dose to normal organs in rads per millicurie administered were whole body, 0.0085; lower large intestine wall, 0.0898; small intestine, 0.0530; upper large intestine wall, 0.0731; and kidneys, 0.0455. The effective dose equivalent predicted was 0.0162 rem/mCi and the effective dose was found to be 0.015 rem/mCi. On the basis of the pharmacokinetics, biodistribution and internal radiation dosimetry information obtained in this study, a diagnostic phase I clinical trial with 99m Tc-labeled humanized MAb R3 conjugate in patients should be supported

  12. A Population Pharmacokinetic Model for Disposition in Plasma, Saliva and Urine of Scopolamine after Intranasal Administration to Healthy Human Subjects

    Science.gov (United States)

    Wu, L.; Tam, V. H.; Chow, D. S. L.; Putcha, L.

    2014-01-01

    An intranasal gel formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness. The bioavailability and pharmacokinetics (PK) were evaluated under the Food and Drug Administration guidelines for clinical trials with an Investigative New Drug (IND) protocol. The aim of this project was to develop a PK model that can predict the relationship between plasma, saliva and urinary scopolamine concentrations using data collected from the IND clinical trials with INSCOP. Methods: Twelve healthy human subjects were administered three dose levels (0.1, 0.2 and 0.4 mg) of INSCOP. Serial blood, saliva and urine samples were collected between 5 min and 24 h after dosing and scopolamine concentrations were measured by using a validated LC-MS-MS assay. Pharmacokinetic Compartmental models, using actual dosing and sampling times, were built using Phoenix (version 1.2). Model selection was based on the likelihood ratio test on the difference of criteria (-2LL) and comparison of the quality of fit plots. Results: The best structural model for INSCOP (minimal -2LL= 502.8) was established. It consisted of one compartment each for plasma, saliva and urine, respectively, which were connected with linear transport processes except the nonlinear PK process from plasma to saliva compartment. The best-fit estimates of PK parameters from individual PK compartmental analysis and Population PK model analysis were shown in Tables 1 and 2, respectively. Conclusion: A population PK model that could predict population and individual PK of scopolamine in plasma, saliva and urine after dosing was developed and validated. Incorporating a non-linear transfer from plasma to saliva compartments resulted in a significantly improved model fitting. The model could be used to predict scopolamine plasma concentrations from salivary and urinary drug levels, allowing non-invasive therapeutic monitoring of scopolamine in space and other remote environments.

  13. Safety, pharmacokinetic, and efficacy studies of oral DB868 in a first stage vervet monkey model of human African trypanosomiasis.

    Directory of Open Access Journals (Sweden)

    John K Thuita

    Full Text Available There are no oral drugs for human African trypanosomiasis (HAT, sleeping sickness. A successful oral drug would have the potential to reduce or eliminate the need for patient hospitalization, thus reducing healthcare costs of HAT. The development of oral medications is a key objective of the Consortium for Parasitic Drug Development (CPDD. In this study, we investigated the safety, pharmacokinetics, and efficacy of a new orally administered CPDD diamidine prodrug, 2,5-bis[5-(N-methoxyamidino-2-pyridyl]furan (DB868; CPD-007-10, in the vervet monkey model of first stage HAT. DB868 was well tolerated at a dose up to 30 mg/kg/day for 10 days, a cumulative dose of 300 mg/kg. Mean plasma levels of biomarkers indicative of liver injury (alanine aminotransferase, aspartate aminotransferase were not significantly altered by drug administration. In addition, no kidney-mediated alterations in creatinine and urea concentrations were detected. Pharmacokinetic analysis of plasma confirmed that DB868 was orally available and was converted to the active compound DB829 in both uninfected and infected monkeys. Treatment of infected monkeys with DB868 began 7 days post-infection. In the infected monkeys, DB829 attained a median C(max (dosing regimen that was 12-fold (3 mg/kg/day for 7 days, 15-fold (10 mg/kg/day for 7 days, and 31-fold (20 mg/kg/day for 5 days greater than the IC50 (14 nmol/L against T. b. rhodesiense STIB900. DB868 cured all infected monkeys, even at the lowest dose tested. In conclusion, oral DB868 cured monkeys with first stage HAT at a cumulative dose 14-fold lower than the maximum tolerated dose and should be considered a lead preclinical candidate in efforts to develop a safe, short course (5-7 days, oral regimen for first stage HAT.

  14. Cannabinoid modulation of executive functions

    NARCIS (Netherlands)

    Pattij, T.; Wiskerke, J.; Schoffelmeer, A.N.M.

    2008-01-01

    Executive functions are higher-order cognitive processes such as attention, behavioural flexibility, decision-making, inhibitory control, planning, time estimation and working memory that exert top-down control over behaviour. In addition to the role of cannabinoid signaling in other cognitive

  15. Population pharmacokinetic model of THC integrates oral, intravenous, and pulmonary dosing and characterizes short- and long-term pharmacokinetics.

    Science.gov (United States)

    Heuberger, Jules A A C; Guan, Zheng; Oyetayo, Olubukayo-Opeyemi; Klumpers, Linda; Morrison, Paul D; Beumer, Tim L; van Gerven, Joop M A; Cohen, Adam F; Freijer, Jan

    2015-02-01

    Δ(9)-Tetrahydrocannobinol (THC), the main psychoactive compound of Cannabis, is known to have a long terminal half-life. However, this characteristic is often ignored in pharmacokinetic (PK) studies of THC, which may affect the accuracy of predictions in different pharmacologic areas. For therapeutic use for example, it is important to accurately describe the terminal phase of THC to describe accumulation of the drug. In early clinical research, the THC challenge test can be optimized through more accurate predictions of the dosing sequence and the wash-out between occasions in a crossover setting, which is mainly determined by the terminal half-life of the compound. The purpose of this study is to better quantify the long-term pharmacokinetics of THC. A population-based PK model for THC was developed describing the profile up to 48 h after an oral, intravenous, and pulmonary dose of THC in humans. In contrast to earlier models, the current model integrates all three major administration routes and covers the long terminal phase of THC. Results show that THC has a fast initial and intermediate half-life, while the apparent terminal half-life is long (21.5 h), with a clearance of 38.8 L/h. Because the current model characterizes the long-term pharmacokinetics, it can be used to assess the accumulation of THC in a multiple-dose setting and to forecast concentration profiles of the drug under many different dosing regimens or administration routes. Additionally, this model could provide helpful insights into the THC challenge test used for the development of (novel) compounds targeting the cannabinoid system for different therapeutic applications and could improve decision making in future clinical trials.

  16. Vaping Synthetic Cannabinoids: A Novel Preclinical Model of E-Cigarette Use in Mice

    Directory of Open Access Journals (Sweden)

    Timothy W Lefever

    2017-03-01

    Full Text Available Smoking is the most common route of administration for cannabis; however, vaping cannabis extracts and synthetic cannabinoids (“fake marijuana” in electronic cigarette devices has become increasingly popular. Yet, most animal models used to investigate biological mechanisms underlying cannabis use employ injection as the route of administration. This study evaluated a novel e-cigarette device that delivers aerosolized cannabinoids to mice. The effects of aerosolized and injected synthetic cannabinoids (CP 55,940, AB-CHMINACA, XLR-11, and JWH-018 in mice were compared in a battery of bioassays in which psychoactive cannabinoids produce characteristic effects. The most potent cannabinoids (CP 55,940 and AB-CHMINACA produced the full cannabinoid profile (ie, hypothermia, hypolocomotion, and analgesia, regardless of the route of administration. In contrast, aerosolized JWH-018 and XLR-11 did not produce the full profile of cannabimimetic effects. Results of time course analysis for hypothermia showed that aerosol exposure to CP 55,940 and AB-CHMINACA produced faster onset of effects and shorter duration of action than injection. The ability to administer cannabinoids to rodents using the most common route of administration among humans provides a method for collecting preclinical data with enhanced translational relevance.

  17. Preclinical and Clinical Assessment of Cannabinoids as Anti-Cancer Agents

    Directory of Open Access Journals (Sweden)

    Daniel A. Ladin

    2016-10-01

    Full Text Available Cancer is the second leading cause of death in the United States with 1.7 million new cases estimated to be diagnosed in 2016. This disease remains a formidable clinical challenge and represents a substantial financial burden to the US health care system. Therefore, research and development of novel therapeutics for the treatment of cancer is of high priority. Cannabinoids and their derivatives have been utilized for their medicinal and therapeutic properties throughout history. Cannabinoid activity is regulated through the endocannabinoid system, which is comprised of cannabinoid receptors, transporters, and enzymes involved in cannabinoid synthesis and breakdown. More recently, cannabinoids have gained special attention for their role in cancer development and reduction. However, many studies investigated these roles using in vitro models which may not adequately mimic tumor growth and metastasis. As such, this article aims to review study results which evaluated effects of cannabinoids from plant, synthetic and endogenous origins on cancer development in preclinical models and to examine the current standing of cannabinoids currently being tested in human cancer patients.

  18. Vaping Synthetic Cannabinoids: A Novel Preclinical Model of E-Cigarette Use in Mice.

    Science.gov (United States)

    Lefever, Timothy W; Marusich, Julie A; Thomas, Brian F; Barrus, Daniel G; Peiper, Nicholas C; Kevin, Richard C; Wiley, Jenny L

    2017-01-01

    Smoking is the most common route of administration for cannabis; however, vaping cannabis extracts and synthetic cannabinoids ("fake marijuana") in electronic cigarette devices has become increasingly popular. Yet, most animal models used to investigate biological mechanisms underlying cannabis use employ injection as the route of administration. This study evaluated a novel e-cigarette device that delivers aerosolized cannabinoids to mice. The effects of aerosolized and injected synthetic cannabinoids (CP 55,940, AB-CHMINACA, XLR-11, and JWH-018) in mice were compared in a battery of bioassays in which psychoactive cannabinoids produce characteristic effects. The most potent cannabinoids (CP 55,940 and AB-CHMINACA) produced the full cannabinoid profile (ie, hypothermia, hypolocomotion, and analgesia), regardless of the route of administration. In contrast, aerosolized JWH-018 and XLR-11 did not produce the full profile of cannabimimetic effects. Results of time course analysis for hypothermia showed that aerosol exposure to CP 55,940 and AB-CHMINACA produced faster onset of effects and shorter duration of action than injection. The ability to administer cannabinoids to rodents using the most common route of administration among humans provides a method for collecting preclinical data with enhanced translational relevance.

  19. A pharmacokinetic evaluation of five H(1) antagonists after an oral and intravenous microdose to human subjects.

    Science.gov (United States)

    Madan, Ajay; O'Brien, Zhihong; Wen, Jianyun; O'Brien, Chris; Farber, Robert H; Beaton, Graham; Crowe, Paul; Oosterhuis, Berend; Garner, R Colin; Lappin, Graham; Bozigian, Haig P

    2009-03-01

    To evaluate the pharmacokinetics (PK) of five H(1) receptor antagonists in human volunteers after a single oral and intravenous (i.v.) microdose (0.1 mg). Five H(1) receptor antagonists, namely NBI-1, NBI-2, NBI-3, NBI-4 and diphenhydramine, were administered to human volunteers as a single 0.1-mg oral and i.v. dose. Blood samples were collected up to 48 h, and the parent compound in the plasma extract was quantified by high-performance liquid chromatography and accelerator mass spectroscopy. The median clearance (CL), apparent volume of distribution (V(d)) and apparent terminal elimination half-life (t(1/2)) of diphenhydramine after an i.v. microdose were 24.7 l h(-1), 302 l and 9.3 h, and the oral C(max) and AUC(0-infinity) were 0.195 ng ml(-1) and 1.52 ng h ml(-1), respectively. These data were consistent with previously published diphenhydramine data at 500 times the microdose. The rank order of oral bioavailability of the five compounds was as follows: NBI-2 > NBI-1 > NBI-3 > diphenhydramine > NBI-4, whereas the rank order for CL was NBI-4 > diphenhydramine > NBI-1 > NBI-3 > NBI-2. Human microdosing provided estimates of clinical PK of four structurally related compounds, which were deemed useful for compound selection.

  20. A pharmacokinetic evaluation of five H1 antagonists after an oral and intravenous microdose to human subjects

    Science.gov (United States)

    Madan, Ajay; O'Brien, Zhihong; Wen, Jianyun; O'Brien, Chris; Farber, Robert H; Beaton, Graham; Crowe, Paul; Oosterhuis, Berend; Garner, R Colin; Lappin, Graham; Bozigian, Haig P

    2009-01-01

    AIMS To evaluate the pharmacokinetics (PK) of five H1 receptor antagonists in human volunteers after a single oral and intravenous (i.v.) microdose (0.1 mg). METHODS Five H1 receptor antagonists, namely NBI-1, NBI-2, NBI-3, NBI-4 and diphenhydramine, were administered to human volunteers as a single 0.1-mg oral and i.v. dose. Blood samples were collected up to 48 h, and the parent compound in the plasma extract was quantified by high-performance liquid chromatography and accelerator mass spectroscopy. RESULTS The median clearance (CL), apparent volume of distribution (Vd) and apparent terminal elimination half-life (t1/2) of diphenhydramine after an i.v. microdose were 24.7 l h−1, 302 l and 9.3 h, and the oral Cmax and AUC0–∞ were 0.195 ng ml−1 and 1.52 ng h ml−1, respectively. These data were consistent with previously published diphenhydramine data at 500 times the microdose. The rank order of oral bioavailability of the five compounds was as follows: NBI-2 > NBI-1 > NBI-3 > diphenhydramine > NBI-4, whereas the rank order for CL was NBI-4 > diphenhydramine > NBI-1 > NBI-3 > NBI-2. CONCLUSIONS Human microdosing provided estimates of clinical PK of four structurally related compounds, which were deemed useful for compound selection. PMID:19523012

  1. Simultaneous determination of atorvastatin, metformin and glimepiride in human plasma by LC–MS/MS and its application to a human pharmacokinetic study

    Directory of Open Access Journals (Sweden)

    Srinivasa Rao Polagani

    2013-02-01

    Full Text Available A simple, rapid and sensitive liquid chromatography-tandem mass spectrometric (LC–MS/MS assay method has been developed and fully validated for the simultaneous quantification of atorvastatin, metformin and glimepiride in human plasma. Carbamazepine was used as internal standard (IS. The analytes were extracted from 200 μL aliquots of human plasma via protein precipitation using acetonitrile. The reconstituted samples were chromatographed on a Alltima HP C18 column by using a 60:40 (v/v mixture of acetonitrile and 10 mM ammonium acetate (pH 3.0 as the mobile phase at a flow rate of 1.1 mL/min. The calibration curves obtained were linear (r2≥0.99 over the concentration range of 0.50–150.03 ng/mL for atorvastatin, 12.14–1207.50 ng/mL for metformin and 4.98–494.29 ng/mL for glimepiride. The API-4000 LC–MS/MS in multiple reaction monitoring (MRM mode was used for detection. The results of the intra- and inter-day precision and accuracy studies were well within the acceptable limits. All the analytes were found to be stable in a battery of stability studies. The method is precise and sensitive enough for its intended purpose. A run time of 2.5 min for each sample made it possible to analyze more than 300 plasma samples per day. The developed assay method was successfully applied to a pharmacokinetic study in human male volunteers. Keywords: Atorvastatin, Metformin, Glimepiride, LC–MS/MS, Human plasma, Pharmacokinetics

  2. Liquid chromatography tandem mass spectrometry method for the estimation of lamotrigine in human plasma: Application to a pharmacokinetic study

    Directory of Open Access Journals (Sweden)

    Santosh Ghatol

    2013-04-01

    Full Text Available A reliable, selective and sensitive liquid chromatography tandem mass spectrometry method was developed and validated for the quantification of lamotrigine in human plasma using lamotrigine-13C3, d3 as an internal standard. Analyte and internal standard were extracted from human plasma by solid-phase extraction and detected in positive ion mode by tandem mass spectrometry with electrospray ionization (ESI interface. Chromatographic separation was performed on a Chromolith® SpeedROD; RP-18e column (50−4.6 mm i.d. using acetonitrile: 5±0.1 mM ammonium formate solution (90:10, v/v as the mobile phase at a flow rate of 0.500 mL/min. The calibration curves were linear over the range of 5.02–1226.47 ng/mL with the lower limit of quantitation validated at 5.02 ng/mL. The analytes were found stable in human plasma through three freeze (−20 °C-thaw (ice-cold water bath cycles and under storage on bench-top in ice-cold water bath for at least 6.8 h, and also in the mobile phase at 10 °C for at least 57 h. The method has shown good reproducibility, as the intra- and inter-day precisions were within 3.0%, while the accuracies were within ±6.0% of nominal values. The validated LC–MS/MS method was applied for the evaluation of pharmacokinetic and bioequivalence parameters of lamotrigine after an oral administration of 50 mg lamotrigine tablet to thirty-two healthy adult male volunteers. Keywords: Lamotrigine, Liquid chromatography/tandem mass spectrometry, Solid phase extraction, Pharmacokinetic study

  3. Pharmacokinetic/pharmacodynamic modeling of cardiac toxicity in human acute overdoses: utility and limitations.

    Science.gov (United States)

    Mégarbane, Bruno; Aslani, Arsia Amir; Deye, Nicolas; Baud, Frédéric J

    2008-05-01

    Hypotension, cardiac failure, QT interval prolongation, dysrhythmias, and conduction disturbances are common complications of overdoses with cardiotoxicants. Pharmacokinetic/pharmacodynamic (PK/PD) relationships are useful to assess diagnosis, prognosis, and treatment efficacy in acute poisonings. To review the utility and limits of PK/PD studies of cardiac toxicity. Discussion of various models, mainly those obtained in digitalis, cyanide, venlafaxine and citalopram poisonings. A sigmoidal E(max) model appears adequate to represent the PK/PD relationships in cardiotoxic poisonings. PK/PD correlations investigate the discrepancies between the time course of the effect magnitude and its evolving concentrations. They may help in understanding the mechanisms of occurrence as well as disappearance of a cardiotoxic effect. When data are sparse, population-based PK/PD modeling using computer-intensive algorithms is helpful to estimate population mean values of PK parameters as well as their individual variability. Further PK/PD studies are needed in medical toxicology to allow understanding of the meaning of blood toxicant concentration in acute poisonings and thus improve management.

  4. A vapourized Δ(9)-tetrahydrocannabinol (Δ(9)-THC) delivery system part II: comparison of behavioural effects of pulmonary versus parenteral cannabinoid exposure in rodents.

    Science.gov (United States)

    Manwell, Laurie A; Ford, Brittany; Matthews, Brittany A; Heipel, Heather; Mallet, Paul E

    2014-01-01

    Studies of the rewarding and addictive properties of cannabinoids using rodents as animal models of human behaviour often fail to replicate findings from human studies. Animal studies typically employ parenteral routes of administration, whereas humans typically smoke cannabis, thus discrepancies may be related to different pharmacokinetics of parenteral and pulmonary routes of administration. Accordingly, a novel delivery system of vapourized Δ(9)-tetrahydrocannabinol (Δ(9)-THC) was developed and assessed for its pharmacokinetic, pharmacodynamic, and behavioural effects in rodents. A commercially available vapourizer was used to assess the effects of pulmonary (vapourized) administration of Δ(9)-THC and directly compared to parenteral (intraperitoneal, IP) administration of Δ(9)-THC. Sprague-Dawley rats were exposed to pure Δ(9)-THC vapour (1, 2, 5, 10, and 20mg/pad), using a Volcano® vapourizing device (Storz and Bickel, Germany) or IP-administered Δ(9)-THC (0.1, 0.3, 0.5, 1.0mg/kg), and drug effects on locomotor activity, food and water consumption, and cross-sensitization to morphine (5mg/kg) were measured. Vapourized Δ(9)-THC significantly increased feeding during the first hour following exposure, whereas IP-administered Δ(9)-THC failed to produce a reliable increase in feeding at all doses tested. Acute administration of 10mg of vapourized Δ(9)-THC induced a short-lasting stimulation in locomotor activity compared to control in the first of four hours of testing over 7days of repeated exposure; this chronic exposure to 10mg of vapourized Δ(9)-THC did not induce behavioural sensitization to morphine. These results suggest vapourized Δ(9)-THC administration produces behavioural effects qualitatively different from those induced by IP administration in rodents. Furthermore, vapourized Δ(9)-THC delivery in rodents may produce behavioural effects more comparable to those observed in humans. We conclude that some of the conflicting findings in animal

  5. Utility of a human FcRn transgenic mouse model in drug discovery for early assessment and prediction of human pharmacokinetics of monoclonal antibodies

    Science.gov (United States)

    Avery, Lindsay B.; Wang, Mengmeng; Kavosi, Mania S.; Joyce, Alison; Kurz, Jeffrey C.; Fan, Yao-Yun; Dowty, Martin E.; Zhang, Minlei; Zhang, Yiqun; Cheng, Aili; Hua, Fei; Jones, Hannah M.; Neubert, Hendrik; Polzer, Robert J.; O'Hara, Denise M.

    2016-01-01

    ABSTRACT Therapeutic antibodies continue to develop as an emerging drug class, with a need for preclinical tools to better predict in vivo characteristics. Transgenic mice expressing human neonatal Fc receptor (hFcRn) have potential as a preclinical pharmacokinetic (PK) model to project human PK of monoclonal antibodies (mAbs). Using a panel of 27 mAbs with a broad PK range, we sought to characterize and establish utility of this preclinical animal model and provide guidance for its application in drug development of mAbs. This set of mAbs was administered to both hemizygous and homozygous hFcRn transgenic mice (Tg32) at a single intravenous dose, and PK parameters were derived. Higher hFcRn protein tissue expression was confirmed by liquid chromatography-high resolution tandem mass spectrometry in Tg32 homozygous versus hemizygous mice. Clearance (CL) was calculated using non-compartmental analysis and correlations were assessed to historical data in wild-type mouse, non-human primate (NHP), and human. Results show that mAb CL in hFcRn Tg32 homozygous mouse correlate with human (r2 = 0.83, r = 0.91, p PK studies, enhancement of the early selection of lead molecules, and ultimately a decrease in the time for a drug candidate to reach the clinic. PMID:27232760

  6. Safety and Toxicology of Cannabinoids

    OpenAIRE

    Sachs, Jane; McGlade, Erin; Yurgelun-Todd, Deborah

    2015-01-01

    There is extensive research on the safety, toxicology, potency, and therapeutic potential of cannabis. However, uncertainty remains facilitating continued debate on medical and recreational cannabis policies at the state and federal levels. This review will include a brief description of cannabinoids and the endocannabinoid system; a summary of the acute and long-term effects of cannabis; and a discussion of the therapeutic potential of cannabis. The conclusions about safety and efficacy will...

  7. Cannabinoids cases in polish athletes

    Directory of Open Access Journals (Sweden)

    A Pokrywka

    2009-07-01

    Full Text Available The aim of this study was to investigate the number of cases and the profiles of Polish athletes who had occasionally been using marijuana or hashish throughout the period of 1998-2004, with respect to: sex, age, and discipline of sport as well as the period of testing (in- and out-of-competition. Results of the study were compared with some data reported by other WADA accredited anti-doping laboratories. Totally, 13 631 urine samples taken from Polish athletes of both sexes, aged 10-67 years, performing 46 disciplines of sport were tested. Cannabinoids were detected in 267 samples. Among Polish athletes the relative number of positive THC (tetrahydrocannabinol samples was one of the highest in Europe. The group of young Polish athletes (aged 16-24 years was the most THC-positive. THC-positive cases were noted more frequently in male athletes tested during out of competitions. The so-called contact sports (rugby, ice hockey, skating, boxing, badminton, body building and acrobatic sports were those sports, where the higher risk of cannabis use was observed. The legal interpretation of some positive cannabinoids results would be difficult because of some accidental and unintentional use of the narcotics by sportsmen. It was concluded that national anti-doping organizations (NADO’s, which are competent to judge whether the anti-doping rules were violated, should take into account the possibility of non-intentional doping use of cannabinoids via passive smoking of marijuana.

  8. Physiologically based pharmacokinetics of radioiodinated human beta-endorphin in rats. An application of the capillary membrane-limited model

    Energy Technology Data Exchange (ETDEWEB)

    Sato, H.; Sugiyama, Y.; Sawada, Y.; Iga, T.; Hanano, M.

    1987-07-01

    In order to simulate the distribution and elimination of radioiodinated human beta-endorphin (/sup 125/I-beta-EP) after iv bolus injection in rats, we proposed a physiologically based pharmacokinetic model incorporating diffusional transport of /sup 125/I-beta-EP across the capillary membrane. This model assumes that the distribution of /sup 125/I-beta-EP is restricted only within the blood and the tissue interstitial fluid, and that a diffusional barrier across the capillary membrane exists in each tissue except the liver. The tissue-to-blood partition coefficients were estimated from the ratios of the concentration in tissues to that in arterial plasma at the terminal (pseudoequilibrium) phase. The total body plasma clearance (9.0 ml/min/kg) was appropriately assigned to the liver and kidney. The transcapillary diffusion clearances of /sup 125/I-beta-EP were also estimated and shown to correlate linearly with that of inulin in several tissues. Numerically solving the mass-balance differential equations as to plasma and each tissue simultaneously, simulated concentration curves of /sup 125/I-beta-EP corresponded well with the observed data. It was suggested by the simulation that the initial rapid disappearance of /sup 125/I-beta-EP from plasma after iv injection could be attributed in part to the transcapillary diffusion of the peptide.

  9. Pharmacokinetics and Pharmacodynamics of a 13-mer LNA-inhibitor-miR-221 in Mice and Non-human Primates

    Directory of Open Access Journals (Sweden)

    Maria Eugenia Gallo Cantafio

    2016-01-01

    Full Text Available Locked nucleic acid (LNA oligonucleotides have been successfully used to efficiently inhibit endogenous small noncoding RNAs in vitro and in vivo. We previously demonstrated that the direct miR-221 inhibition by the novel 13-mer LNA-i-miR-221 induces significant antimyeloma activity and upregulates canonical miR-221 targets in vitro and in vivo. To evaluate the LNA-i-miR-221 pharmacokinetics and pharmacodynamics, novel assays for oligonucleotides quantification in NOD.SCID mice and Cynomolgus monkeys (Macaca fascicularis plasma, urine and tissues were developed. To this aim, a liquid chromatography/mass spectrometry method, after solid-phase extraction, was used for the detection of LNA-i-miR-221 in plasma and urine, while a specific in situ hybridization assay for tissue uptake analysis was designed. Our analysis revealed short half-life, optimal tissue biovailability and minimal urine excretion of LNA-i-miR-221 in mice and monkeys. Up to 3 weeks, LNA-i-miR-221 was still detectable in mice vital organs and in xenografted tumors, together with p27 target upregulation. Importantly, no toxicity in the pilot monkey study was observed. Overall, our findings indicate the suitability of LNA-i-miR-221 for clinical use and we provide here pilot data for safety analysis and further development of LNA-miRNA-based therapeutics for human cancer.

  10. Rapid Determination of Imatinib in Human Plasma by Liquid Chromatography-Tandem Mass Spectrometry: Application to a Pharmacokinetic Study

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Jeong Soo; Cho, Eun Gi; Huh, Wooseong; Ko, Jaewook; Jung, Jin Ah; Lee, Sooyoun [Samsung Medical Center, Seoul (Korea, Republic of)

    2013-08-15

    A simple, fast and robust analytical method was developed to determine imatinib in human plasma using liquid chromatography-tandem mass spectrometry with electrospray ionization in the positive ion mode. Imatinib and labeled internal standard were extracted from plasma with a simple protein precipitation. The chromatographic separation was performed using an isocratic elution of mobile phase involving 5.0 mM ammonium formate in water -5.0 mM ammonium formate in methanol (30:70, v/v) over 3.0 min on reversed-stationary phase. The detection was performed using a triple-quadrupole tandem mass spectrometer in multiple-reaction monitoring mode. The developed method was validated with lower limit of quantification of 10 ng/mL. The calibration curve was linear over 10-2000 ng/mL (R{sup 2} > 0.99). The method validation parameters met the acceptance criteria. The spiked samples and standard solutions were stable under conditions for storage and handling. The reliable method was successfully applied to real sample analyses and thus a pharmacokinetic study in 27 healthy Korean male volunteers.

  11. Determination of cyclovirobuxine D in human plasma by liquid chromatography tandem mass spectrometry and application in a pharmacokinetic study

    Directory of Open Access Journals (Sweden)

    Ling-li Mu

    2011-10-01

    Full Text Available A sensitive and reliable method based on liquid chromatography tandem mass spectrometry (LC–MS/MS for the quantitation of cyclovirobuxine D in human plasma has been developed and validated. Sample preparation by solid phase extraction was followed by separation on a CN column with a mobile phase of methanol–water (95:5, v/v containing 0.2% formic acid. Mass spectrometric detection in the positive ion mode was carried out by selected reaction monitoring (SRM of the transitions at m/z 403.0→372.0 for cyclovirobuxine D and m/z 325.0→234.0 for citalopram (internal standard. The method was linear in the range 10–200 ng/L with LLOQ of 10 ng/L, recovery >85%, and no significant matrix effects. Intra- and inter-day precisions were all <9% with accuracies of 94.0–104.8%. The method was successfully applied to a pharmacokinetic study involving a single oral administration of a 2 mg cyclovirobuxine D tablet to twenty-two healthy Chinese volunteers.

  12. Determination of fenticonazole in human plasma by HPLC–MS/MS and its application to pharmacokinetic studies

    Directory of Open Access Journals (Sweden)

    Weixing Mao

    2017-02-01

    Full Text Available Two simple and sensitive high performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS methods were developed and validated for the determination of fenticonazole in human plasma after percutaneous and intravaginal administration. Mifepristone was used as an internal standard (IS, and simple protein precipitation by acetonitrile containing 2% acetic acid was utilized for extracting the analytes from the plasma samples. Chromatographic separation was performed on a Kinetex XB-C18 column. The quantitation was performed by a mass spectrometer equipped with an electrospray ionization source in multiple reactions monitoring (MRM positive ion mode using precursor-to-product ion transitions of m/z 455.2–199.1 for fenticonazole and m/z 430.2–372.3 for mifepristone. The validated linear ranges were 5–1000 pg/mL and 0.1–20 ng/mL fenticonazole in plasma for the methods A and B, respectively. For the two methods, the accuracy data ranged from 85% to 115%, the intra- and inter-batch precision data were less than 15%, the recovery data were more than 90%, and no matrix interference was observed. The methods A and B were successfully validated and applied to the pharmacokinetic studies of fenticonazole gel in Chinese healthy volunteers after percutaneous and intravaginal administration, respectively.

  13. Separate and combined effects of the cannabinoid agonists nabilone and Δ⁹-THC in humans discriminating Δ⁹-THC.

    Science.gov (United States)

    Lile, Joshua A; Kelly, Thomas H; Hays, Lon R

    2011-07-01

    Agonist replacement treatment is a promising strategy to manage cannabis-use disorders. The aim of this study was to assess the combined effects of the synthetic cannabinoid agonist nabilone and Δ⁹-tetrahydrocannabinol (Δ⁹-THC) using drug-discrimination procedures, which are sensitive to drug interactions. Testing the concurrent administration of nabilone and Δ⁹-THC was also conducted to provide initial safety and tolerability data, which is important because cannabis users will likely lapse during treatment. Six cannabis users learned to discriminate 30 mg oral Δ⁹-THC from placebo and then received nabilone (0, 1 and 3mg) and Δ⁹-THC (0, 5, 15 and 30 mg), alone and in combination. Subjects completed the multiple-choice procedure to assess drug reinforcement, and self-report, task performance and physiological measures were collected. Δ⁹-THC and nabilone alone shared discriminative-stimulus effects with the training dose of Δ⁹-THC, increased crossover point on the multiple-choice procedure, produced overlapping subject ratings and decreased skin temperature. Nabilone alone also elevated heart rate. In combination, nabilone shifted the discriminative-stimulus effects of Δ⁹-THC leftward/upward and enhanced Δ⁹-THC effects on the other outcome measures. These results replicate a previous study demonstrating that nabilone shares agonist effects with the active constituent of cannabis in cannabis users, and contribute further by indicating that nabilone would likely be safe and well tolerated when combined with cannabis. These data support the conduct of future studies to determine if nabilone treatment would produce cross-tolerance to the abuse-related effects of cannabis and reduce cannabis use. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  14. Biodistribution and dosimetry in humans of two inverse agonists to image cannabinoid CB{sub 1} receptors using positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Terry, Garth E. [National Institute of Mental Health, Molecular Imaging Branch, Bethesda, MD (United States); Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Stockholm (Sweden); Hirvonen, Jussi; Liow, Jeih-San; Seneca, Nicholas; Morse, Cheryl L.; Pike, Victor W.; Innis, Robert B. [National Institute of Mental Health, Molecular Imaging Branch, Bethesda, MD (United States); Tauscher, Johannes T.; Schaus, John M.; Phebus, Lee; Felder, Christian C. [Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN (United States); Halldin, Christer [Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Stockholm (Sweden)

    2010-08-15

    Cannabinoid subtype 1 (CB{sub 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. We recently reported brain imaging of CB{sub 1} receptors with two PET radioligands: {sup 11}C-MePPEP and {sup 18}F-FMPEP-d{sub 2}. Here we describe the biodistribution and dosimetry estimates for these two radioligands. Seven healthy subjects (four men and three women) underwent whole-body PET scans for 120 min after injection with {sup 11}C-MePPEP. Another seven healthy subjects (two men and five women) underwent whole-body PET scans for 300 min after injection with {sup 18}F-FMPEP-d{sub 2}. 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 {sup 18}F-FMPEP-d{sub 2}. The effective doses of {sup 11}C-MePPEP and {sup 18}F-FMPEP-d{sub 2} are 4.6 and 19.7 {mu}Sv/MBq, respectively. 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. After injection of {sup 11}C-MePPEP, radioactivity apparently underwent hepatobiliary excretion only, while radioactivity from {sup 18}F-FMPEP-d{sub 2} showed both hepatobiliary and urinary excretion. {sup 11}C-MePPEP and {sup 18}F-FMPEP-d{sub 2} yield an effective dose similar to other PET radioligands labeled with either {sup 11}C or {sup 18}F. The high uptake in brain confirms the utility of these two radioligands to image CB{sub 1} receptors in brain, and both may also be useful to image CB{sub 1} receptors in the periphery. (orig.)

  15. The absorption and uptake of recombinant human follicle-stimulating hormone through vaginal subcutaneous injections - a pharmacokinetic study

    Science.gov (United States)

    Hsu, Chao-Chin; Kuo, Hsin-Chih; Hsu, Chao-Tien; Gu, Qing

    2009-01-01

    Background Follicle stimulating hormone (FSH) has been routinely used for ovulation induction. Because of rapid clearance of the hormone, FSH is commonly administered by daily intramuscular or subcutaneous injections in in-vitro fertilization (IVF). To reduce the number of visits to the clinic, an intermittent vaginal injection of rhFSH every 3 days employing the concepts of mesotherapy and uterine first-pass effect was invented and has successfully been applied in women receiving IVF treatment. This study was designed to monitor the pharmacokinetic pattern of rhFSH administered vaginally. Methods Twelve healthy women with regular ovulatory cycles were recruited. All volunteers received gonadotrophin-releasing hormone agonist to suppress pituitary function and were assigned to receive single dose recombinant human FSH (rhFSH, Puregon 300) either using conventional abdominal subcutaneous injection or vaginal subcutaneous injection in a randomized cross-over study. Serum samples were collected at pre- scheduled time intervals after injections of rhFSH to determine immunoreactive FSH levels. Pharmacokinetic parameters characterizing rate [maximal plasma concentrations (Cmax) and time of maximal plasma concentrations (tmax)] and extent [area under the plasma concentration-time curve (AUC) and clearance] of absorption of rhFSH were compared. Results Vaginal injection of rhFSH was well tolerated and no drug-related adverse reaction was noted. Our analysis revealed that tmax was significantly earlier (mean 6.67 versus 13.33 hours) and Cmax was significantly higher (mean 17.77 versus 13.96 IU/L) in vaginal versus abdominal injections. The AUC0-∞ was 1640 versus 1134 IU·hour/L in vaginal and abdominal injections, respectively. Smaller plasma elimination rate constant (0.011 versus 0.016 hour-1), longer mean residence time (106.58 versus 70.47 hours), and slower total body clearance (292.2 versus 400.1 mL/hour) were also found in vaginal injection. Conclusion The vaginal

  16. The absorption and uptake of recombinant human follicle-stimulating hormone through vaginal subcutaneous injections - a pharmacokinetic study

    Directory of Open Access Journals (Sweden)

    Kuo Hsin-Chih

    2009-10-01

    Full Text Available Abstract Background Follicle stimulating hormone (FSH has been routinely used for ovulation induction. Because of rapid clearance of the hormone, FSH is commonly administered by daily intramuscular or subcutaneous injections in in-vitro fertilization (IVF. To reduce the number of visits to the clinic, an intermittent vaginal injection of rhFSH every 3 days employing the concepts of mesotherapy and uterine first-pass effect was invented and has successfully been applied in women receiving IVF treatment. This study was designed to monitor the pharmacokinetic pattern of rhFSH administered vaginally. Methods Twelve healthy women with regular ovulatory cycles were recruited. All volunteers received gonadotrophin-releasing hormone agonist to suppress pituitary function and were assigned to receive single dose recombinant human FSH (rhFSH, Puregon 300 either using conventional abdominal subcutaneous injection or vaginal subcutaneous injection in a randomized cross-over study. Serum samples were collected at pre- scheduled time intervals after injections of rhFSH to determine immunoreactive FSH levels. Pharmacokinetic parameters characterizing rate [maximal plasma concentrations (Cmax and time of maximal plasma concentrations (tmax] and extent [area under the plasma concentration-time curve (AUC and clearance] of absorption of rhFSH were compared. Results Vaginal injection of rhFSH was well tolerated and no drug-related adverse reaction was noted. Our analysis revealed that tmax was significantly earlier (mean 6.67 versus 13.33 hours and Cmax was significantly higher (mean 17.77 versus 13.96 IU/L in vaginal versus abdominal injections. The AUC0-∞ was 1640 versus 1134 IU·hour/L in vaginal and abdominal injections, respectively. Smaller plasma elimination rate constant (0.011 versus 0.016 hour-1, longer mean residence time (106.58 versus 70.47 hours, and slower total body clearance (292.2 versus 400.1 mL/hour were also found in vaginal injection

  17. Determination of Acyclovir in Human Plasma Samples by HPLC Method with UV Detection: Application to Single-Dose Pharmacokinetic Study

    Directory of Open Access Journals (Sweden)

    Dragica Zendelovska

    2015-03-01

    CONCLUSION: Good precision, accuracy, simplicity, sensitivity and shorter time of analysis of the method makes it particularly useful for processing of multiple samples in a limited period of time for pharmacokinetic study of acyclovir.

  18. Pharmacokinetics of IDX184, a liver-targeted oral prodrug of 2'-methylguanosine-5'-monophosphate, in the monkey and formulation optimization for human exposure.

    Science.gov (United States)

    Pan-Zhou, Xin-Ru; Mayes, Benjamin A; Rashidzadeh, Hassan; Gasparac, Rahela; Smith, Steven; Bhadresa, Sanjeev; Gupta, Kusum; Cohen, Marita Larsson; Bu, Charlie; Good, Steven S; Moussa, Adel; Rush, Roger

    2016-10-01

    IDX184 is a phosphoramidate prodrug of 2'-methylguanosine-5'-monophosphate, developed to treat patients infected with hepatitis C virus. A mass balance study of radiolabeled IDX184 and pharmacokinetic studies of IDX184 in portal vein-cannulated monkeys revealed relatively low IDX184 absorption but higher exposure of IDX184 in the portal vein than in the systemic circulation, indicating >90 % of the absorbed dose was subject to hepatic extraction. Systemic exposures to the main metabolite, 2'-methylguanosine (2'-MeG), were used as a surrogate for liver levels of the pharmacologically active entity 2'-MeG triphosphate, and accordingly, systemic levels of 2'-MeG in the monkey were used to optimize formulations for further clinical development of IDX184. Capsule formulations of IDX184 delivered acceptable levels of 2'-MeG in humans; however, the encapsulation process introduced low levels of the genotoxic impurity ethylene sulfide (ES), which necessitated formulation optimization. Animal pharmacokinetic data guided the development of a tablet with trace levels of ES and pharmacokinetic performance equal to that of the clinical capsule in the monkey. Under fed conditions in humans, the new tablet formulation showed similar exposure to the capsule used in prior clinical trials.

  19. Phase I metabolism of the carbazole derived synthetic cannabinoids EG-018, EG-2201 and MDMB-CHMCZCA and detection in human urine samples.

    Science.gov (United States)

    Mogler, Lukas; Franz, Florian; Wilde, Maurice; Huppertz, Laura M; Halter, Sebastian; Angerer, Verena; Moosmann, Bjoern; Auwärter, Volker

    2018-05-04

    Synthetic cannabinoids (SCs) are a structurally diverse class of new psychoactive substances. Most SCs used for recreational purposes are based on indole or indazole core structures. EG-018 (naphthalen-1-yl(9-pentyl-9H-carbazol-3-yl)methanone), EG-2201 ((9-(5-fluoropentyl)-9H-carbazol-3-yl)(naphthalen-1-yl)methanone) and MDMB-CHMCZCA (methyl 2-(9-(cyclohexylmethyl)-9H-carbazole-3-carboxamido)-3,3-dimethylbutanoate) are three representatives of a structural subclass of SCs, characterized by a carbazole core system. In vitro and in vivo phase I metabolism studies were conducted to identify the most suitable metabolites for the detection of these substances in urine screening. Detection and characterization of metabolites were performed by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) and liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry (LC-ESI-QToF-MS). Eleven in vivo metabolites were detected in urine samples positive for metabolites of EG-018 (n=8). A hydroxypentyl metabolite, most probably the 4-hydroxypentyl isomer, and an N-dealkylated metabolite mono-hydroxylated at the carbazole core system were most abundant. In vitro studies of EG-018 and EG-2201 indicated that oxidative defluorination of the 5-fluoropentyl side chain of EG-2201 as well as dealkylation led to common metabolites with EG-018. This has to be taken into account for interpretation of analytical findings. A differentiation between EG-018 and EG-2201 (n=1) uptake is possible by the detection of compound-specific in vivo phase I metabolites evaluated in this study. Out of 30 metabolites detected in urine samples of MDMB-CHMCZCA users (n=20), one metabolite mono-hydroxylated at the cyclohexyl methyl tail is considered the most suitable compound-specific consumption marker while a biotransformation product of mono-hydroxylation in combination with hydrolysis of the terminal methyl ester function provides best sensitivity

  20. Cannabis and Cannabinoids for Chronic Pain.

    Science.gov (United States)

    Romero-Sandoval, E Alfonso; Kolano, Ashley L; Alvarado-Vázquez, P Abigail

    2017-10-05

    The purpose of this study was to provide the most up-to-date scientific evidence of the potential analgesic effects, or lack thereof, of the marijuana plant (cannabis) or cannabinoids, and of safety or tolerability of their long-term use. We found that inhaled (smoked or vaporized) cannabis is consistently effective in reducing chronic non-cancer pain. Oral cannabinoids seem to improve some aspects of chronic pain (sleep and general quality of life), or cancer chronic pain, but they do not seem effective in acute postoperative pain, abdominal chronic pain, or rheumatoid pain. The available literature shows that inhaled cannabis seems to be more tolerable and predictable than oral cannabinoids. Cannabis or cannabinoids are not universally effective for pain. Continued research on cannabis constituents and improving bioavailability for oral cannabinoids is needed. Other aspects of pain management in patients using cannabis require further open discussion: concomitant opioid use, medical vs. recreational cannabis, abuse potential, etc.

  1. The pharmacokinetics, distribution and degradation of human recombinant interleukin 1 beta in normal rats

    DEFF Research Database (Denmark)

    Reimers, J; Wogensen, L D; Welinder, B

    1991-01-01

    Based upon in vivo rat experiments it was recently suggested that interleukin 1 in the circulation may be implicated in the initial events of beta-cell destruction leading to insulin-dependent diabetes mellitus (IDDM) in humans. The aim of the present study was to estimate half-lives of distribut......Based upon in vivo rat experiments it was recently suggested that interleukin 1 in the circulation may be implicated in the initial events of beta-cell destruction leading to insulin-dependent diabetes mellitus (IDDM) in humans. The aim of the present study was to estimate half......-lives of distribution (T1/2 alpha) and elimination phases (T1/2 beta) of human recombinant interleukin 1 beta (rIL-1 beta), and its tissue distribution and cellular localization by means of mono-labelled, biologically active 125I-rIL-1 beta. After intravenous (i.v.) injection, 125I-rIL-1 beta was eliminated from.......v., intraperitoneal (i.p.) and subcutaneous (s.c.) injections, as demonstrated by high performance size exclusion chromatography, trichloracetic acid precipitation and SDS-PAGE until 5 h after tracer injection. Pre-treatment with 'cold' rIL-1 beta enhanced degradation of a subsequent injection of tracer. The route...

  2. Combined image guided monitoring the pharmacokinetics of rapamycin loaded human serum albumin nanoparticles with a split luciferase reporter

    Science.gov (United States)

    Wang, Fu; Yang, Kai; Wang, Zhe; Ma, Ying; Gutkind, J. Silvio; Hida, Naoki; Niu, Gang; Tian, Jie

    2016-02-01

    Imaging guided techniques have been increasingly employed to investigate the pharmacokinetics (PK) and biodistribution of nanoparticle based drug delivery systems. In most cases, however, the PK profiles of drugs could vary significantly from those of drug delivery carriers upon administration in the blood circulation, which complicates the interpretation of image findings. Herein we applied a genetically encoded luciferase reporter in conjunction with near infrared (NIR) fluorophores to investigate the respective PK profiles of a drug and its carrier in a biodegradable drug delivery system. In this system, a prototype hydrophobic agent, rapamycin (Rapa), was encapsulated into human serum albumin (HSA) to form HSA Rapa nanoparticles, which were then labeled with Cy5 fluorophore to facilitate the fluorescence imaging of HSA carrier. Meanwhile, we employed transgenetic HN12 cells that were modified with a split luciferase reporter, whose bioluminescence function is regulated by Rapa, to reflect the PK profile of the encapsulated agent. It was interesting to discover that there existed an obvious inconsistency of PK behaviors between HSA carrier and rapamycin in vitro and in vivo through near infrared fluorescence imaging (NIFRI) and bioluminescence imaging (BLI) after treatment with Cy5 labeled HSA Rapa. Nevertheless, HSA Rapa nanoparticles manifested favorable in vivo PK and tumor suppression efficacy in a follow-up therapeutic study. The developed strategy of combining a molecular reporter and a fluorophore in this study could be extended to other drug delivery systems to provide profound insights for non-invasive real-time evaluation of PK profiles of drug-loaded nanoparticles in pre-clinical studies.Imaging guided techniques have been increasingly employed to investigate the pharmacokinetics (PK) and biodistribution of nanoparticle based drug delivery systems. In most cases, however, the PK profiles of drugs could vary significantly from those of drug delivery

  3. Population Physiologically-Based Pharmacokinetic Modeling for the Human Lactational Transfer of PCB 153 with Consideration of Worldwide Human Biomonitoring Results

    Energy Technology Data Exchange (ETDEWEB)

    Redding, Laurel E.; Sohn, Michael D.; McKone, Thomas E.; Wang, Shu-Li; Hsieh, Dennis P. H.; Yang, Raymond S. H.

    2008-03-01

    We developed a physiologically based pharmacokinetic model of PCB 153 in women, and predict its transfer via lactation to infants. The model is the first human, population-scale lactational model for PCB 153. Data in the literature provided estimates for model development and for performance assessment. Physiological parameters were taken from a cohort in Taiwan and from reference values in the literature. We estimated partition coefficients based on chemical structure and the lipid content in various body tissues. Using exposure data in Japan, we predicted acquired body burden of PCB 153 at an average childbearing age of 25 years and compare predictions to measurements from studies in multiple countries. Forward-model predictions agree well with human biomonitoring measurements, as represented by summary statistics and uncertainty estimates. The model successfully describes the range of possible PCB 153 dispositions in maternal milk, suggesting a promising option for back estimating doses for various populations. One example of reverse dosimetry modeling was attempted using our PBPK model for possible exposure scenarios in Canadian Inuits who had the highest level of PCB 153 in their milk in the world.

  4. Pharmacokinetics of resveratrol metabolic profile in healthy humans after moderate consumption of red wine and grape extract tablets.

    Science.gov (United States)

    Rotches-Ribalta, Maria; Andres-Lacueva, Cristina; Estruch, Ramon; Escribano, Elvira; Urpi-Sarda, Mireia

    2012-11-01

    A pharmacokinetic study of the metabolic profile of resveratrol has been performed in healthy men after moderate red wine (RW) consumption. The bioavailability of resveratrol is highly influenced by several factors such as the food matrix and, therefore, this study has been compared with a pilot study in which men ingested grape extract (GE) tablets as a nutraceutical, containing similar total amounts of resveratrol than RW. Blood and urine samples were taken before and at several time points after intervention and then analyzed by SPE and LC-ESI-MS/MS. Up to 17 resveratrol and piceid derivatives were identified, including those formed by the intestinal microbiota. Resveratrol glucosides were found in plasma as intact forms and reached the lowest maximum concentrations 1h after both interventions. Higher plasma concentrations and longer times (t(max)) were observed for resveratrol glucuronides due to phase II metabolism and even higher values for conjugates derived from microbiota, such as dihydroresveratrol-glucuronides. The same trend was observed for total excreted amounts in urine samples. When both treatments were compared, statistically significant differences for some metabolites were obtained, which may be due to the different composition of resveratrol and piceid in both sources. However, GE formulation seems to delay resveratrol absorption, staying longer in the gut where could be metabolized to a greater degree, since 2.1-3.6-fold higher urinary concentrations of microbial metabolites were observed after GE intervention at 12-24h urinary fraction. Therefore, supplement intake could be also a way to bring resveratrol benefits to human health. Copyright © 2012 Elsevier Ltd. All rights reserved.

  5. A model-based meta-analysis of monoclonal antibody pharmacokinetics to guide optimal first-in-human study design

    Science.gov (United States)

    Davda, Jasmine P; Dodds, Michael G; Gibbs, Megan A; Wisdom, Wendy; Gibbs, John P

    2014-01-01

    The objectives of this retrospective analysis were (1) to characterize the population pharmacokinetics (popPK) of four different monoclonal antibodies (mAbs) in a combined analysis of individual data collected during first-in-human (FIH) studies and (2) to provide a scientific rationale for prospective design of FIH studies with mAbs. The data set was composed of 171 subjects contributing a total of 2716 mAb serum concentrations, following intravenous (IV) and subcutaneous (SC) doses. mAb PK was described by an open 2-compartment model with first-order elimination from the central compartment and a depot compartment with first-order absorption. Parameter values obtained from the popPK model were further used to generate optimal sampling times for a single dose study. A robust fit to the combined data from four mAbs was obtained using the 2-compartment model. Population parameter estimates for systemic clearance and central volume of distribution were 0.20 L/day and 3.6 L with intersubject variability of 31% and 34%, respectively. The random residual error was 14%. Differences (> 2-fold) in PK parameters were not apparent across mAbs. Rich designs (22 samples/subject), minimal designs for popPK (5 samples/subject), and optimal designs for non-compartmental analysis (NCA) and popPK (10 samples/subject) were examined by stochastic simulation and estimation. Single-dose PK studies for linear mAbs executed using the optimal designs are expected to yield high-quality model estimates, and accurate capture of NCA estimations. This model-based meta-analysis has determined typical popPK values for four mAbs with linear elimination and enabled prospective optimization of FIH study designs, potentially improving the efficiency of FIH studies for this class of therapeutics. PMID:24837591

  6. Preclinical Characterization and Human Microdose Pharmacokinetics of ITMN-8187, a Nonmacrocyclic Inhibitor of the Hepatitis C Virus NS3 Protease.

    Science.gov (United States)

    Rajagopalan, Ravi; Pan, Lin; Schaefer, Caralee; Nicholas, John; Lim, Sharlene; Misialek, Shawn; Stevens, Sarah; Hooi, Lisa; Aleskovski, Natalia; Ruhrmund, Donald; Kossen, Karl; Huang, Lea; Yap, Sophia; Beigelman, Leonid; Serebryany, Vladimir; Liu, Jyanwei; Sastry, Srikonda; Seiwert, Scott; Buckman, Brad

    2017-01-01

    The current paradigm for the treatment of chronic hepatitis C virus (HCV) infection involves combinations of agents that act directly on steps of the HCV life cycle. Here we report the preclinical characteristics of ITMN-8187, a nonmacrocyclic inhibitor of the NS3/4A HCV protease. X-ray crystallographic studies of ITMN-8187 and simeprevir binding to NS3/4A protease demonstrated good agreement between structures. Low nanomolar biochemical potency was maintained against NS3/4A derived from HCV genotypes 1, 2b, 4, 5, and 6. In cell-based potency assays, half-maximal reduction of genotype 1a and 1b HCV replicon RNA was afforded by 11 and 4 nM doses of ITMN-8187, respectively. Combinations of ITMN-8187 with other directly acting antiviral agents in vitro displayed additive antiviral efficacy. A 30-mg/kg of body weight dose of ITMN-8187 administered for 4 days yielded significant viral load reductions through day 5 in a chimeric mouse model of HCV. A 3-mg/kg oral dose administered to rats, dogs, or monkeys yielded concentrations in plasma 16 h after dosing that exceeded the half-maximal effective concentration of ITMN-8187. Human microdose pharmacokinetics showed low intersubject variability and prolonged oral absorption with first-order elimination kinetics compatible with once-daily dosing. These preclinical characteristics compare favorably with those of other NS3/4A inhibitors approved for the treatment of chronic HCV infection. Copyright © 2016 American Society for Microbiology.

  7. In vitro enantioselective human liver microsomal metabolism and prediction of in vivo pharmacokinetic parameters of tetrabenazine by DLLME-CE.

    Science.gov (United States)

    Bocato, Mariana Zuccherato; de Lima Moreira, Fernanda; de Albuquerque, Nayara Cristina Perez; de Gaitani, Cristiane Masetto; de Oliveira, Anderson Rodrigo Moraes

    2016-09-05

    A new capillary electrophoresis method for the enantioselective analysis of cis- and trans- dihydrotetrabenazine (diHTBZ) after in vitro metabolism by human liver microsomes (HLMs) was developed. The chiral electrophoretic separations were performed by using tris-phosphate buffer (pH 2.5) containing 1% (w/v) carboxymethyl-β-CD as background electrolyte with an applied voltage of +15kV and capillary temperature kept at 15°C. Dispersive liquid-liquid microextraction was employed to extract the analytes from HLMs. Dichloromethane was used as extraction solvent (75μL) and acetone as disperser solvent (150μL). The method was validated according to official guidelines and showed to be linear over the concentration range of 0.29-19.57μmolL(-1) (r=0.9955) for each metabolite enantiomer. Within- and between-day precision and accuracy evaluated by relative standard deviation and relative error were lower than 15% for all enantiomers. The stability assay showed that the analytes kept stable under handling, storage and in metabolism conditions. After method validation, an enantioselective in vitro metabolism and in vivo pharmacokinetic prediction was carried out. This study showed a stereoselective metabolism and the observed kinetic profile indicated a substrate inhibition behavior. DiHTBZ enantiomers were catalyzed mainly by CYP2C19 and the predicted clearance suggests that liver metabolism is the main route for TBZ elimination which supports the literature data. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Prediction of Deoxypodophyllotoxin Disposition in Mouse, Rat, Monkey and Dog by Physiologically-based Pharmacokinetic Model and the Extrapolation to Human

    Directory of Open Access Journals (Sweden)

    Yang Chen

    2016-12-01

    Full Text Available Deoxypodophyllotoxin (DPT is a potential anti-tumor candidate prior to its clinical phase. The aim of the study was to develop a physiologically-based pharmacokinetic (PBPK model consisting of 13 tissue compartments to predict DPT disposition in mouse, rat, monkey and dog based on in vitro and in silico inputs. Since large interspecies difference was found in unbound fraction of DPT in plasma, we assumed that Kt:pl,u (unbound tissue-to-plasma concentration ratio was identical across species. The predictions of our model were then validated by in vivo data of corresponding preclinical species, along with visual predictive checks. Reasonable matches were found between observed and predicted plasma concentrations and pharmacokinetic parameters in all four animal species. The prediction in the related seven tissues of mouse was also desirable. We also attempted to predict human pharmacokinetic profile by both the developed PBPK model and interspecies allometric scaling across mouse, rat and monkey, while dog was excluded from the scaling. The two approaches reached similar results. We hope the study will help in the efficacy and safety assessment of DPT in future clinical studies and provide a reference to the preclinical screening of similar compounds by PBPK model.

  9. Safety and Toxicology of Cannabinoids.

    Science.gov (United States)

    Sachs, Jane; McGlade, Erin; Yurgelun-Todd, Deborah

    2015-10-01

    There is extensive research on the safety, toxicology, potency, and therapeutic potential of cannabis. However, uncertainty remains facilitating continued debate on medical and recreational cannabis policies at the state and federal levels. This review will include a brief description of cannabinoids and the endocannabinoid system; a summary of the acute and long-term effects of cannabis; and a discussion of the therapeutic potential of cannabis. The conclusions about safety and efficacy will then be compared with the current social and political climate to suggest future policy directions and general guidelines.

  10. Safety, pharmacokinetics, metabolism and radiation dosimetry of 18F-tetrafluoroborate (18F-TFB) in healthy human subjects.

    Science.gov (United States)

    Jiang, Huailei; Schmit, Nicholas R; Koenen, Alex R; Bansal, Aditya; Pandey, Mukesh K; Glynn, Robert B; Kemp, Bradley J; Delaney, Kera L; Dispenzieri, Angela; Bakkum-Gamez, Jamie N; Peng, Kah-Whye; Russell, Stephen J; Gunderson, Tina M; Lowe, Val J; DeGrado, Timothy R

    2017-10-27

    18 F-Tetrafluoroborate ( 18 F-TFB) is a promising iodide analog for PET imaging of thyroid cancer and sodium/iodide symporter (NIS) reporter activity in viral therapy applications. The aim of this study was to evaluate the safety, pharmacokinetics, biodistribution, and radiation dosimetry of high-specific activity 18 F-TFB in healthy human subjects. 18 F-TFB was synthesized with specific activity of 3.2 ± 1.3 GBq/μmol (at the end of synthesis). Dynamic and whole-body static PET/CT scans over 4 h were performed after intravenous administration of 18 F-TFB (333-407 MBq) in four female and four male healthy volunteers (35 ± 11 years old). Samples of venous blood and urine were collected over the imaging period and analyzed by ion-chromatography HPLC to determine tracer stability. Vital signs and clinical laboratory safety assays were measured to evaluate safety. 18 F-TFB administration was well tolerated with no significant findings on vital signs and no clinically meaningful changes in clinical laboratory assays. Left-ventricular blood pool time-activity curves showed a multi-phasic blood clearance of 18 F-radioactivity with the two rapid clearance phases over the first 20 min, followed by a slower clearance phase. HPLC analysis showed insignificant 18 F-labeled metabolites in the blood and urine over the length of the study (4 h). High uptakes were seen in the thyroid, stomach, salivary glands, and bladder. Urinary clearance of 18 F-TFB was prominent. Metabolic stability was evidenced by low accumulation of 18 F-radioactivity in the bone. Effective doses were 0.036 mSv/MBq in males and 0.064 mSv/MBq in females (p = 0.08, not significant). This initial study in healthy human subjects showed 18 F-TFB was safe and distributed in the human body similar to other iodide analogs. These data support further translational studies with 18 F-TFB as NIS gene reporter and imaging biomarker for thyroid cancer and other disease processes that import iodide.

  11. Pharmacokinetic characteristics of formulated alendronate transdermal delivery systems in rats and humans.

    Science.gov (United States)

    Choi, Ahyoung; Gang, Hyesil; Whang, Jiae; Gwak, Hyesun

    2010-05-01

    The objective of this study was to examine the absorption of alendronate from formulated transdermal delivery systems in rats and humans. When alendronate was applied to rats by transdermal delivery systems (7.2 mg) and oral administration (30 mg/kg), a statistically significant difference was found in the amount remaining to be excreted at time t (Ae(t)) and the amount remaining to be excreted at time 0 (Ae(infinity)) (p transdermal delivery systems. There was a linear relationship (r(2) = 0.9854) between the drug loading dose and Ae(infinity). The Ae(infinity) values from the transdermal delivery system containing 6% caprylic acid (53.8 mg as alendronate) and an oral product (Fosamax), 70 mg as alendronate) in humans were 127.0 +/- 34.2 microg and 237.2 +/- 56.3 microg, respectively. The dose-adjusted relative Ae(infinity) ratio of the transdermal delivery system to oral product was calculated to be 69.7%. The long half-life of alendronate in the transdermal delivery system (50.6 +/- 6.4 h), compared to that of the oral product (3.5 +/- 1.1 h) could allow less-frequent dosing. In conclusion, this study showed that a transdermal delivery system containing 6% caprylic acid in PG could be a favorable alternative for alendronate administration.

  12. The pharmacokinetics, distribution and degradation of human recombinant interleukin 1 beta in normal rats

    DEFF Research Database (Denmark)

    Wogensen, L D; Welinder, B; Hejnaes, K R

    1991-01-01

    -lives of distribution (T1/2 alpha) and elimination phases (T1/2 beta) of human recombinant interleukin 1 beta (rIL-1 beta), and its tissue distribution and cellular localization by means of mono-labelled, biologically active 125I-rIL-1 beta. After intravenous (i.v.) injection, 125I-rIL-1 beta was eliminated from...... the circulation with a T1/2 alpha of 2.9 min and a T1/2 beta of 41.1 min. The central and peripheral volume of distribution was 20.7 and 19.1 ml/rat, respectively, and the metabolic clearance rate was 16.9 ml/min/kg. The kidney and liver showed the highest accumulation of tracer, and autoradiography demonstrated...

  13. Human volunteer studies with non-pharmaceutical chemicals: metabolism and pharmacokinetic studies.

    Science.gov (United States)

    Wilks, M F; Woollen, B H

    1994-06-01

    1. Human volunteer studies are an essential part of drug development but their use in the area of non-pharmaceutical chemicals has so far been very limited. Such studies can have considerable value in the assessment and improvement of the safe use of chemicals. 2. Once metabolic pathways and target metabolites have been identified in volunteers this information can be used in studies in the workplace or in the general population. Studies should be performed selectively only if there is both a toxic hazard and a significant exposure potential. In addition, they should only be carried out if the required information cannot be obtained in any other way. 3. Volunteer studies with non-pharmaceuticals have become increasingly acceptable in the light of established international guidelines, no-fault compensation, improvements in study design and technical developments which allow the use of very low dose levels. The final decision on whether to carry out a study must always rest with an independent ethical committee. 4. The practical aspects of the study should be specified in a detailed protocol conforming with the principles of good clinical practice. The safety of volunteers must be of paramount concern throughout. Depending on the nature of the chemical and the study, it may be advisable to carry out studies in a clinical facility where equipment is available for the treatment of any emergencies that might occur. 5. Numerous investigators have now shown that human volunteer studies are ethically acceptable, practicable and yield important information. The risk to volunteers is minimal and this approach can lead to an improved foundation for occupational hygiene standards, more accurate risk assessment and thus better protection of the workforce and the general population.

  14. Seventh European Workshop on Cannabinoid Research and IACM Eighth Conference on Cannabinoids in Medicine

    OpenAIRE

    Cheer, Joseph F.; Maccarrone, Mauro; Piomelli, Daniele

    2016-01-01

    Abstract The joint 7th European Workshop on Cannabinoid Research and IACM 8th Conference on Cannabinoids in Medicine was held in the beach town of Sestri Levante, Italy, on September 17?19, 2015. In this beautiful setting, world-leading investigators in the field of (endo)cannabinoid research presented exciting new data spanning a broad array of preclinical and clinical topics?from cellular electrophysiology to drug discovery and from potential indications for the therapeutic use of cannabis ...

  15. Marijuana and cannabinoid regulation of brain reward circuits.

    Science.gov (United States)

    Lupica, Carl R; Riegel, Arthur C; Hoffman, Alexander F

    2004-09-01

    The reward circuitry of the brain consists of neurons that synaptically connect a wide variety of nuclei. Of these brain regions, the ventral tegmental area (VTA) and the nucleus accumbens (NAc) play central roles in the processing of rewarding environmental stimuli and in drug addiction. The psychoactive properties of marijuana are mediated by the active constituent, Delta(9)-THC, interacting primarily with CB1 cannabinoid receptors in a large number of brain areas. However, it is the activation of these receptors located within the central brain reward circuits that is thought to play an important role in sustaining the self-administration of marijuana in humans, and in mediating the anxiolytic and pleasurable effects of the drug. Here we describe the cellular circuitry of the VTA and the NAc, define the sites within these areas at which cannabinoids alter synaptic processes, and discuss the relevance of these actions to the regulation of reinforcement and reward. In addition, we compare the effects of Delta(9)-THC with those of other commonly abused drugs on these reward circuits, and we discuss the roles that endogenous cannabinoids may play within these brain pathways, and their possible involvement in regulating ongoing brain function, independently of marijuana consumption. We conclude that, whereas Delta(9)-THC alters the activity of these central reward pathways in a manner that is consistent with other abused drugs, the cellular mechanism through which this occurs is likely different, relying upon the combined regulation of several afferent pathways to the VTA.

  16. Cannabinoid-like anti-inflammatory compounds from flax fiber.

    Science.gov (United States)

    Styrczewska, Monika; Kulma, Anna; Ratajczak, Katarzyna; Amarowicz, Ryszard; Szopa, Jan

    2012-09-01

    Flax is a valuable source of fibers, linseed and oil. The compounds of the latter two products have already been widely examined and have been proven to possess many health-beneficial properties. In the course of analysis of fibers extract from previously generated transgenic plants overproducing phenylpropanoids a new terpenoid compound was discovered.The UV spectra and the retention time in UPLC analysis of this new compound reveal similarity to a cannabinoid-like compound, probably cannabidiol (CBD). This was confirmed by finding two ions at m/z 174.1 and 231.2 in mass spectra analysis. Further confirmation of the nature of the compound was based on a biological activity assay. It was found that the compound affects the expression of genes involved in inflammatory processes in mouse and human fibroblasts and likely the CBD from Cannabis sativa activates the specific peripheral cannabinoid receptor 2 (CB2) gene expression. Besides fibers, the compound was also found in all other flax tissues. It should be pointed out that the industrial process of fabric production does not affect CBD activity.The presented data suggest for the first time that flax products can be a source of biologically active cannabinoid-like compounds that are able to influence the cell immunological response. These findings might open up many new applications for medical flax products, especially for the fabric as a material for wound dressing with anti-inflammatory properties.

  17. Improved physiologically based pharmacokinetic model for oral exposures to chromium in mice, rats, and humans to address temporal variation and sensitive populations.

    Science.gov (United States)

    Kirman, C R; Suh, M; Proctor, D M; Hays, S M

    2017-06-15

    A physiologically based pharmacokinetic (PBPK) model for hexavalent chromium [Cr(VI)] in mice, rats, and humans developed previously (Kirman et al., 2012, 2013), was updated to reflect an improved understanding of the toxicokinetics of the gastrointestinal tract following oral exposures. Improvements were made to: (1) the reduction model, which describes the pH-dependent reduction of Cr(VI) to Cr(III) in the gastrointestinal tract under both fasted and fed states; (2) drinking water pattern simulations, to better describe dosimetry in rodents under the conditions of the NTP cancer bioassay; and (3) parameterize the model to characterize potentially sensitive human populations. Important species differences, sources of non-linear toxicokinetics, and human variation are identified and discussed within the context of human health risk assessment. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  18. Distribution and pharmacokinetics of methamphetamine in the human body: clinical implications

    International Nuclear Information System (INIS)

    Volkow, N.D.; Fowler, J.S.; Wang, G.-J.; Shumay, E.; Telang, F.; Thanos, P.; Alexoff, D.

    2010-01-01

    Methamphetamine is one of the most toxic of the drugs of abuse, which may reflect its distribution and accumulation in the body. However no studies have measured methamphetamine's organ distribution in the human body. Positron Emission Tomography (PET) was used in conjunction with ( 11 C)d-methamphetamine to measure its whole-body distribution and bioavailability as assessed by peak uptake (% Dose/cc), rate of clearance (time to reach 50% peak-clearance) and accumulation (area under the curve) in healthy participants (9 Caucasians and 10 African Americans). Methamphetamine distributed through most organs. Highest uptake (whole organ) occurred in lungs (22% Dose; weight ∼1246 g), liver (23%; weight ∼1677 g) and intermediate in brain (10%; weight ∼1600 g). Kidneys also showed high uptake (per/cc basis) (7%; weight 305 g). Methamphetamine's clearance was fastest in heart and lungs (7-16 minutes), slowest in brain, liver and stomach (>75 minutes), and intermediate in kidneys, spleen and pancreas (22-50 minutes). Lung accumulation of ( 11 C)d-methamphetamine was 30% higher for African Americans than Caucasians (p < 0.05) but did not differ in other organs. The high accumulation of methamphetamine, a potent stimulant drug, in most body organs is likely to contribute to the medical complications associated with methamphetamine abuse. In particular, we speculate that methamphetamine's high pulmonary uptake could render this organ vulnerable to infections (tuberculosis) and pathology (pulmonary hypertension). Our preliminary findings of a higher lung accumulation of methamphetamine in African Americans than Caucasians merits further investigation and questions whether it could contribute to the infrequent use of methamphetamine among African Americans.

  19. Plasma pharmacokinetics of catechin metabolite 4'-O-Me-EGC in healthy humans.

    Science.gov (United States)

    Renouf, Mathieu; Redeuil, Karine; Longet, Karin; Marmet, Cynthia; Dionisi, Fabiola; Kussmann, Martin; Williamson, Gary; Nagy, Kornél

    2011-10-01

    Tea is an infusion of the leaves of the Camellia sinensis plant and is the most widely consumed beverage in the world after water. Green tea contains significant amounts of polyphenol catechins and represents a promising dietary component to maintain health and well-being. Epidemiological studies indicate that polyphenol intake may have potential health benefits, such as, reducing the incidence of coronary heart disease, diabetes and cancer. While bioavailability of green tea bioactives is fairly well understood, some gaps still remain to be filled, especially the identification and quantification of conjugated metabolites in plasma, such as, sulphated, glucuronidated or methylated compounds. In the present study, we aimed to quantify the appearance of green tea catechins in plasma with particular emphasis on their methylated forms. After feeding 400 mL of green tea, 1.25% infusion to 9 healthy subjects, we found significant amounts of EC, EGC and EGCg in plasma as expected. EGC was the most bioavailable catechin, and its methylated form (4'-O-Me-EGC) was also present in quantifiable amounts. Its kinetics followed that of its parent compound. However, the relative amount of the methylated form of EGC was lower than that of the parent compound, an important aspect which, in the literature, has been controversial so far. The quantitative results presented in our study were confirmed by co-chromatography and accurate mass analysis of the respective standards. We show that the relative abundance of 4'-O-Me-EGC is ~40% compared to the parent EGC. 4'-O-Me-EGC is an important metabolite derived from catechin metabolism. Its presence in significant amounts should not be overlooked when assessing human bioavailability of green tea.

  20. Distribution and pharmacokinetics of methamphetamine in the human body: clinical implications

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D.; Fowler, J.; Volkow, N.D.; Fowler, J.S.; Wang, G.-J.; Shumay, E.; Telang, F.; Thanos, P.; Alexoff, D.

    2010-12-01

    Methamphetamine is one of the most toxic of the drugs of abuse, which may reflect its distribution and accumulation in the body. However no studies have measured methamphetamine's organ distribution in the human body. Positron Emission Tomography (PET) was used in conjunction with [{sup 11}C]d-methamphetamine to measure its whole-body distribution and bioavailability as assessed by peak uptake (% Dose/cc), rate of clearance (time to reach 50% peak-clearance) and accumulation (area under the curve) in healthy participants (9 Caucasians and 10 African Americans). Methamphetamine distributed through most organs. Highest uptake (whole organ) occurred in lungs (22% Dose; weight {approx}1246 g), liver (23%; weight {approx}1677 g) and intermediate in brain (10%; weight {approx}1600 g). Kidneys also showed high uptake (per/cc basis) (7%; weight 305 g). Methamphetamine's clearance was fastest in heart and lungs (7-16 minutes), slowest in brain, liver and stomach (>75 minutes), and intermediate in kidneys, spleen and pancreas (22-50 minutes). Lung accumulation of [{sup 11}C]d-methamphetamine was 30% higher for African Americans than Caucasians (p < 0.05) but did not differ in other organs. The high accumulation of methamphetamine, a potent stimulant drug, in most body organs is likely to contribute to the medical complications associated with methamphetamine abuse. In particular, we speculate that methamphetamine's high pulmonary uptake could render this organ vulnerable to infections (tuberculosis) and pathology (pulmonary hypertension). Our preliminary findings of a higher lung accumulation of methamphetamine in African Americans than Caucasians merits further investigation and questions whether it could contribute to the infrequent use of methamphetamine among African Americans.

  1. High-performance liquid chromatographic method for the determination of nicardipine in pure, pharmaceutical preparations and plasma and its application to pharmacokinetics in humans

    Directory of Open Access Journals (Sweden)

    Sheikha Mohammed Al-Ghannam

    2008-12-01

    Full Text Available A simple, sensitive and reproducible reversed-phase liquid chromatographic method has been developed and validated for the determination of nicardipine hydrochloride (NC in pure, pharmaceutical preparations, human plasma and the study of the pharmacokinetics of the drug in human body. Nicardipine in plasma were extracted with hexane-butanol (12:1,v/v after addition of borate buffer (0.5 M, pH=9.0, and then measured by HPLC-UV using a Waters Symmetry C18 column as stationary phase and methanol– triethylamine buffer (0.01M pH 4 with acetic acid (70:30 as mobile phase. Nicardipine was quantified by ultraviolet absorbance at 353 nm. The method proved to be linear in the pure drug in the ranges of 15-200 ng/mL (r=0.9989 and 5-40 µg/mL (r=0.9995, and for the pharmaceutical preparations and plasma for drug concentrations in the range of 5-40 µg/mL (r =0.9992 and 25-150 ng/mL (r=0.9991, respectively. The lower limit of detection and the lower quantitation limit of NC in plasma were 11.74 and 35.57 ng/mL, respectively. The method is sensitive and reliable for pharmacokinetic studies of nicardipine in humans after the oral administration of immediate-release capsules to healthy subjects.

  2. Prediction of human pharmacokinetics of activated recombinant factor VII and B-domain truncated factor VIII from animal population pharmacokinetic models of haemophilia

    DEFF Research Database (Denmark)

    Larsen, Malte Selch; Juul, Rasmus Vestergaard; Groth, Andreas Velsing

    2018-01-01

    activated factor VII (rFVIIa) and recombinant factor VIII (rFVIII) in several experimental animal models using population PK modelling, and apply a simulation-based approach to evaluate how well the developed animal population PK models predict human PK. PK models were developed for rFVIIa and r...

  3. Biotransformation of a novel antimitotic agent, I-387, by mouse, rat, dog, monkey, and human liver microsomes and in vivo pharmacokinetics in mice.

    Science.gov (United States)

    Ahn, Sunjoo; Kearbey, Jeffrey D; Li, Chien-Ming; Duke, Charles B; Miller, Duane D; Dalton, James T

    2011-04-01

    3-(1H-Indol-2-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone (I-387) is a novel indole compound with antitubulin action and potent antitumor activity in various preclinical models. I-387 avoids drug resistance mediated by P-glycoprotein and showed less neurotoxicity than vinca alkaloids during in vivo studies. We examined the pharmacokinetics and metabolism of I-387 in mice as a component of our preclinical development of this compound and continued interest in structure-activity relationships for antitubulin agents. After a 1 mg/kg intravenous dose, noncompartmental pharmacokinetic analysis in plasma showed that clearance (CL), volume of distribution at steady state (Vd(ss)), and terminal half-life (t(1/2)) of I-387 were 27 ml per min/kg, 5.3 l/kg, and 7 h, respectively. In the in vitro metabolic stability study, half-lives of I-387 were between 10 and 54 min by mouse, rat, dog, monkey, and human liver microsomes in the presence of NADPH, demonstrating interspecies variability. I-387 was most stable in rat liver microsomes and degraded quickly in monkey liver microsomes. Liquid chromatography-tandem mass spectrometry was used to identify phase I metabolites. Hydroxylation, reduction of a ketone group, and O-demethylation were the major metabolites formed by the liver microsomes of the five species. The carbonyl group of I-387 was reduced and identified as the most labile site in human liver microsomes. The results of these drug metabolism and pharmacokinetic studies provide the foundation for future structural modification of this pharmacophore to improve stability of drugs with potent anticancer effects in cancer patients.

  4. Comparative pharmacokinetics between a microdose and therapeutic dose for clarithromycin, sumatriptan, propafenone, paracetamol (acetaminophen), and phenobarbital in human volunteers.

    Science.gov (United States)

    Lappin, Graham; Shishikura, Yoko; Jochemsen, Roeline; Weaver, Richard John; Gesson, Charlotte; Brian Houston, J; Oosterhuis, Berend; Bjerrum, Ole J; Grynkiewicz, Grzegorz; Alder, Jane; Rowland, Malcolm; Garner, Colin

    2011-06-14

    A clinical study was conducted to assess the ability of a microdose (100 μg) to predict the human pharmacokinetics (PK) following a therapeutic dose of clarithromycin, sumatriptan, propafenone, paracetamol (acetaminophen) and phenobarbital, both within the study and by reference to the existing literature on these compounds and to explore the source of any nonlinearity if seen. For each drug, 6 healthy male volunteers were dosed with 100 μg (14)C-labelled compound. For clarithromycin, sumatriptan, and propafenone this labelled dose was administered alone, i.e. as a microdose, orally and intravenously (iv) and as an iv tracer dose concomitantly with an oral non-labelled therapeutic dose, in a 3-way cross over design. The oral therapeutic doses were 250, 50, and 150 mg, respectively. Paracetamol was given as the labelled microdose orally and iv using a 2-way cross over design, whereas phenobarbital was given only as the microdose orally. Plasma concentrations of total (14)C and parent drug were measured using accelerator mass spectrometry (AMS) or HPLC followed by AMS. Plasma concentrations following non-(14)C-labelled oral therapeutic doses were measured using either HPLC-electrochemical detection (clarithromycin) or HPLC-UV (sumatriptan, propafenone). For all five drugs an oral microdose predicted reasonably well the PK, including the shape of the plasma profile, following an oral therapeutic dose. For clarithromycin, sumatriptan, and propafenone, one parameter, oral bioavailability, was marginally outside of the normally acceptable 2-fold prediction interval around the mean therapeutic dose value. For clarithromycin, sumatriptan and propafenone, data obtained from an oral and iv microdose were compared within the same cohort of subjects used in the study, as well as those reported in the literature. For paracetamol (oral and iv) and phenobarbital (oral), microdose data were compared with those reported in the literature only. Where 100 μg iv (14)C-doses were

  5. Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition

    Directory of Open Access Journals (Sweden)

    Flores Juana M

    2010-07-01

    Full Text Available Abstract Background ErbB2-positive breast cancer is characterized by highly aggressive phenotypes and reduced responsiveness to standard therapies. Although specific ErbB2-targeted therapies have been designed, only a small percentage of patients respond to these treatments and most of them eventually relapse. The existence of this population of particularly aggressive and non-responding or relapsing patients urges the search for novel therapies. The purpose of this study was to determine whether cannabinoids might constitute a new therapeutic tool for the treatment of ErbB2-positive breast tumors. We analyzed their antitumor potential in a well established and clinically relevant model of ErbB2-driven metastatic breast cancer: the MMTV-neu mouse. We also analyzed the expression of cannabinoid targets in a series of 87 human breast tumors. Results Our results show that both Δ9-tetrahydrocannabinol, the most abundant and potent cannabinoid in marijuana, and JWH-133, a non-psychotropic CB2 receptor-selective agonist, reduce tumor growth, tumor number, and the amount/severity of lung metastases in MMTV-neu mice. Histological analyses of the tumors revealed that cannabinoids inhibit cancer cell proliferation, induce cancer cell apoptosis, and impair tumor angiogenesis. Cannabinoid antitumoral action relies, at least partially, on the inhibition of the pro-tumorigenic Akt pathway. We also found that 91% of ErbB2-positive tumors express the non-psychotropic cannabinoid receptor CB2. Conclusions Taken together, these results provide a strong preclinical evidence for the use of cannabinoid-based therapies for the management of ErbB2-positive breast cancer.

  6. Computer modeling of Cannabinoid receptor type 1

    Directory of Open Access Journals (Sweden)

    Sapundzhi Fatima

    2018-01-01

    Full Text Available Cannabinoid receptors are important class of receptors as they are involved in various physiological processes such as appetite, pain-sensation, mood, and memory. It is important to design receptor-selective ligands in order to treat a particular disorder. The aim of the present study is to model the structure of cannabinoid receptor CB1 and to perform docking between obtained models and known ligands. Two models of CBR1 were prepared with two different methods (Modeller of Chimera and MOE. They were used for docking with GOLD 5.2. It was established a high correlation between inhibitory constant Ki of CB1 cannabinoid ligands and the ChemScore scoring function of GOLD, which concerns both models. This suggests that the models of the CB1 receptors obtained could be used for docking studies and in further investigation and design of new potential, selective and active cannabinoids with the desired effects.

  7. A first‐in‐human pharmacodynamic and pharmacokinetic study of a fully human anti‐glucagon receptor monoclonal antibody in normal healthy volunteers

    Science.gov (United States)

    Kostic, Ana; King, Thomas Alexander; Yang, Feng; Chan, Kuo‐Chen; Yancopoulos, George D.; Gromada, Jesper

    2017-01-01

    Aims Glucagon receptor (GCGR) blockers are being investigated as potential therapeutics for type 1 and type 2 diabetes. Here we report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of REGN1193, a fully human glucagon receptor blocking monoclonal antibody from a first‐in‐human healthy volunteer randomized double‐blinded trial. Methods Healthy men and women received single ascending doses of REGN1193 ranging from 0.05 to 0.6 mg/kg (n = 42) or placebo (n = 14) intravenously. Safety, tolerability and PK were assessed over 106 days. The glucose‐lowering effect of REGN1193 was assessed after induction of hyperglycaemia by serial glucagon challenges. Results REGN1193 was generally well tolerated. There were small (50 mg/dL, and did not require treatment or medical assistance. Concentration‐time profiles suggest a 2‐compartment disposition and marked nonlinearity, consistent with target‐mediated clearance. REGN1193 inhibited the glucagon‐stimulated glucose increase in a dose‐dependent manner. The 0.6 mg/kg dose inhibited the glucagon‐induced glucose area under the curve for 0 to 90 minutes (AUC0‐90 minutes) by 80% to 90% on days 3 and 15, while blunting the increase in C‐peptide. REGN1193 dose‐dependently increased total GLP‐1, GLP‐2 and glucagon, with plasma levels returning to baseline by day 29 in all dose groups. Conclusion REGN1193, a GCGR‐blocking monoclonal antibody, produced a safety, tolerability and PK/PD profile suitable for further clinical development. The occurrence of transient elevations in serum hepatic aminotransferases observed here and reported with several small molecule glucagon receptor antagonists suggests an on‐target effect of glucagon receptor blockade. The underlying mechanism is unknown. PMID:28755409

  8. Cannabinoid Hyperemesis Relieved by Compulsive Bathing

    OpenAIRE

    Chang, Yoon Hee; Windish, Donna M.

    2009-01-01

    Cannabinoid hyperemesis is a clinical syndrome characterized by repeated vomiting and associated learned compulsive hot water bathing behavior due to long-term marijuana use. Research has indentified type 1 cannabinoid receptors in the intestinal nerve plexus that have an inhibitory effect on gastrointestinal motility. This inhibitory effect may lead to hyperemesis in marijuana users. The thermoregulatory role of endocannabinoids may be responsible for the patient's need to take hot showers. ...

  9. Single-dose pharmacokinetic study comparing the pharmacokinetics of recombinant human chorionic gonadotropin in healthy Japanese and Caucasian women and recombinant human chorionic gonadotropin and urinary human chorionic gonadotropin in healthy Japanese women.

    Science.gov (United States)

    Bagchus, Wilhelmina; Wolna, Peter; Uhl, Wolfgang

    2018-01-01

    Recombinant hCG (r-hCG) was approved in Japan in 2016. As a prerequisite for a Phase III study in Japan related to this approval, the pharmacokinetic (PK) profile of r-hCG was investigated. An open-label, partly randomized, single-center, single-dose, group-comparison, Phase I PK-bridging study was done that compared a single 250 μg dose of r-hCG with a single 5000 IU dose of urinary hCG (u-hCG) in healthy Japanese women, as well as comparing a single 250 μg dose of r-hCG in Japanese and Caucasian women. The Japanese participants were randomized 1:1 to receive either r-hCG or u-hCG, while the Caucasian participants were weight-matched to the Japanese participants who were receiving r-hCG in a 1:1 fashion. The primary PK parameters were the area under the serum concentration-time curve from time 0 extrapolated to infinity (AUC 0-∞ ) and the maximum serum concentration (C max ). The mean serum hCG concentration-time profiles of r-hCG in the Japanese and Caucasian participants were a similar shape, but the level of overall exposure was ~20% lower in the Japanese participants. For the Japanese participants, r-hCG resulted in an 11% lower C max but a 19% higher AUC 0-∞ compared with u-hCG. No new safety signal was identified. This study cannot exclude a potential difference in the PK profile of r-hCG between Japanese and Caucasian participants. However, this study does not indicate that there are clinically relevant differences in the serum PK of r-hCG and u-hCG in the Japanese participants.

  10. Pharmacokinetics of flomoxef in mucosal tissue of the middle ear and mastoid following intravenous administration in humans.

    Science.gov (United States)

    Saito, H; Kimura, T; Takeda, T; Kishimoto, S; Oguma, T; Shimamura, K

    1990-01-01

    The pharmacokinetics of flomoxef in serum and in the mucosal tissue of the middle ear and mastoid were studied in 9 patients undergoing tympanoplasties. All patients received 1 g of flomoxef intravenously. Flomoxef levels in serum and in mucosal tissue were determined by a bioassay method. The peak value of mean concentrations of flomoxef in the mucosal tissue was 30.3 +/- 11.7 micrograms/ml at 10 min after the administrations. Pharmacokinetic analyses showed that the concentration of flomoxef in the mucosal tissue was over 1.56 micrograms/ml (which is the MIC90 for the common pathogens of otitis media) for more than 2 h and decreased parallel with serum concentration with a half-life of about 40 min.

  11. 24-hour human urine and serum profiles of bisphenol A following ingestion in soup: Individual pharmacokinetic data and emographics

    Directory of Open Access Journals (Sweden)

    Justin G. Teeguarden

    2015-09-01

    Full Text Available Here we present data to evaluate potential absorption of Bisphenol A through non-metabolizing tissues of the upper digestive tract. Concurrent serum and urine concentrations of d6-BPA, and its glucuronide and sulfate conjugates, were measured over a 24 h period in 10 adult male volunteers following ingestion of 30 μg d6-BPA/kg body weight in soup. The pharmacokinetic behavior of BPA and its metabolites in this cohort (rapid absorption, complete elimination, evidence against sublingual absorption was reported. This Data in Brief article contains the corresponding individual pharmacokinetic data, reports the demographics of the cohort and provides additional details related to the analytical methods employed and is related to [4].

  12. 24-hour human urine and serum profiles of bisphenol A following ingestion in soup: Individual pharmacokinetic data and emographics

    Science.gov (United States)

    Teeguarden, Justin G.; Twaddle, Nathan C.; Churchwell, Mona I.; Yang, Xiaoxia; Fisher, Jeffrey W.; Seryak, Liesel M.; Doerge, Daniel R.

    2015-01-01

    Here we present data to evaluate potential absorption of Bisphenol A through non-metabolizing tissues of the upper digestive tract. Concurrent serum and urine concentrations of d6-BPA, and its glucuronide and sulfate conjugates, were measured over a 24 h period in 10 adult male volunteers following ingestion of 30 μg d6-BPA/kg body weight in soup. The pharmacokinetic behavior of BPA and its metabolites in this cohort (rapid absorption, complete elimination, evidence against sublingual absorption) was reported. This Data in Brief article contains the corresponding individual pharmacokinetic data, reports the demographics of the cohort and provides additional details related to the analytical methods employed and is related to [4]. PMID:26217767

  13. Human pharmacokinetics, biodistribution and dosimetry of the kit of monoclonal antibody IOR EGF/R3 labelled with {sup 99m} Tc

    Energy Technology Data Exchange (ETDEWEB)

    Torres, L.A.; Ramos, M.; Perera, A.; Hernandez, A.; Iznaga, M.E. N. [Solano, Ivette Alvarez, Jose L. Rodriguez. Centro de InvestigacionesClinicas. 34 no.4501 e/45 y 47 Kohly, Playa, C. Habana (Cuba)

    1998-12-31

    The aim of this work was to assess the human pharmacokinetics, biodistribution and dosimetry of the {sup 99m} Tc-labeled MAb ior egf/r3. Five patients were included in the biodistribution and dosimetric studies and three in the pharmacokinetic analysis. Multiple blood and urine samples we recollected and sequential anterior and posterior whole-body scintigraphies u pto 24 hr post-injection were performed to all patients . The internal radiation dosimetry was estimated from gamma camera imaging data using the methods developed by the Medical Internal radiation dosimetry (MIRD)committee. Raw data were computed from operations between gamma graphic images and regions of interest (ROI) using the Bio-Dose software and time-activity curves were calculated in order to determine the residence times of the source organs. The Pharmacokinetics and Biodistribution results showed that this compound have a bio exponential plasmatic and blood clearance with a rapid biodistribution phase of 9.1 {+-} 8.4 min and 12.2{+-}4.4 min, respectively, and a slower elimination phase of 6.6 {+-} 1.6 hr and 10.8 {+-} 6.8 hr. respectively. The urinary and hepatobiliary excretion showed 4.7 {+-} 0.4 % and 9.9 {+-} 1.8 % of the total administered dose,eliminated by these ways. Liver was the target organ of this product and had an uptake peak at 1 hr post-injection (61.2%) and a great retention of the MAb(T 1/2 eff = 5.3 hr, T 1/2 Biol. = 45.0 hr). The dosimetric results showed that liver, gallbladder and spleen received the higher absorbed. The effective dose and the effective equivalent dose were 1,2E-01 mSv/MBq and 9,2E-02 mSv/MBq respectively. These results allow to see the i or egf/r3 kit in a safe and controlled way. (Author)

  14. Evaluation of principal cannabinoids in airborne particulates

    Energy Technology Data Exchange (ETDEWEB)

    Balducci, C [Italian National Research Council, Institute for Atmospheric Pollution (CNR-IIA), Monterotondo Stazione (Italy); Nervegna, G; Cecinato, A [Italian National Research Council, Institute for Atmospheric Pollution (CNR-IIA), Monterotondo Stazione (Italy)

    2009-05-08

    The determination of delta(9)-tetrahydrocannabinol ({Delta}{sup 9}-THC), cannabidiol (CND) and cannabinol (CNB), primary active components in cannabis preparation, was carried out on airborne particulates by applying a specific procedure consisting of soot extraction by ultrasonic bath, purification by solvent partitioning, derivatization with N-(t-butyldimethylsilyl)-N-methyl-trifluoroacetamide, and separation/detection through gas chromatography coupled with tandem mass spectrometry. The optimized procedure was found suitable for measuring the three psychotropic substances at concentrations ranging from ca. 0.001 to ca. 5.0 ng cm{sup -3} of air, with recoveries always higher than 82%, accuracy >7.3% and precision >90%. Application of the procedure performed on field in Rome and Bari, Italy, demonstrated that all three compounds contaminate the air in Italian cities whereas in Algiers, Algeria, only cannabinol, the most stable in the atmosphere, exceeded the limit of quantification of the method. The relative percentages of the three cannabinoids in general reproduced those typical of the Cannabis sativa plant and were very different from those found in human blood, urine and sweat.

  15. Evaluation of principal cannabinoids in airborne particulates

    International Nuclear Information System (INIS)

    Balducci, C.; Nervegna, G.; Cecinato, A.

    2009-01-01

    The determination of delta(9)-tetrahydrocannabinol (Δ 9 -THC), cannabidiol (CND) and cannabinol (CNB), primary active components in cannabis preparation, was carried out on airborne particulates by applying a specific procedure consisting of soot extraction by ultrasonic bath, purification by solvent partitioning, derivatization with N-(t-butyldimethylsilyl)-N-methyl-trifluoroacetamide, and separation/detection through gas chromatography coupled with tandem mass spectrometry. The optimized procedure was found suitable for measuring the three psychotropic substances at concentrations ranging from ca. 0.001 to ca. 5.0 ng cm -3 of air, with recoveries always higher than 82%, accuracy >7.3% and precision >90%. Application of the procedure performed on field in Rome and Bari, Italy, demonstrated that all three compounds contaminate the air in Italian cities whereas in Algiers, Algeria, only cannabinol, the most stable in the atmosphere, exceeded the limit of quantification of the method. The relative percentages of the three cannabinoids in general reproduced those typical of the Cannabis sativa plant and were very different from those found in human blood, urine and sweat.

  16. A validated high-performance liquid chromatographic method for the determination of glibenclamide in human plasma and its application to pharmacokinetic studies.

    Science.gov (United States)

    Niopas, Ioannis; Daftsios, Athanasios C

    2002-05-15

    Glibenclamide is a potent second generation oral sulfonylurea antidiabetic agent widely used for the treatment of type II diabetes melitus. A rapid, sensitive, precise, accurate and specific HPLC assay for the determination of glibenclamide in human plasma was developed and validated. After addition of flufenamic acid as internal standard, the analytes were isolated from human plasma by liquid-liquid extraction. The method was linear in the 10-400 ng/ml concentration range (r > 0.999). Recovery for glibenclamide was greater than 91.5% and for internal standard was 93.5%. Within-day and between-day precision, expressed as the relative standard deviation (RSD%), ranged from 1.4 to 5.9% and 5.8 to 6.6%, respectively. Assay accuracy was better than 93.4%. The assay was used to estimate the pharmacokinetics of glibenclamide after oral administration of a 5 mg tablet of glibenclamide to 18 healthy volunteers.

  17. Estimation of the binding modes with important human cytochrome P450 enzymes, drug interaction potential, pharmacokinetics, and hepatotoxicity of ginger components using molecular docking, computational, and pharmacokinetic modeling studies.

    Science.gov (United States)

    Qiu, Jia-Xuan; Zhou, Zhi-Wei; He, Zhi-Xu; Zhang, Xueji; Zhou, Shu-Feng; Zhu, Shengrong

    2015-01-01

    Ginger is one of the most commonly used herbal medicines for the treatment of numerous ailments and improvement of body functions. It may be used in combination with prescribed drugs. The coadministration of ginger with therapeutic drugs raises a concern of potential deleterious drug interactions via the modulation of the expression and/or activity of drug-metabolizing enzymes and drug transporters, resulting in unfavorable therapeutic outcomes. This study aimed to determine the molecular interactions between 12 main active ginger components (6-gingerol, 8-gingerol, 10-gingerol, 6-shogaol, 8-shogaol, 10-shogaol, ar-curcumene, β-bisabolene, β-sesquiphelandrene, 6-gingerdione, (-)-zingiberene, and methyl-6-isogingerol) and human cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4 and to predict the absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the 12 ginger components using computational approaches and comprehensive literature search. Docking studies showed that ginger components interacted with a panel of amino acids in the active sites of CYP1A2, 2C9, 2C19, 2D6, and 3A4 mainly through hydrogen bond formation, to a lesser extent, via π-π stacking. The pharmacokinetic simulation studies showed that the [I]/[Ki ] value for CYP2C9, 2C19, and 3A4 ranged from 0.0002 to 19.6 and the R value ranged from 1.0002 to 20.6 and that ginger might exhibit a high risk of drug interaction via inhibition of the activity of human CYP2C9 and CYP3A4, but a low risk of drug interaction toward CYP2C19-mediated drug metabolism. Furthermore, it has been evaluated that the 12 ginger components possessed a favorable ADMET profiles with regard to the solubility, absorption, permeability across the blood-brain barrier, interactions with CYP2D6, hepatotoxicity, and plasma protein binding. The validation results showed that there was no remarkable effect of ginger on the metabolism of warfarin in humans, whereas concurrent use of ginger and nifedipine exhibited a

  18. Sustainable production of cannabinoids with supercritical carbon dioxide technologies

    NARCIS (Netherlands)

    Perrotin-Brunel, H.

    2011-01-01

    This thesis concerns the production of natural compounds from plant material for pharmaceutical and food applications. It describes the production (extraction and isolation) of cannabinoids, the active components present in cannabis. Many cannabinoids have medicinal properties but not all

  19. Sustainable Production of Cannabinoids with Supercritical Carbon Dioxide Technologies

    NARCIS (Netherlands)

    Perrotin-Brunel, H.

    2011-01-01

    This thesis concerns the production of natural compounds from plant material for pharmaceutical and food applications. It describes the production (extraction and isolation) of cannabinoids, the active components present in cannabis. Many cannabinoids have medicinal properties but not all

  20. Toxic Effects of Cannabis and Cannabinoids: Animal Data

    Directory of Open Access Journals (Sweden)

    Pierre Beaulieu

    2005-01-01

    Full Text Available The present article reviews the main toxic effects of cannabis and cannabinoids in animals. Toxic effects can be separated into acute and chronic classifications. Acute toxicity studies show that it is virtually impossible to die from acute administration of marijuana or tetrahydrocannabinol, the main psychoactive component of cannabis. Chronic toxicity involves lesions of airway and lung tissues, as well as problems of neurotoxicity, tolerance and dependence, and dysregulations in the immune and hormonal systems. Animal toxicity data, however, are difficult to extrapolate to humans.

  1. Pharmacokinetics of Snake Venom

    Directory of Open Access Journals (Sweden)

    Suchaya Sanhajariya

    2018-02-01

    Full Text Available Understanding snake venom pharmacokinetics is essential for developing risk assessment strategies and determining the optimal dose and timing of antivenom required to bind all venom in snakebite patients. This review aims to explore the current knowledge of snake venom pharmacokinetics in animals and humans. Literature searches were conducted using EMBASE (1974–present and Medline (1946–present. For animals, 12 out of 520 initially identified studies met the inclusion criteria. In general, the disposition of snake venom was described by a two-compartment model consisting of a rapid distribution phase and a slow elimination phase, with half-lives of 5 to 48 min and 0.8 to 28 h, respectively, following rapid intravenous injection of the venoms or toxins. When the venoms or toxins were administered intramuscularly or subcutaneously, an initial absorption phase and slow elimination phase were observed. The bioavailability of venoms or toxins ranged from 4 to 81.5% following intramuscular administration and 60% following subcutaneous administration. The volume of distribution and the clearance varied between snake species. For humans, 24 out of 666 initially identified publications contained sufficient information and timed venom concentrations in the absence of antivenom therapy for data extraction. The data were extracted and modelled in NONMEM. A one-compartment model provided the best fit, with an elimination half-life of 9.71 ± 1.29 h. It is intended that the quantitative information provided in this review will provide a useful basis for future studies that address the pharmacokinetics of snakebite in humans.

  2. The plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite (OSI-420) after intravenous administration of erlotinib in non-human primates.

    Science.gov (United States)

    Meany, Holly J; Fox, Elizabeth; McCully, Cynthia; Tucker, Chris; Balis, Frank M

    2008-08-01

    Erlotinib hydrochloride is a small molecule inhibitor of epidermal growth factor receptor (EGFR). EGFR is over-expressed in primary brain tumors and solid tumors that metastasize to the central nervous system. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics of erlotinib and its active metabolite OSI-420 after an intravenous (IV) dose in a non-human primate model. Erlotinib was administered as a 1 h IV infusion to four adult rhesus monkeys. Serial blood and CSF samples were drawn over 48 h and erlotinib and OSI-420 were quantified with an HPLC/tandem mass spectroscopic assay. Pharmacokinetic parameters were estimated using non-compartmental and compartmental methods. CSF penetration was calculated from the AUC(CSF):AUC(plasma). Erlotinib disappearance from plasma after a short IV infusion was biexponential with a mean terminal half-life of 5.2 h and a mean clearance of 128 ml/min per m(2). OSI-420 exposure (AUC) in plasma was 30% (range 12-59%) of erlotinib, and OSI-420 clearance was more than 5-fold higher than erlotinib. Erlotinib and OSI-420 were detectable in CSF. The CSF penetration (AUC(CSF):AUC(plasma)) of erlotinib and OSI-420 was OSI-420 are measurable in CSF after an IV dose. The drug exposure (AUC) in the CSF is limited relative to total plasma concentrations but is substantial relative the free drug exposure in plasma.

  3. Therapeutic Mechanisms for Cannabinoid-Promoted Survival of Oligodendrocytes

    Science.gov (United States)

    2013-06-21

    Studies in vivo were performed to characterize the effect of a novel synthetic cannabinoid compound in preventing inflammation, demyelination and...studied as a possible treatment for MS and one class of compounds that is showing particular promise are the cannabinoids. Cannabis, or marijuana , as it...thus differing in their chemical structures (77). The third class of cannabinoids relates to the synthetic cannabinoids. These synthetic

  4. The therapeutic potential of cannabis and cannabinoids.

    Science.gov (United States)

    Grotenhermen, Franjo; Müller-Vahl, Kirsten

    2012-07-01

    Cannabis-based medications have been a topic of intense study since the endogenous cannabinoid system was discovered two decades ago. In 2011, for the first time, a cannabis extract was approved for clinical use in Germany. Selective literature review. Cannabis-based medications exert their effects mainly through the activation of cannabinoid receptors (CB1 and CB2). More than 100 controlled clinical trials of cannabinoids or whole-plant preparations for various indications have been conducted since 1975. The findings of these trials have led to the approval of cannabis-based medicines (dronabinol, nabilone, and a cannabis extract [THC:CBD=1:1]) in several countries. In Germany, a cannabis extract was approved in 2011 for the treatment of moderate to severe refractory spasticity in multiple sclerosis. It is commonly used off label for the treatment of anorexia, nausea, and neuropathic pain. Patients can also apply for government permission to buy medicinal cannabis flowers for self-treatment under medical supervision. The most common side effects of cannabinoids are tiredness and dizziness (in more than 10% of patients), psychological effects, and dry mouth. Tolerance to these side effects nearly always develops within a short time. Withdrawal symptoms are hardly ever a problem in the therapeutic setting. There is now clear evidence that cannabinoids are useful for the treatment of various medical conditions.

  5. Cannabinoids inhibit angiogenic capacities of endothelial cells via release of tissue inhibitor of matrix metalloproteinases-1 from lung cancer cells.

    Science.gov (United States)

    Ramer, Robert; Fischer, Sascha; Haustein, Maria; Manda, Katrin; Hinz, Burkhard

    2014-09-15

    Cannabinoids inhibit tumor neovascularization as part of their tumorregressive action. However, the underlying mechanism is still under debate. In the present study the impact of cannabinoids on potential tumor-to-endothelial cell communication conferring anti-angiogenesis was studied. Cellular behavior of human umbilical vein endothelial cells (HUVEC) associated with angiogenesis was evaluated by Boyden chamber, two-dimensional tube formation and fibrin bead assay, with the latter assessing three-dimensional sprout formation. Viability was quantified by the WST-1 test. Conditioned media (CM) from A549 lung cancer cells treated with cannabidiol, Δ(9)-tetrahydrocannabinol, R(+)-methanandamide or the CB2 agonist JWH-133 elicited decreased migration as well as tube and sprout formation of HUVEC as compared to CM of vehicle-treated cancer cells. Inhibition of sprout formation was further confirmed for cannabinoid-treated A549 cells co-cultured with HUVEC. Using antagonists to cannabinoid-activated receptors the antimigratory action was shown to be mediated via cannabinoid receptors or transient receptor potential vanilloid 1. SiRNA approaches revealed a cannabinoid-induced expression of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) as well as its upstream trigger, the intercellular adhesion molecule-1, to be causally linked to the observed decrease of HUVEC migration. Comparable anti-angiogenic effects were not detected following direct exposure of HUVEC to cannabinoids, but occurred after addition of recombinant TIMP-1 to HUVEC. Finally, antimigratory effects were confirmed for CM of two other cannabinoid-treated lung cancer cell lines (H460 and H358). Collectively, our data suggest a pivotal role of the anti-angiogenic factor TIMP-1 in intercellular tumor-endothelial cell communication resulting in anti-angiogenic features of endothelial cells. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. The Effects of Cannabinoids on Executive Functions: Evidence from Cannabis and Synthetic Cannabinoids—A Systematic Review

    Directory of Open Access Journals (Sweden)

    Koby Cohen

    2018-02-01

    Full Text Available Background—Cannabis is the most popular illicit drug in the Western world. Repeated cannabis use has been associated with short and long-term range of adverse effects. Recently, new types of designer-drugs containing synthetic cannabinoids have been widespread. These synthetic cannabinoid drugs are associated with undesired adverse effects similar to those seen with cannabis use, yet, in more severe and long-lasting forms. Method—A literature search was conducted using electronic bibliographic databases up to 31 December 2017. Specific search strategies were employed using multiple keywords (e.g., “synthetic cannabinoids AND cognition,” “cannabis AND cognition” and “cannabinoids AND cognition”. Results—The search has yielded 160 eligible studies including 37 preclinical studies (5 attention, 25 short-term memory, 7 cognitive flexibility and 44 human studies (16 attention, 15 working memory, 13 cognitive flexibility. Both pre-clinical and clinical studies demonstrated an association between synthetic cannabinoids and executive-function impairment either after acute or repeated consumptions. These deficits differ in severity depending on several factors including the type of drug, dose of use, quantity, age of onset and duration of use. Conclusions—Understanding the nature of the impaired executive function following consumption of synthetic cannabinoids is crucial in view of the increasing use of these drugs.

  7. Cannabinoid-induced effects on the nociceptive system: a neurophysiological study in patients with secondary progressive multiple sclerosis.

    Science.gov (United States)

    Conte, Antonella; Bettolo, Chiara Marini; Onesti, Emanuela; Frasca, Vittorio; Iacovelli, Elisa; Gilio, Francesca; Giacomelli, Elena; Gabriele, Maria; Aragona, Massimiliano; Tomassini, Valentina; Pantano, Patrizia; Pozzilli, Carlo; Inghilleri, Maurizio

    2009-05-01

    Although clinical studies show that cannabinoids improve central pain in patients with multiple sclerosis (MS) neurophysiological studies are lacking to investigate whether they also suppress these patients' electrophysiological responses to noxious stimulation. The flexion reflex (FR) in humans is a widely used technique for assessing the pain threshold and for studying spinal and supraspinal pain pathways and the neurotransmitter system involved in pain control. In a randomized, double-blind, placebo-controlled, cross-over study we investigated cannabinoid-induced changes in RIII reflex variables (threshold, latency and area) in a group of 18 patients with secondary progressive MS. To investigate whether cannabinoids act indirectly on the nociceptive reflex by modulating lower motoneuron excitability we also evaluated the H-reflex size after tibial nerve stimulation and calculated the H wave/M wave (H/M) ratio. Of the 18 patients recruited and randomized 17 completed the study. After patients used a commercial delta-9-tetrahydrocannabinol (THC) and cannabidiol mixture as an oromucosal spray the RIII reflex threshold increased and RIII reflex area decreased. The visual analogue scale score for pain also decreased, though not significantly. Conversely, the H/M ratio measured before patients received cannabinoids remained unchanged after therapy. In conclusion, the cannabinoid-induced changes in the RIII reflex threshold and area in patients with MS provide objective neurophysiological evidence that cannabinoids modulate the nociceptive system in patients with MS.

  8. Physiologically based pharmacokinetic and pharmacodynamic modeling of an antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in a mouse xenograft model of human breast cancer.

    Science.gov (United States)

    Zhang, Tao; Li, Yanyan; Zou, Peng; Yu, Jing-yu; McEachern, Donna; Wang, Shaomeng; Sun, Duxin

    2013-09-01

    The inhibitors of apoptosis proteins (IAPs) are a class of key apoptosis regulators overexpressed or dysregulated in cancer. SM-406/AT-406 is a potent and selective small molecule mimetic of Smac that antagonizes the inhibitor of apoptosis proteins (IAPs). A physiologically based pharmacokinetic and pharmacodynamic (PBPK-PD) model was developed to predict the tissue concentration-time profiles of SM-406, the related onco-protein levels in tumor, and the tumor growth inhibition in a mouse model bearing human breast cancer xenograft. In the whole body physiologically based pharmacokinetic (PBPK) model for pharmacokinetics characterization, a well stirred (perfusion rate-limited) model was used to describe SM-406 pharmacokinetics in the lung, heart, kidney, intestine, liver and spleen, and a diffusion rate-limited (permeability limited) model was used for tumor. Pharmacodynamic (PD) models were developed to correlate the SM-406 concentration in tumor to the cIAP1 degradation, pro-caspase 8 decrease, CL-PARP accumulation and tumor growth inhibition. The PBPK-PD model well described the experimental pharmacokinetic data, the pharmacodynamic biomarker responses and tumor growth. This model may be helpful to predict tumor and plasma SM-406 concentrations in the clinic. Copyright © 2013 John Wiley & Sons, Ltd.

  9. Improved physiologically based pharmacokinetic model for oral exposures to chromium in mice, rats, and humans to address temporal variation and sensitive populations

    Energy Technology Data Exchange (ETDEWEB)

    Kirman, C.R., E-mail: ckirman@summittoxicology.com [Summit Toxicology, PO Box 3209, Bozeman, MT 59715 (United States); Suh, M.; Proctor, D.M. [ToxStrategies, Mission Viejo, CA (United States); Hays, S.M. [Summit Toxicology, PO Box 3209, Bozeman, MT 59715 (United States)

    2017-06-15

    A physiologically based pharmacokinetic (PBPK) model for hexavalent chromium [Cr(VI)] in mice, rats, and humans developed previously (Kirman et al., 2012, 2013), was updated to reflect an improved understanding of the toxicokinetics of the gastrointestinal tract following oral exposures. Improvements were made to: (1) the reduction model, which describes the pH-dependent reduction of Cr(VI) to Cr(III) in the gastrointestinal tract under both fasted and fed states; (2) drinking water pattern simulations, to better describe dosimetry in rodents under the conditions of the NTP cancer bioassay; and (3) parameterize the model to characterize potentially sensitive human populations. Important species differences, sources of non-linear toxicokinetics, and human variation are identified and discussed within the context of human health risk assessment. - Highlights: • An improved version of the PBPK model for Cr(VI) toxicokinetics was developed. • The model incorporates data collected to fill important data gaps. • Model predictions for specific age groups and sensitive subpopulations are provided. • Implications to human health risk assessment are discussed.

  10. The Effects of Synthetic Cannabinoids on Alveolar-Arterial Oxygen Gradient

    Directory of Open Access Journals (Sweden)

    Egemen Kucuk

    2016-09-01

    Full Text Available Aim: Synthetic cannabinoids are chemicals that produce several marijuana-like effects in humans. Aim of this study is to investigate the effects of synthetic cannabinoids on to alveolar-arterial oxygen gradient. Material and Method: A total of 112 patients, who admitted directly to emergency clinic with synthetic cannabinoid usage, were determined between February 2014 and August 2014. Blood gases of 41 patients were determined as arterial blood gases on room air, and included in to study. Patients were evaluated according to age, sex, decade, partial pressure of arterial oxygen, partial pressure of arterial carbon dioxide, pH, bicarbonate, metabolic status, age consistent expected alveolar-arterial oxygen gradient and calculated alveolar-arterial oxygen gradient. Results: Synthetic cannabinoid using was higher in males, mean age of patients was 23.32±6.14 years. Number of patients in the third decade were significantly higher than the other decades. The calculated alveolar-arterial oxygen gradient value of patients was significantly higher than age consistent expected alveolar-arterial oxygen gradient value. Respiratory acidosis, was significantly higher than the other types of the metabolic disorders. The best cutoff point for calculated alveolar-arterial oxygen gradient was 12.70, with sensitivity of 90% and specifity of 85%. Area under curve was 0.70 for calculated alveolar-arterial oxygen gradient. Discussion: The value of alveolar-arterial oxygen gradient has been increased due to synthetic cannabinoid usage. This can be used as a supportive parameter in the diagnosis of synthetic cannabinoid usage.

  11. Emergency Physicians' Knowledge of Cannabinoid Designer Drugs

    Directory of Open Access Journals (Sweden)

    Patrick M Lank

    2013-09-01

    Full Text Available Introduction: The use of synthetic drugs of abuse in the United States has grown in the last few years, with little information available on how much physicians know about these drugs and how they are treating patients using them. The objective of this study was to assess emergency physician (EP knowledge of synthetic cannabinoids (SC.Methods: A self-administered internet-based survey of resident and attending EPs at a large urban emergency department (ED was administered to assess familiarity with the terms Spice or K2 and basic knowledge of SC, and to describe some practice patterns when managing SC intoxication in the ED.Results: Of the 83 physicians invited to participate, 73 (88% completed surveys. The terms “Spice” and “K2” for SC were known to 25/73 (34% and 36/73 (49% of respondents. Knowledge of SC came most commonly (72% from non-medical sources, with lay publications and the internet providing most respondents with information. Among those with previous knowledge of synthetic cannabinoids, 25% were not aware that SC are synthetic drugs, and 17% did not know they are chemically most similar to marijuana. Among all participants, 80% felt unprepared caring for a patient in the ED who had used synthetic cannabinoids.Conclusion: Clinically active EPs are unfamiliar with synthetic cannabinoids. Even those who stated they had heard of synthetic cannabinoids answered poorly on basic knowledge questions. More education is needed among EPs of all ages and levels of training on synthetic cannabinoids. [West J Emerg Med. 2013;14(5:467–470.

  12. Cannabinoids modulate hippocampal memory and plasticity.

    Science.gov (United States)

    Abush, Hila; Akirav, Irit

    2010-10-01

    Considerable evidence demonstrates that cannabinoid agonists impair whereas cannabinoid antagonists improve memory and plasticity. However, recent studies suggest that the effects of cannabinoids on learning do not necessarily follow these simple patterns, particularly when emotional memory processes are involved. We investigated the involvement of the cannabinoid system in hippocampal learning and plasticity using the fear-related inhibitory avoidance (IA) and the non-fear-related spatial learning paradigms, and cellular models of learning and memory, i.e., long-term potentiation (LTP) and long-term depression (LTD). We found that microinjection into the CA1 of the CB1/CB2 receptor agonist WIN55,212-2 (5 μg/side) and an inhibitor of endocannabinoid reuptake and breakdown AM404 (200 ng/side) facilitated the extinction of IA, while the CB1 receptor antagonist AM251 (6 ng/side) impaired it. WIN55,212-2 and AM251 did not affect IA conditioning, while AM404 enhanced it, probably due to a drug-induced increase in pain sensitivity. However, in the water maze, systemic or local CA1 injections of AM251, WIN55,212-2, and AM404 all impaired spatial learning. We also found that i.p. administration of WIN55,212-2 (0.5 mg/kg), AM404 (10 mg/kg), and AM251 (2 mg/kg) impaired LTP in the Schaffer collateral-CA1 projection, whereas AM404 facilitated LTD. Our findings suggest diverse effects of the cannabinoid system on CA1 memory and plasticity that cannot be categorized simply into an impairing or an enhancing effect of cannabinoid activation and deactivation, respectively. Moreover, they provide preclinical support for the suggestion that targeting the endocannabinoid system may aid in the treatment of disorders associated with impaired extinction-like processes, such as post-traumatic stress disorder. © 2009 Wiley-Liss, Inc.

  13. Preclinical Science Regarding Cannabinoids as Analgesics: An Overview

    Directory of Open Access Journals (Sweden)

    ME Lynch

    2005-01-01

    Full Text Available Modern pharmacology of cannabinoids began in 1964 with the isolation and partial synthesis of delta-9-tetrahydrocannabinol, the main psychoactive agent in herbal cannabis. Since then, potent antinociceptive and antihyperalgesic effects of cannabinoid agonists in animal models of acute and chronic pain; the presence of cannabinoid receptors in pain-processing areas of the brain, spinal cord and periphery; and evidence supporting endogenous modulation of pain systems by cannabinoids has provided support that cannabinoids exhibit significant potential as analgesics. The present article presents an overview of the preclinical science.

  14. Synthetic cannabinoid JWH-018 and psychosis: an explorative study.

    Science.gov (United States)

    Every-Palmer, Susanna

    2011-09-01

    Aroma, Spice, K2 and Dream are examples of a class of new and increasingly popular recreational drugs. Ostensibly branded "herbal incense", they have been intentionally adulterated with synthetic cannabinoids such as JWH-018 in order to confer on them cannabimimetic psychoactive properties while circumventing drug legislation. JWH-018 is a potent cannabinoid receptor agonist. Little is known about its pharmacology and toxicology in humans. This is the first research considering the effects of JWH-018 on a psychiatric population and exploring the relationship between JWH-018 and psychotic symptoms. This paper presents the results of semi-structured interviews regarding the use and effects of JWH-018 in 15 patients with serious mental illness in a New Zealand forensic and rehabilitative service. All 15 subjects were familiar with a locally available JWH-018 containing product called "Aroma" and 86% reported having used it. They credited the product's potent psychoactivity, legality, ready availability and non-detection in drug testing as reasons for its popularity, with most reporting it had replaced cannabis as their drug of choice. Most patients had assumed the product was "natural" and "safe". Anxiety and psychotic symptoms were common after use, with 69% of users experiencing or exhibiting symptoms consistent with psychotic relapse after smoking JWH-018. Although psychological side effects were common, no one reported becoming physically unwell after using JWH-018. Three subjects described developing some tolerance to the product, but no one reported withdrawal symptoms. It seems likely that JWH-018 can precipitate psychosis in vulnerable individuals. People with risk factors for psychosis should be counseled against using synthetic cannabinoids. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  15. Application of physiologically based pharmacokinetic modeling in predicting drug–drug interactions for sarpogrelate hydrochloride in humans

    Directory of Open Access Journals (Sweden)

    Min JS

    2016-09-01

    Full Text Available Jee Sun Min,1 Doyun Kim,1 Jung Bae Park,1 Hyunjin Heo,1 Soo Hyeon Bae,2 Jae Hong Seo,1 Euichaul Oh,1 Soo Kyung Bae1 1Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, 2Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, South Korea Background: Evaluating the potential risk of metabolic drug–drug interactions (DDIs is clinically important. Objective: To develop a physiologically based pharmacokinetic (PBPK model for sarpogrelate hydrochloride and its active metabolite, (R,S-1-{2-[2-(3-methoxyphenylethyl]-phenoxy}-3-(dimethylamino-2-propanol (M-1, in order to predict DDIs between sarpogrelate and the clinically relevant cytochrome P450 (CYP 2D6 substrates, metoprolol, desipramine, dextromethorphan, imipramine, and tolterodine. Methods: The PBPK model was developed, incorporating the physicochemical and pharmacokinetic properties of sarpogrelate hydrochloride, and M-1 based on the findings from in vitro and in vivo studies. Subsequently, the model was verified by comparing the predicted concentration-time profiles and pharmacokinetic parameters of sarpogrelate and M-1 to the observed clinical data. Finally, the verified model was used to simulate clinical DDIs between sarpogrelate hydrochloride and sensitive CYP2D6 substrates. The predictive performance of the model was assessed by comparing predicted results to observed data after coadministering sarpogrelate hydrochloride and metoprolol. Results: The developed PBPK model accurately predicted sarpogrelate and M-1 plasma concentration profiles after single or multiple doses of sarpogrelate hydrochloride. The simulated ratios of area under the curve and maximum plasma concentration of metoprolol in the presence of sarpogrelate hydrochloride to baseline were in good agreement with the observed ratios. The predicted fold-increases in the area under the curve ratios of metoprolol

  16. Comparison of outcome expectancies for synthetic cannabinoids and botanical marijuana.

    Science.gov (United States)

    Lauritsen, Kirstin J; Rosenberg, Harold

    2016-07-01

    Although initially developed for medical purposes, synthetic cannabinoids have also been consumed for recreational purposes. To evaluate whether agreement with positive and negative outcome expectancies differed for synthetic cannabinoids versus botanical marijuana, and assess reported reasons for using synthetic cannabinoids. Using a web-based recruitment and data collection procedure, 186 adults who had used both synthetic cannabinoids and botanical marijuana and 181 adults who had used botanical marijuana but not synthetic cannabinoids, completed measures of outcome expectancies and other relevant questionnaires. A significant interaction revealed that participants who had used both synthetic cannabinoids and botanical marijuana indicated lower agreement with positive expectancies for synthetic cannabinoids, and higher agreement with positive expectancies for botanical marijuana, than did those participants who used only botanical marijuana. There was no interaction between type of drug and use history on agreement with negative expectancies, and participants agreed more strongly with negative outcome expectancies for synthetic cannabinoids than for botanical marijuana whether they had used one or both types of these drugs. The most frequently provided reasons for using synthetic cannabinoids included availability, perceived legality, cost, curiosity, and social interaction. Given growing public acceptance of recreational and medical marijuana, coupled with negative perceptions and increasing regulation of synthetic cannabinoid compounds, botanical marijuana is likely to remain more available and more popular than synthetic cannabinoids.

  17. Determination of human insulin in dog plasma by a selective liquid chromatography-tandem mass spectrometry method: Application to a pharmacokinetic study.

    Science.gov (United States)

    Dong, Shiqi; Zeng, Yong; Wei, Guangli; Si, Duanyun; Liu, Changxiao

    2018-03-01

    A simple, sensitive and selective LC-MS/MS method for quantitative analysis of human insulin was developed and validated in dog plasma. Insulin glargine was used as the internal standard. After a simple step of solid-phase extraction, the chromatographic separation of human insulin was achieved by using InertSustain Bio C18 column with a mobile phase of acetonitrile containing 1% formic acid (A)-water containing 1% formic acid (B). The detection was performed by positive ion electrospray ionization in multiple-reaction monitoring (MRM) mode. Good linearity was observed in the concentration range of 1-1000 μIU/mL (r 2  > 0.99), and the lower limit of quantification was 1 μIU/mL (equal to 38.46 pg/mL). The intra- and inter-day precision (expressed as relative standard deviation, RSD) of human insulin were ≤12.1% and ≤13.0%, respectively, and the accuracy (expressed as relative error, RE) was in the range of -7.23-11.9%. The recovery and matrix effect were both within acceptable limits. This method was successfully applied for the pharmacokinetic study of human insulin in dogs after subcutaneous administration. Copyright © 2018 Elsevier B.V. All rights reserved.

  18. Simultaneous determination of sibutramine and its active metabolites in human plasma by LC-MS/MS and its application to a pharmacokinetic study.

    Science.gov (United States)

    Bae, Jung-Woo; Choi, Chang-Ik; Jang, Choon-Gon; Lee, Seok-Yong

    2011-11-01

    A simple and sensitive liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) technique was developed and validated for the determination of sibutramine and its N-desmethyl metabolites (M1 and M2) in human plasma. After extraction with methyl t-butyl ether, chromatographic separation of analytes in human plasma was performed using a reverse-phase Luna C18 column with a mobile phase of acetonitrile-10 mm ammonium formate buffer (50:50, v/v) and quantified by ESI-MS/MS detection in positive ion mode. The flow rate of the mobile phase was 200 μL/min and the retention times of sibutramine, M1, M2 and internal standard (chlorpheniramine) were 1.5, 1.4, 1.3 and 0.9 min, respectively. The calibration curves were linear over the range 0.05-20 ng/mL, for sibutramine, M1 and M2. The lower limit of quantification was 0.05 ng/mL using 500 μL of human plasma. The mean accuracy and the precision in the intra- and inter-day validation for sibutramine, M1 and M2 were acceptable. This LC-MS/MS method showed improved sensitivity and a short run time for the quantification of sibutramine and its two active metabolites in plasma. The validated method was successfully applied to a pharmacokinetic study in human. Copyright © 2011 John Wiley & Sons, Ltd.

  19. Cannabinoid hyperemesis syndrome: potential mechanisms for the benefit of capsaicin and hot water hydrotherapy in treatment.

    Science.gov (United States)

    Richards, John R; Lapoint, Jeff M; Burillo-Putze, Guillermo

    2018-01-01

    Cannabinoid hyperemesis syndrome is a clinical disorder that has become more prevalent with increasing use of cannabis and synthetic cannabinoids, and which is difficult to treat. Standard antiemetics commonly fail to alleviate the severe nausea and vomiting characteristic of the syndrome. Curiously, cannabinoid hyperemesis syndrome patients often report dramatic relief of symptoms with hot showers and baths, and topical capsaicin. In this review, we detail the pharmacokinetics and pharmacodynamics of capsaicin and explore possible mechanisms for its beneficial effect, including activation of transient receptor potential vanilloid 1 and neurohumoral regulation. Putative mechanisms responsible for the benefit of hot water hydrotherapy are also investigated. An extensive search of PubMed, OpenGrey, and Google Scholar from inception to April 2017 was performed to identify known and theoretical thermoregulatory mechanisms associated with the endocannabinoid system. The searches resulted in 2417 articles. These articles were screened for relevant mechanisms behind capsaicin and heat activation having potential antiemetic effects. References from the selected articles were also hand-searched. A total of 137 articles were considered relevant and included. Capsaicin: Topical capsaicin is primarily used for treatment of neuropathic pain, but it has also been used successfully in some 20 cases of cannabinoid hyperemesis syndrome. The pharmacokinetics and pharmacodynamics of capsaicin as a transient receptor potential vanilloid 1 agonist may explain this effect. Topical capsaicin has a longer half-life than oral administration, thus its potential duration of benefit is longer. Capsaicin and transient receptor potential vanilloid 1: Topical capsaicin binds and activates the transient receptor potential vanilloid 1 receptor, triggering influx of calcium and sodium, as well as release of inflammatory neuropeptides leading to transient burning, stinging, and itching. This elicits

  20. A simple physiologically based pharmacokinetic model evaluating the effect of anti-nicotine antibodies on nicotine disposition in the brains of rats and humans

    Energy Technology Data Exchange (ETDEWEB)

    Saylor, Kyle, E-mail: saylor@vt.edu; Zhang, Chenming, E-mail: chzhang2@vt.edu

    2016-09-15

    Physiologically based pharmacokinetic (PBPK) modeling was applied to investigate the effects of anti-nicotine antibodies on nicotine disposition in the brains of rats and humans. Successful construction of both rat and human models was achieved by fitting model outputs to published nicotine concentration time course data in the blood and in the brain. Key parameters presumed to have the most effect on the ability of these antibodies to prevent nicotine from entering the brain were selected for investigation using the human model. These parameters, which included antibody affinity for nicotine, antibody cross-reactivity with cotinine, and antibody concentration, were broken down into different, clinically-derived in silico treatment levels and fed into the human PBPK model. Model predictions suggested that all three parameters, in addition to smoking status, have a sizable impact on anti-nicotine antibodies' ability to prevent nicotine from entering the brain and that the antibodies elicited by current human vaccines do not have sufficient binding characteristics to reduce brain nicotine concentrations. If the antibody binding characteristics achieved in animal studies can similarly be achieved in human studies, however, nicotine vaccine efficacy in terms of brain nicotine concentration reduction is predicted to meet threshold values for alleviating nicotine dependence. - Highlights: • Modelling of nicotine disposition in the presence of anti-nicotine antibodies • Key vaccine efficacy factors are evaluated in silico in rats and in humans. • Model predicts insufficient antibody binding in past human nicotine vaccines. • Improving immunogenicity and antibody specificity may lead to vaccine success.

  1. A simple physiologically based pharmacokinetic model evaluating the effect of anti-nicotine antibodies on nicotine disposition in the brains of rats and humans

    International Nuclear Information System (INIS)

    Saylor, Kyle; Zhang, Chenming

    2016-01-01

    Physiologically based pharmacokinetic (PBPK) modeling was applied to investigate the effects of anti-nicotine antibodies on nicotine disposition in the brains of rats and humans. Successful construction of both rat and human models was achieved by fitting model outputs to published nicotine concentration time course data in the blood and in the brain. Key parameters presumed to have the most effect on the ability of these antibodies to prevent nicotine from entering the brain were selected for investigation using the human model. These parameters, which included antibody affinity for nicotine, antibody cross-reactivity with cotinine, and antibody concentration, were broken down into different, clinically-derived in silico treatment levels and fed into the human PBPK model. Model predictions suggested that all three parameters, in addition to smoking status, have a sizable impact on anti-nicotine antibodies' ability to prevent nicotine from entering the brain and that the antibodies elicited by current human vaccines do not have sufficient binding characteristics to reduce brain nicotine concentrations. If the antibody binding characteristics achieved in animal studies can similarly be achieved in human studies, however, nicotine vaccine efficacy in terms of brain nicotine concentration reduction is predicted to meet threshold values for alleviating nicotine dependence. - Highlights: • Modelling of nicotine disposition in the presence of anti-nicotine antibodies • Key vaccine efficacy factors are evaluated in silico in rats and in humans. • Model predicts insufficient antibody binding in past human nicotine vaccines. • Improving immunogenicity and antibody specificity may lead to vaccine success.

  2. The effects of human CYP2C8 genotype and fluvoxamine on the pharmacokinetics of rosiglitazone in healthy subjects

    DEFF Research Database (Denmark)

    Pedersen, Rasmus S; Damkier, Per; Brosen, Kim

    2006-01-01

    = 0.0066) increase in the AUC(0-infinity) of rosiglitazone, with a geometric mean ratio of 1.21 [95% confidence interval (CI) 1.06-1.39]. The elimination half-life (t(1/2)) was also significantly higher (P = 0.0203) with a geometric mean ratio of 1.38 [95% CI 1.06-1.79]. The coadministration...... of fluvoxamine had no influence on the pharmacokinetics of N-desmethylrosiglitazone. CONCLUSION: The importance of the CYP2C8*3 mutation in the in vivo metabolism of rosiglitazone could not be confirmed. Fluvoxamine increased the AUC(0-infinity) and t(1/2) of rosiglitazone moderately and hence may be a weak...

  3. Suspected synthetic cannabinoid toxicosis in a dog.

    Science.gov (United States)

    Williams, Keysa; Wells, Raegan J; McLean, Mary Kay

    2015-01-01

    To describe the effects of suspected synthetic cannabinoid (SC) toxicosis and the response to intravenous lipid emulsion (ILE) therapy in a dog. A 2-year-8-month-old male Boxer dog was evaluated at an emergency hospital for progressive ataxia and inappropriate mentation. The initial physical examination identified marked hypothermia (32.7°C [90.9°F]), intermittent sinus bradycardia (60/min), stuporous mentation with intermittent aggression, and severe ataxia. Neurologic status deteriorated to comatose mentation within 2 hours of presentation. The initial diagnostic evaluation (eg, CBC, serum biochemistry profile, venous blood gas, and electrolyte determination) revealed a respiratory acidosis and thrombocytopenia. The owner reported that the dog was exposed to an SC containing Damiana leaf, Marshmallow leaf, and Athaea leaves. Initial treatment included IV fluids and supplemental oxygen. Mechanical ventilation was provided due to hypoventilation and periods of apnea. Intravenous lipid emulsion therapy was administered as a bolus (1.5 mL/kg) and continued as a continuous rate infusion (0.5 mL/kg/h) for a total of 6 hours. The dog became rousable and was weaned from mechanical ventilation approximately 15 hours following presentation. The dog was eating and walking with no ataxia, had a normal mentation at approximately 33 hours following presentation, and was discharged home at that time. Communication with the owners 5 days following discharge revealed that the dog was apparently normal. Based on this case and other reports in the literature regarding human exposures, SC ingestion may result in more severe clinical signs than marijuana ingestion in dogs. Significant clinical intervention may be necessary. Intravenous lipid emulsion treatment may be beneficial due to the lipophilicity of SC. © Veterinary Emergency and Critical Care Society 2015.

  4. Human pharmacokinetics, biodistribution and dosimetry of the kit of monoclonal antibody IOR EGF/R3 labelled with 99m Tc

    International Nuclear Information System (INIS)

    Torres, L.A.; Ramos, M.; Perera, A.; Hernandez, A.; Iznaga, M.E. N.

    1998-01-01

    The aim of this work was to assess the human pharmacokinetics, biodistribution and dosimetry of the 99m Tc-labeled MAb ior egf/r3. Five patients were included in the biodistribution and dosimetric studies and three in the pharmacokinetic analysis. Multiple blood and urine samples we recollected and sequential anterior and posterior whole-body scintigraphies u pto 24 hr post-injection were performed to all patients . The internal radiation dosimetry was estimated from gamma camera imaging data using the methods developed by the Medical Internal radiation dosimetry (MIRD)committee. Raw data were computed from operations between gamma graphic images and regions of interest (ROI) using the Bio-Dose software and time-activity curves were calculated in order to determine the residence times of the source organs. The Pharmacokinetics and Biodistribution results showed that this compound have a bio exponential plasmatic and blood clearance with a rapid biodistribution phase of 9.1 ± 8.4 min and 12.2±4.4 min, respectively, and a slower elimination phase of 6.6 ± 1.6 hr and 10.8 ± 6.8 hr. respectively. The urinary and hepatobiliary excretion showed 4.7 ± 0.4 % and 9.9 ± 1.8 % of the total administered dose,eliminated by these ways. Liver was the target organ of this product and had an uptake peak at 1 hr post-injection (61.2%) and a great retention of the MAb(T 1/2 eff = 5.3 hr, T 1/2 Biol. = 45.0 hr). The dosimetric results showed that liver, gallbladder and spleen received the higher absorbed. The effective dose and the effective equivalent dose were 1,2E-01 mSv/MBq and 9,2E-02 mSv/MBq respectively. These results allow to see the i or egf/r3 kit in a safe and controlled way. (Author)

  5. Estimation of the binding modes with important human cytochrome P450 enzymes, drug interaction potential, pharmacokinetics, and hepatotoxicity of ginger components using molecular docking, computational, and pharmacokinetic modeling studies

    Directory of Open Access Journals (Sweden)

    Qiu JX

    2015-02-01

    2, 2C9, 2C19, 2D6, and 3A4 mainly through hydrogen bond formation, to a lesser extent, via π–π stacking. The pharmacokinetic simulation studies showed that the [I]/[Ki] value for CYP2C9, 2C19, and 3A4 ranged from 0.0002 to 19.6 and the R value ranged from 1.0002 to 20.6 and that ginger might exhibit a high risk of drug interaction via inhibition of the activity of human CYP2C9 and CYP3A4, but a low risk of drug interaction toward CYP2C19-mediated drug metabolism. Furthermore, it has been evaluated that the 12 ginger components possessed a favorable ADMET profiles with regard to the solubility, absorption, permeability across the blood–brain barrier, interactions with CYP2D6, hepatotoxicity, and plasma protein binding. The validation results showed that there was no remarkable effect of ginger on the metabolism of warfarin in humans, whereas concurrent use of ginger and nifedipine exhibited a synergistic effect on platelet aggregation in humans. Moreover, ginger components showed a rapid half-life and no to low toxicity in humans. Taken together, this study shows that ginger components may regulate the activity and expression of various human CYPs, probably resulting in alterations in drug clearance and response. More studies are warranted to identify and confirm potential ginger–drug interactions and explore possible interactions of ginger with human CYPs and other functionally important proteins, to reduce and avoid side effects induced by unfavorable ginger–drug interactions.Keywords: CYP, drug metabolism, ginger, drug interaction, docking

  6. Precolumn derivatization LC–MS/MS method for the determination and pharmacokinetic study of glucosamine in human plasma and urine

    Directory of Open Access Journals (Sweden)

    Min Song

    2012-02-01

    Full Text Available A selective precolumn derivatization liquid chromatography–tandem mass spectrometric (LC–MS/MS method for the determination of glucosamine in human plasma and urine has been developed and validated. Glucosamine was derivatized by o-phthalaldehyde/3-mercaptopropionic acid. Chromatographic separation was performed on a Phenomenex ODS column (150 mm×4.6 mm, 5 μm using linear gradient elution by a mobile phase consisting of methanol (A, and an aqueous solution containing 0.2% ammonium acetate and 0.1% formic acid (B at a flow rate of 1 mL/min. Tolterodine tartrate was used as the internal standard (IS. With protein precipitation by acetonitrile and then the simple one-step derivatization, a sensitive bio-assay was achieved with the lower limit of quantitation (LLOQ as low as 12 ng/mL for plasma. The standard addition calibration curves suitable for clinical sample analysis showed good linearity over the range of 0.012–8.27 μg/mL in plasma and 1.80–84.1 μg/mL in urine. The fully validated method has been successfully applied to a pharmacokinetic study of compound glucosamine sulfate dispersible tablets in health Chinese volunteers receiving single oral doses at 500, 1000 and 1500 mg of glucosamine sulfate, as well as multiple oral doses of 500 mg t.i.d. for 7 consecutive days. Keywords: Glucosamine, Pharmacokinetics, Precolumn derivatization, LC–MS/MS

  7. Phenol-Explorer 2.0: a major update of the Phenol-Explorer database integrating data on polyphenol metabolism and pharmacokinetics in humans and experimental animals

    Science.gov (United States)

    Rothwell, Joseph A.; Urpi-Sarda, Mireia; Boto-Ordoñez, Maria; Knox, Craig; Llorach, Rafael; Eisner, Roman; Cruz, Joseph; Neveu, Vanessa; Wishart, David; Manach, Claudine; Andres-Lacueva, Cristina; Scalbert, Augustin

    2012-01-01

    Phenol-Explorer, launched in 2009, is the only comprehensive web-based database on the content in foods of polyphenols, a major class of food bioactives that receive considerable attention due to their role in the prevention of diseases. Polyphenols are rarely absorbed and excreted in their ingested forms, but extensively metabolized in the body, and until now, no database has allowed the recall of identities and concentrations of polyphenol metabolites in biofluids after the consumption of polyphenol-rich sources. Knowledge of these metabolites is essential in the planning of experiments whose aim is to elucidate the effects of polyphenols on health. Release 2.0 is the first major update of the database, allowing the rapid retrieval of data on the biotransformations and pharmacokinetics of dietary polyphenols. Data on 375 polyphenol metabolites identified in urine and plasma were collected from 236 peer-reviewed publications on polyphenol metabolism in humans and experimental animals and added to the database by means of an extended relational design. Pharmacokinetic parameters have been collected and can be retrieved in both tabular and graphical form. The web interface has been enhanced and now allows the filtering of information according to various criteria. Phenol-Explorer 2.0, which will be periodically updated, should prove to be an even more useful and capable resource for polyphenol scientists because bioactivities and health effects of polyphenols are dependent on the nature and concentrations of metabolites reaching the target tissues. The Phenol-Explorer database is publicly available and can be found online at http://www.phenol-explorer.eu. Database URL: http://www.phenol-explorer.eu PMID:22879444

  8. A first-in-human phase I and pharmacokinetic study of CP-4126 (CO-101), a nucleoside analogue, in patients with advanced solid tumours.

    Science.gov (United States)

    Venugopal, B; Awada, A; Evans, T R J; Dueland, S; Hendlisz, A; Rasch, W; Hernes, K; Hagen, S; Aamdal, S

    2015-10-01

    CP-4126 (gemcitabine elaidate, previously CO-101) is a lipid-drug conjugate of gemcitabine designed to circumvent human equilibrative nucleoside transporter1-related resistance to gemcitabine. The purpose of this study was to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of CP-4126, and to describe its pharmacokinetic profile. Eligible patients with advanced refractory solid tumours, and adequate performance status, haematological, renal and hepatic function, were treated with one of escalating doses of CP-4126 administered by a 30-min intravenous infusion on days 1, 8 and 15 of a 28-day cycle. Blood and urine samples were collected to determine the pharmacokinetics (PKs) of CP-4126. Forty-three patients, median age 59 years (range 18-76; male = 27, female = 16), received one of ten dose levels (30-1600 mg/m(2)). Dose-limiting toxicities included grade 3 anaemia, grade 3 fatigue and grade 3 elevation of transaminases. The MTD and RP2D were 1250 mg/m(2) on basis of the toxicity and PK data. CP-4126 followed dose-dependent kinetics and maximum plasma concentrations occurred at the end of CP-4126 infusion. Seven patients achieved stable disease sustained for ≥3 months, including two patients with pancreatic cancer who had progressed on or after gemcitabine exposure. CP-4126 was well tolerated with comparable toxicity profile to gemcitabine. Future studies are required to determine its anti-tumour efficacy, either alone or in combination with other cytotoxic chemotherapy regimens.

  9. Human pharmacokinetics, biodistribution and dosimetry of 99m Tc labelled monoclonal antibody ior egf/r3 in patients with tumors of epithelial origin: preliminary results

    International Nuclear Information System (INIS)

    Iznaga-Escobar, Normando E.; Morales, Alejo; Ramos, Mayra; Perez, Niuvis; Torres, Leonel A.; Alavarez, Ivette; Rodriguez, Nelson; Fraxedas, Roberto; Rodriguez, Oscar; Stabin, Michael G.

    1997-01-01

    Human pharmacokinetics, biodistribution and internal radiation dosimetry to normal organs and total body of 99m Tc-labeled monoclonal antibody ior egf/r 3 was investigated following intravenous injection in 5 patients. Following administration, blood and urine samples were collected from 4 patients up to 24 hr after injection Pharmacokinetics obtained from whole blood radioactivity showed blood disappearance described most properly by a biexponential model with a mean distribution half-life value of 0.14±0.02 hr and elimination half-life value of 31.0±13.6 hr. Whole body anterior and posterior scans were obtained at 10 min, 1,3,5 and 24 hr after injection. ROIs were drawn over the heart, liver spleen and bladder to measure the activity in the source organs. Time-activity curves for each source organ were fitted to mono- or biexponential functions by non-linear least squares regression using the flexible polyhedral method and integrated to determine organ residence times. The mean absorbed dose to the whole body and various normal organs were then estimated from residence times and from blood and urine samples using the MIRD method. The effective dose equivalent (EDE) and effective dose (ED) were calculated. Estimates of radiation absorbed dose to normal organs in rads/mCi administered (mean ± SD, n=4) were: whole body, 0.0185± 0.0023, gallbladder wall, 0.0755± 0.00761, spleen, 0.0637± 0.0167 and liver, 0.276± 0.029. The effective dose equivalent and effective dose estimates for adults were 0.039± 0.008 and 0.028± 0.004 rem/m Ci administered. (author). 15 refs., 3 figs., 3 tabs

  10. Simultaneous determination of dextromethorphan, dextrorphan and doxylamine in human plasma by HPLC coupled to electrospray ionization tandem mass spectrometry: application to a pharmacokinetic study.

    Science.gov (United States)

    Donato, J L; Koizumi, F; Pereira, A S; Mendes, G D; De Nucci, G

    2012-06-15

    In the present study, a fast, sensitive and robust method to quantify dextromethorphan, dextrorphan and doxylamine in human plasma using deuterated internal standards (IS) is described. The analytes and the IS were extracted from plasma by a liquid-liquid extraction (LLE) using diethyl-ether/hexane (80/20, v/v). Extracted samples were analyzed by high performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). Chromatographic separation was performed by pumping the mobile phase (acetonitrile/water/formic acid (90/9/1, v/v/v) during 4.0min at a flow-rate of 1.5 mL min⁻¹ into a Phenomenex Gemini® C18, 5 μm analytical column (150 × 4.6 mm i.d.). The calibration curve was linear over the range from 0.2 to 200 ng mL⁻¹ for dextromethorphan and doxylamine and 0.05 to 10 ng mL⁻¹ for dextrorphan. The intra-batch precision and accuracy (%CV) of the method ranged from 2.5 to 9.5%, and 88.9 to 105.1%, respectively. Method inter-batch precision (%CV) and accuracy ranged from 6.7 to 10.3%, and 92.2 to 107.1%, respectively. The run-time was for 4 min. The analytical procedure herein described was used to assess the pharmacokinetics of dextromethorphan, dextrorphan and doxylamine in healthy volunteers after a single oral dose of a formulation containing 30 mg of dextromethorphan hydrobromide and 12.5mg of doxylamine succinate. The method has high sensitivity, specificity and allows high throughput analysis required for a pharmacokinetic study. Copyright © 2012 Elsevier B.V. All rights reserved.

  11. Human pharmacokinetics, biodistribution and dosimetry of {sup 99m} Tc labelled monoclonal antibody ior egf/r3 in patients with tumors of epithelial origin: preliminary results

    Energy Technology Data Exchange (ETDEWEB)

    Iznaga-Escobar, Normando E.; Morales, Alejo; Ramos, Mayra; Perez, Niuvis [Center of Molecular Immunology (CIM), Havana (Cuba); Torres, Leonel A.; Alavarez, Ivette [Center of Clinical Researches (CIC), Havana (Cuba); Rodriguez, Nelson [Center of Medical-Surgical Researches (CIMEQ), Havana (Cuba); Fraxedas, Roberto [Institute of Nephrology (INEF), Havana (Cuba); Rodriguez, Oscar [Orthopedic Hospital Frank Pais, Havana (Cuba); Stabin, Michael G. [Radiation Internal Dose Information Center (RIDIC), Oak Ridge, TN (United States)

    1997-12-01

    Human pharmacokinetics, biodistribution and internal radiation dosimetry to normal organs and total body of {sup 99m} Tc-labeled monoclonal antibody ior egf/r{sup 3} was investigated following intravenous injection in 5 patients. Following administration, blood and urine samples were collected from 4 patients up to 24 hr after injection Pharmacokinetics obtained from whole blood radioactivity showed blood disappearance described most properly by a biexponential model with a mean distribution half-life value of 0.14{+-}0.02 hr and elimination half-life value of 31.0{+-}13.6 hr. Whole body anterior and posterior scans were obtained at 10 min, 1,3,5 and 24 hr after injection. ROIs were drawn over the heart, liver spleen and bladder to measure the activity in the source organs. Time-activity curves for each source organ were fitted to mono- or biexponential functions by non-linear least squares regression using the flexible polyhedral method and integrated to determine organ residence times. The mean absorbed dose to the whole body and various normal organs were then estimated from residence times and from blood and urine samples using the MIRD method. The effective dose equivalent (EDE) and effective dose (ED) were calculated. Estimates of radiation absorbed dose to normal organs in rads/mCi administered (mean {+-} SD, n=4) were: whole body, 0.0185{+-} 0.0023, gallbladder wall, 0.0755{+-} 0.00761, spleen, 0.0637{+-} 0.0167 and liver, 0.276{+-} 0.029. The effective dose equivalent and effective dose estimates for adults were 0.039{+-} 0.008 and 0.028{+-} 0.004 rem/m Ci administered. (author). 15 refs., 3 figs., 3 tabs.

  12. Interactions of Cannabinoids With Biochemical Substrates

    Directory of Open Access Journals (Sweden)

    Brian F Thomas

    2017-05-01

    Full Text Available Recent decades have seen much progress in the identification and characterization of cannabinoid receptors and the elucidation of the mechanisms by which derivatives of the Cannabis sativa plant bind to receptors and produce their physiological and psychological effects. The information generated in this process has enabled better understanding of the fundamental physiological and psychological processes controlled by the central and peripheral nervous systems and has fostered the development of natural and synthetic cannabinoids as therapeutic agents. A negative aspect of this decades-long effort is the proliferation of clandestinely synthesized analogs as recreational street drugs with dangerous effects. Currently, the interactions of cannabinoids with their biochemical substrates are extensively but inadequately understood, and the clinical application of derived and synthetic receptor ligands remains quite limited. The wide anatomical distribution and functional complexity of the cannabinoid system continue to indicate potential for both therapeutic and side effects, which offers challenges and opportunities for medicinal chemists involved in drug discovery and development.

  13. The Endocannabinoid System, Aggression, and the Violence of Synthetic Cannabinoid Use, Borderline Personality Disorder, Antisocial Personality Disorder, and Other Psychiatric Disorders.

    Science.gov (United States)

    Kolla, Nathan J; Mishra, Achal

    2018-01-01

    Endogenous and exogenous cannabinoids bind to central cannabinoid receptors to control a multitude of behavioral functions, including aggression. The first main objective of this review is to dissect components of the endocannabinoid system, including cannabinoid 1 and cannabinoid 2 receptors; the endogenous cannabinoids anandamide and 2-arachidonoylglycerol; and the indirect cannabinoid modulators fatty acid amide hydrolase and monoacylglycerol lipase; that have shown abnormalities in basic research studies investigating mechanisms of aggression. While most human research has concluded that the active ingredient of marijuana, Δ9-tetrahydrocannabinol, tends to dampen rather than provoke aggression in acute doses, recent evidence supports a relationship between the ingestion of synthetic cannabinoids and emergence of violent or aggressive behavior. Thus, another objective is to evaluate the emerging clinical data. This paper also discusses the relationship between prenatal and perinatal exposure to cannabis as well as use of cannabis in adolescence on aggressive outcomes. A final objective of the paper is to discuss endocannabinoid abnormalities in psychotic and affective disorders, as well as clinically aggressive populations, such as borderline personality disorder and antisocial personality disorder. With regard to the former condition, decreased anandamide metabolites have been reported in the cerebrospinal fluid, while some preliminary evidence suggests that fatty acid amide hydrolase genetic polymorphisms are linked to antisocial personality disorder and impulsive-antisocial psychopathic traits. To summarize, this paper will draw upon basic and clinical research to explain how the endocannabinoid system may contribute to the genesis of aggressive behavior.

  14. The Endocannabinoid System, Aggression, and the Violence of Synthetic Cannabinoid Use, Borderline Personality Disorder, Antisocial Personality Disorder, and Other Psychiatric Disorders

    Directory of Open Access Journals (Sweden)

    Nathan J. Kolla

    2018-03-01

    Full Text Available Endogenous and exogenous cannabinoids bind to central cannabinoid receptors to control a multitude of behavioral functions, including aggression. The first main objective of this review is to dissect components of the endocannabinoid system, including cannabinoid 1 and cannabinoid 2 receptors; the endogenous cannabinoids anandamide and 2-arachidonoylglycerol; and the indirect cannabinoid modulators fatty acid amide hydrolase and monoacylglycerol lipase; that have shown abnormalities in basic research studies investigating mechanisms of aggression. While most human research has concluded that the active ingredient of marijuana, Δ9-tetrahydrocannabinol, tends to dampen rather than provoke aggression in acute doses, recent evidence supports a relationship between the ingestion of synthetic cannabinoids and emergence of violent or aggressive behavior. Thus, another objective is to evaluate the emerging clinical data. This paper also discusses the relationship between prenatal and perinatal exposure to cannabis as well as use of cannabis in adolescence on aggressive outcomes. A final objective of the paper is to discuss endocannabinoid abnormalities in psychotic and affective disorders, as well as clinically aggressive populations, such as borderline personality disorder and antisocial personality disorder. With regard to the former condition, decreased anandamide metabolites have been reported in the cerebrospinal fluid, while some preliminary evidence suggests that fatty acid amide hydrolase genetic polymorphisms are linked to antisocial personality disorder and impulsive-antisocial psychopathic traits. To summarize, this paper will draw upon basic and clinical research to explain how the endocannabinoid system may contribute to the genesis of aggressive behavior.

  15. Phase I dose escalation pharmacokinetic assessment of intravenous humanized anti-MUC1 antibody AS1402 in patients with advanced breast cancer.

    Science.gov (United States)

    Pegram, Mark D; Borges, Virginia F; Ibrahim, Nuhad; Fuloria, Jyotsna; Shapiro, Charles; Perez, Susan; Wang, Karen; Schaedli Stark, Franziska; Courtenay Luck, Nigel

    2009-01-01

    MUC1 is a cell-surface glycoprotein that establishes a molecular barrier at the epithelial surface and engages in morphogenetic signal transduction. Alterations in MUC1 glycosylation accompany the development of cancer and influence cellular growth, differentiation, transformation, adhesion, invasion, and immune surveillance. A 20-amino-acid tandem repeat that forms the core protein of MUC1 is overexpressed and aberrantly glycosylated in the majority of epithelial tumors. AS1402 (formerly R1550) is a humanized IgG1k monoclonal antibody that binds to PDTR sequences within this tandem repeat that are not exposed in normal cells. AS1402 is a potent inducer of antibody-dependent cellular cytotoxicity (ADCC), specifically against MUC1-expressing tumor cells. The objective of this study was to determine the safety, tolerability, and pharmacokinetic (PK) characteristics of AS1402 monotherapy in patients with locally advanced or metastatic MUC1-positive breast cancer that had progressed after anthracyclines- and taxane-based therapy. Patients received AS1402 over a 1- to 3-hour intravenous (i.v.) infusion at doses between 1 and 16 mg/kg, with repeated dosing every 1 to 3 weeks (based on patient-individualized PK assessment) until disease progression. Serum AS1402 levels were measured at multiple times after i.v. administration. Human anti-human antibody (HAHA) responses were measured to determine the immunogenicity of AS1402. Noncompartmental pharmacokinetic parameters were determined and were used to assess dose dependency across the dose range studied. Twenty-six patients were treated. AS1402 was generally well tolerated. Two grade 3/4 drug-related adverse events were reported, both at the 3-mg/kg dose. Neither was observed in expanded or subsequent dosing cohorts. No anti-human antibodies were detected. Plasma concentrations of AS1402 appeared to be proportional to dose within the 1- to 16-mg/kg dose range assessed, with a mean terminal half-life of 115.4 +/- 37.1 hours

  16. High-performance liquid chromatographic method for the determination of nicardipine in pure, pharmaceutical preparations and plasma and its application to pharmacokinetics in humans

    Directory of Open Access Journals (Sweden)

    Sheikha M. Al-Ghannam

    2009-01-01

    Full Text Available A simple, sensitive and reproducible reversed-phase liquid chromatographic method has been developed and validated for the determination of nicardipine hydrochloride (NC in pure, pharmaceutical preparations, human plasma and the study of the pharmacokinetics of the drug in human body. Nicardipine in plasma were extracted with hexane-butanol (12:1,v/v after addition of borate buffer (0.5 M, pH=9.0, and then measured by HPLC-UV using a Waters Symmetry C18 column as stationary phase and methanol– triethylamine buffer (0.01M pH 4 with acetic acid (70:30 as mobile phase. Nicardipine was quantified by ultraviolet absorbance at 353 nm. The method proved to be linear in the pure drug in the ranges of 15-200 ng/mL (r=0.9989 and 5-40 ?g/mL (r=0.9995, and for the pharmaceutical preparations and plasma for drug concentrations in the range of 5-40 ?g/mL (r =0.9992 and 25-150 ng/mL (r=0.9991, respectively. The lower limit of detection and the lower quantitation limit of NC in plasma were 11.74 and 35.57 ng/mL, respectively. The method is sensitive and reliable for harmacokineticstudies of nicardipine in humans after the oral administration of immediate-release capsules to healthy subjects.

  17. Pharmacokinetics and immunogenicity investigation of a human anti-interleukin-17 monoclonal antibody in non-naïve cynomolgus monkeys.

    Science.gov (United States)

    Han, Chao; Gunn, George R; Marini, Joseph C; Shankar, Gopi; Han Hsu, Helen; Davis, Hugh M

    2015-05-01

    The pharmacokinetics (PK) of biologic therapeutics, especially monoclonal antibodies (mAbs), in monkeys generally presents the most relevant predictive PK information for humans. However, human mAbs, xenogeneic proteins to monkeys, are likely to be immunogenic. Monkeys previously treated with a human mAb (non-naïve) may have developed antidrug antibodies (ADAs) that cross-react with another test mAb in subsequent studies. Unlike PK studies for small-molecule therapeutics, in which animals may be reused, naïve monkeys have been used almost exclusively for preclinical PK studies of biologic therapeutics to avoid potential pre-existing immunologic cross-reactivity issues. The propensity and extent of pre-existing ADAs have not been systematically investigated to date. In this study, the PK and immunogenicity of mAb A, a human anti-human interkeukin-17 mAb, were investigated in a colony of 31 cynomolgus monkeys previously exposed to other human mAbs against different targets. We screened the monkeys for pre-existing antibodies to mAb A prior to the PK study and showed that 44% of the monkeys had pre-existing cross-reactive antibodies to mAb A, which could affect the PK characterization of the antibody. In the subcolony of monkeys without measurable pre-existing ADAs, PK and immunogenicity of mAb A were successfully characterized. The impact of ADAs on mAb A PK was also demonstrated in the monkeys with pre-existing ADAs. Here we report the results and propose a pragmatic approach for the use of non-naïve monkeys when conducting PK studies of biologic therapeutics. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  18. Pharmacokinetics and pharmacokinetic variability of heroin and its metabolites: review of the literature

    NARCIS (Netherlands)

    Rook, Elisabeth J.; Huitema, Alwin D. R.; van den Brink, Wim; van Ree, Jan M.; Beijnen, Jos H.

    2006-01-01

    This article reviews the pharmacokinetics of heroin after intravenous, oral, intranasal, intramuscular and rectal application and after inhalation in humans, with a special focus on heroin maintenance therapy in heroin dependent patients. In heroin maintenance therapy high doses pharmaceutically

  19. Suppression of vascular endothelial growth factor expression by cannabinoids in a canine osteosarcoma cell line

    Directory of Open Access Journals (Sweden)

    Figueiredo AS

    2013-07-01

    Full Text Available Andreza S Figueiredo,1 Hiram J García-Crescioni,1 Sandra C Bulla,1 Matthew K Ross,2 Chelsea McIntosh,1 Kari Lunsford,3 Camilo Bulla11Department of Pathobiology and Population Medicine, 2Department of Basic Sciences, 3Department of Clinical Sciences and Animal Health Center, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS, USAAbstract: Vascular endothelial growth factor (VEGF is a key regulator in both physiologic and pathologic angiogenesis, and cannabinoids decrease VEGF release in human and murine cancer cells. The aim of this study was to assess the in vitro effects of a synthetic cannabinoid, WIN-55,212-2, on the expression of the proangiogenic factor VEGF-A in the canine osteosarcoma cell line 8. After analysis of gene expression by quantitative real-time polymerase chain reaction, the compound decreased VEGF-A expression by 35% ± 10% (P < 0.0001 as compared with the control. This synthetic cannabinoid shows promise as a potential inhibitor of angiogenesis, and further studies are warranted to investigate its in vivo effects and to explore the potential of this and related compounds as adjuvant cancer therapy in the dog.Keywords: dog, cancer, angiogenesis, cannabinoids

  20. Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD.

    Science.gov (United States)

    Han, Jing; Kesner, Philip; Metna-Laurent, Mathilde; Duan, Tingting; Xu, Lin; Georges, Francois; Koehl, Muriel; Abrous, Djoher Nora; Mendizabal-Zubiaga, Juan; Grandes, Pedro; Liu, Qingsong; Bai, Guang; Wang, Wei; Xiong, Lize; Ren, Wei; Marsicano, Giovanni; Zhang, Xia

    2012-03-02

    Impairment of working memory is one of the most important deleterious effects of marijuana intoxication in humans, but its underlying mechanisms are presently unknown. Here, we demonstrate that the impairment of spatial working memory (SWM) and in vivo long-term depression (LTD) of synaptic strength at hippocampal CA3-CA1 synapses, induced by an acute exposure of exogenous cannabinoids, is fully abolished in conditional mutant mice lacking type-1 cannabinoid receptors (CB(1)R) in brain astroglial cells but is conserved in mice lacking CB(1)R in glutamatergic or GABAergic neurons. Blockade of neuronal glutamate N-methyl-D-aspartate receptors (NMDAR) and of synaptic trafficking of glutamate α-amino-3-hydroxy-5-methyl-isoxazole propionic acid receptors (AMPAR) also abolishes cannabinoid effects on SWM and LTD induction and expression. We conclude that the impairment of working memory by marijuana and cannabinoids is due to the activation of astroglial CB(1)R and is associated with astroglia-dependent hippocampal LTD in vivo. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. Involvement of cannabinoid system in the nucleus accumbens on delay-based decision making in the rat.

    Science.gov (United States)

    Fatahi, Zahra; Sadeghi, Bahman; Haghparast, Abbas

    2018-01-30

    The nucleus accumbens (NAc) plays a fundamental role in decision making and anticipation of reward. In addition, exogenous cannabinoids affect the behavior of humans and animals including disruption of short-term memory and cognitive impairments. Therefore, in this study, cannabinoid agonist and antagonist were administrated into the NAc to determine the effect of cannabinoid activation in the entire NAc on delay-based decision making. Rats were trained on a cost-benefit T-maze decision making task in which the animals were well-trained to choose between a small/immediate reward and a large/delay reward. After training, the animals were implanted with guide cannulae in the NAc. On test day, they received cannabinoid agonist (Win 55,212-2; 10, 50 and 100μM) and/or antagonist (AM251; 45μM) into the NAc. Percentage of high reward choice and latency of reward achievement were evaluated. Results showed that cannabinoid agonist administration caused a decrease in high reward choice such that rats selected small/immediate reward instead of large/delay reward. Moreover, in agonist-treated animals latency of reward achievement increased. Effects of cannabinoid activation on delay-based decision making with equivalent delays demonstrated that if the delay was equated on both arm goals, animals still had a preference for the high/delay reward, showing the results was not caused by an impairment of spatial preference or memory. These finding clarified that cannabinoid system activation in the entire NAc plays a critical role in the regulation of delay-based decision making. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. The anabolic steroid nandrolone alters cannabinoid self-administration and brain CB1 receptor density and function.

    Science.gov (United States)

    Struik, Dicky; Fadda, Paola; Zara, Tamara; Zamberletti, Erica; Rubino, Tiziana; Parolaro, Daniela; Fratta, Walter; Fattore, Liana

    2017-01-01

    Clinical and pre-clinical observations indicate that anabolic-androgenic steroids can induce neurobiological changes that alter the rewarding effects of drugs of abuse. In this study, we investigated the effect of the anabolic steroid nandrolone on the rewarding properties of the cannabinoid CB 1 receptor agonist WIN55,212-2 (WIN) in rats. Lister Hooded male rats were treated intramuscularly with nandrolone (15mg/kg) or vehicle for 14 consecutive days, and then allowed to self-administer WIN (12.5μg/kg/infusion) intravenously. After reaching stable drug intake, self-administration behavior was extinguished to examine drug- and cue-induced reinstatement of cannabinoid-seeking behavior. Other behavioral parameters presumed to influence drug-taking and drug-seeking behaviors were examined to gain more insight into the behavioral specificity of nandrolone treatment. Finally, animals were sacrificed for analysis of CB 1 receptor density and function in selected brain areas. We found that nandrolone-treated rats self-administered up to 2 times more cannabinoid than vehicle-treated rats, but behaved similarly to control rats when tested for drug- and cue-induced reinstatement of cannabinoid-seeking behavior. Enhanced cannabinoid intake by nandrolone-treated rats was not accompanied by changes in locomotor activity, sensorimotor gating, or memory function. However, our molecular data show that after chronic WIN self-administration nandrolone-treated rats display altered CB 1 receptor density and function in selected brain areas. We hypothesize that increased cannabinoid self-administration in nandrolone-treated rats results from a nandrolone-induced decrease in reward function, which rats seem to compensate by voluntarily increasing their cannabinoid intake. Altogether, our findings corroborate the hypothesis that chronic exposure to anabolic-androgenic steroids induces dysfunction of the reward pathway in rats and might represent a potential risk factor for abuse of

  3. A validated HPLC-MS/MS assay for quantifying unstable pharmacologically active metabolites of clopidogrel in human plasma: application to a clinical pharmacokinetic study.

    Science.gov (United States)

    Furlong, Michael T; Savant, Ishani; Yuan, Moucun; Scott, Laura; Mylott, William; Mariannino, Thomas; Kadiyala, Pathanjali; Roongta, Vikram; Arnold, Mark E

    2013-05-01

    Clopidogrel is prescribed for the treatment of Acute Coronary Syndrome and recent myocardial infarction, recent stroke, or established peripheral arterial disease. A sensitive and reliable high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay was developed and validated to enable reliable quantification of four diastereomeric and chemically reactive thiol metabolites, two of which are pharmacologically active, in human plasma. The metabolites were stabilized by alkylation of their reactive thiol moieties with 2-bromo-3'-methoxyacetophenone (MPB). Following organic solvent mediated-protein precipitation in a 96-well plate format, chromatographic separation was achieved by gradient elution on an Ascentis Express RP-amide column. Chromatographic conditions were optimized to ensure separation of the four derivatized active metabolites. Derivatized metabolites and stable isotope-labeled internal standards were detected by positive ion electrospray tandem mass spectrometry. The HPLC-MS/MS assay was validated over concentration ranges of 0.125-125 ng/mL for metabolites H1-H3 and 0.101-101 ng/mL for H4. Intra- and inter-assay precision values for replicate quality control samples were within 14.3% for all analytes during the assay validation. Mean quality control accuracy values were within ±6.3% of nominal values for all analytes. Assay recoveries were high (>79%). The four derivatized analytes were stable in human blood for at least 2 h at room temperature and on ice. The analytes were also stable in human plasma for at least 25 h at room temperature, 372 days at -20 °C and -70 °C, and following at least five freeze-thaw cycles. The validated assay was successfully applied to the quantification of all four thiol metabolites in human plasma in support of a human pharmacokinetic study. Copyright © 2013 Elsevier B.V. All rights reserved.

  4. Simple protein precipitation extraction technique followed by validated chromatographic method for linezolid analysis in real human plasma samples to study its pharmacokinetics.

    Science.gov (United States)

    Mohammed, Samah A; Eissa, Maya S; Ahmed, Hytham M

    2017-02-01

    Fast and sensitive HPLC method was developed, optimized and validated for quantification of linezolid (LNZ) in human plasma using guaifenesin as an internal standard (IS). Analyte and IS were extracted from plasma by simple protein precipitation extraction technique using methanol as the precipitating solvent. The pretreated samples were injected in a mobile phase formed of acetonitrile:water:methanol (20:70:10v/v/v) in an isocratic mode at a flow rate of 1.5mL/min with UV detection at 251nm. Separation was done using Aglient ODS C 18 . The method showed linearity in the range of 0.75-50μg/mL with correlation coefficients equals to 0.9991. Precision and accuracy were in conformity with the criteria normally accepted in bio-analytical method validation. The RSDs for intra- and inter-day assays were <3.56 and 4.63%, respectively. The intra- and inter-day accuracies were 94.67-98.28% and 91.25-96.18%, respectively. The mean absolute recoveries ranged from 92.56±1.78 to 95.24±2.84. According to stability results, LNZ was stable in human plasma during the storage and analysis. LNZ a pharmacokinetic behavior was studied by applying the proposed analytical method. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Simultaneous quantitation of lamivudine, zidovudine and nevirapine in human plasma by liquid chromatography–tandem mass spectrometry and application to a pharmacokinetic study

    Directory of Open Access Journals (Sweden)

    Murali Krishna Matta

    2012-10-01

    Full Text Available A rapid and sensitive LC–MS/MS method for the simultaneous quantitation of lamivudine, zidovudine and nevirapine in human plasma using abacavir as internal standard has been developed and validated. The analytes and IS were extracted from plasma by solid phase extraction using Oasis HLB cartridges and separated on a Hypurity Advance C18 column using a mixture of acetonitrile:0.1% formic acid (76:24, v/v at a flow rate of 0.8 mL/min. Detection involved an API-4000 LC–MS/MS with electrospray ionization in the positive ion mode and multiple-reaction monitoring for analysis. The method was validated according to FDA guidelines and shown to provide intra- and inter-day precision and accuracy within acceptable limits in a run time of only 3.5 min. The method was successfully applied to a pharmacokinetic study involving a single oral administration of a combination tablet to human male volunteers.

  6. Validation of a LC/MS method for the determination of gemfibrozil in human plasma and its application to a pharmacokinetic study

    Science.gov (United States)

    Rower, Joseph E.; Bushman, Lane R.; Hammond, Kyle P.; Kadam, Rajendra S.; Aquilante, Christina L.

    2011-01-01

    Gemfibrozil, a fibric acid hypolipidemic agent, is increasingly being used in clinical drug-drug interaction studies as an inhibitor of drug metabolizing enzymes and drug transporters. The validation of a fast, accurate, and precise LC/MS method is described for the quantitative determination of gemfibrozil in an EDTA-anticoagulated human plasma matrix. Briefly, gemfibrozil was extracted from human plasma by an acetonitrile protein precipitation method. The assay was reproducible with intra-assay precision between 1.6% and 10.7%, and inter-assay precision ranging from 4.4% to 7.8%. The assay also showed good accuracy, with intra-assay concentrations within 85.6% and 108.7% of the expected value, and inter-assay concentrations within 89.4 to 104.0% of the expected value. The linear concentration range was between 0.5 and 50 μg/mL with a lower limit of quantitation of 0.5 μg/mL when 125 μL of plasma were extracted. This LC/MS method yielded a quick, simple, and reliable protocol for determining gemfibrozil concentrations in plasma and is applicable to clinical pharmacokinetic studies. PMID:21077249

  7. Validation of an LC/MS method for the determination of gemfibrozil in human plasma and its application to a pharmacokinetic study.

    Science.gov (United States)

    Rower, Joseph E; Bushman, Lane R; Hammond, Kyle P; Kadam, Rajendra S; Aquilante, Christina L

    2010-12-01

    Gemfibrozil, a fibric acid hypolipidemic agent, is increasingly being used in clinical drug-drug interaction studies as an inhibitor of drug metabolizing enzymes and drug transporters. The validation of a fast, accurate and precise LC/MS method is described for the quantitative determination of gemfibrozil in an EDTA-anticoagulated human plasma matrix. Briefly, gemfibrozil was extracted from human plasma by an acetonitrile protein precipitation method. The assay was reproducible with intra-assay precision between 1.6 and 10.7%, and inter-assay precision ranging from 4.4 to 7.8%. The assay also showed good accuracy, with intra-assay concentrations within 85.6-108.7% of the expected value, and inter-assay concentrations within 89.4-104.0% of the expected value. The linear concentration range was between 0.5 and 50 µg/mL with a lower limit of quantitation of 0.5 µg/mL when 125 µL of plasma were extracted. This LC/MS method yielded a quick, simple and reliable protocol for determining gemfibrozil concentrations in plasma and is applicable to clinical pharmacokinetic studies. Copyright © 2010 John Wiley & Sons, Ltd.

  8. The Pharmacologic and Clinical Effects of Illicit Synthetic Cannabinoids.

    Science.gov (United States)

    White, C Michael

    2017-03-01

    This article presents information on illicitly used synthetic cannabinoids. Synthetic cannabinoids are structurally heterogeneous and commonly used drugs of abuse that act as full agonists of the cannabinoid type-1 receptor but have a variety of additional pharmacologic effects. There are numerous cases of patient harm and death in the United States, Europe, and Australia with many psychological, neurological, cardiovascular, pulmonary, and renal adverse events. Although most users prefer using cannabis, there are convenience, legal, and cost reasons driving the utilization of synthetic cannabinoids. Clinicians should be aware of pharmacologic and clinical similarities and differences between synthetic cannabinoid and cannabis use, the limited ability to detect synthetic cannabinoids in the urine or serum, and guidance to treat adverse events. © 2016, The American College of Clinical Pharmacology.

  9. Distribution of Synthetic Cannabinoids JWH-210, RCS-4 and Δ 9-Tetrahydrocannabinol After Intravenous Administration to Pigs.

    Science.gov (United States)

    Schaefer, Nadine; Kettner, Mattias; Laschke, Matthias W; Schlote, Julia; Ewald, Andreas H; Menger, Michael D; Maurer, Hans H; Schmidt, Peter H

    2017-01-01

    Synthetic cannabinoids (SCs) have become an increasing issue in forensic toxicology. Controlled human studies evaluating pharmacokinetic data of SCs are lacking and only few animal studies have been published. Thus, an interpretation of analytical results found in intoxicated or poisoned individuals is difficult. Therefore, the distribution of two selected SCs, namely 4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210) and 2-(4-methoxyphenyl)-1-(1- pentyl-indol-3-yl)methanone (RCS-4) as well as Δ9-tetrahydrocannabinol (THC) as reference were examined in pigs. Pigs (n = 6 per drug) received a single intravenous 200 μg/kg BW dose of JWH-210, RCS- 4, or THC. Six hours after administration, the animals were exsanguinated and relevant organs, important body fluids such as bile, and tissues such as muscle and adipose tissue, as well as the bradytrophic specimens dura and vitreous humor were collected. After hydrolysis and solid phase extraction, analysis was performed by LC-MS/MS. To overcome matrix effects of the LC-MS/MS analysis, a standard addition method was applied for quantification. The parent compounds could be detected in every analyzed specimen with the exception of THC that was not present in dura and vitreous humor. Moderate concentrations were present in brain, the site of biological effect. Metabolite concentrations were highest in tissues involved in metabolism and/or elimination Conclusions: Besides kidneys and lungs routinely analyzed in postmortem toxicology, brain, adipose, and muscle tissue could serve as alternative sources, particularly if other specimens are not available. Bile fluid is the most appropriate specimen for SCs and THC metabolites detection. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Distribution of Synthetic Cannabinoids JWH-210, RCS-4 and ∆ 9-Tetrahydrocannabinol After Intravenous Administration to Pigs

    Science.gov (United States)

    Schaefer, Nadine; Kettner, Mattias; Laschke, Matthias W.; Schlote, Julia; Ewald, Andreas H.; Menger, Michael D.; Maurer, Hans H.; Schmidt, Peter H.

    2017-01-01

    Background: Synthetic cannabinoids (SCs) have become an increasing issue in forensic toxicology. Controlled human studies evaluating pharmacokinetic data of SCs are lacking and only few animal studies have been published. Thus, an interpretation of analytical results found in intoxicated or poisoned individuals is difficult. Therefore, the distribution of two selected SCs, namely 4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210) and 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4) as well as ∆9-tetrahydrocannabinol (THC) as reference were examined in pigs. Methods: Pigs (n = 6 per drug) received a single intravenous 200 µg/kg BW dose of JWH-210, RCS-4, or THC. Six hours after administration, the animals were exsanguinated and relevant organs, important body fluids such as bile, and tissues such as muscle and adipose tissue, as well as the bradytrophic specimens dura and vitreous humor were collected. After hydrolysis and solid phase extraction, analysis was performed by LC-MS/MS. To overcome matrix effects of the LC-MS/MS analysis, a standard addition method was applied for quantification. Results: The parent compounds could be detected in every analyzed specimen with the exception of THC that was not present in dura and vitreous humor. Moderate concentrations were present in brain, the site of biological effect. Metabolite concentrations were highest in tissues involved in metabolism and/or elimination. Conclusions: Besides kidneys and lungs routinely analyzed in postmortem toxicology, brain, adipose, and muscle tissue could serve as alternative sources, particularly if other specimens are not available. Bile fluid is the most appropriate specimen for SCs and THC metabolites detection. PMID:27834143

  11. Comparative study of chitosan- and PEG-coated lipid and PLGA nanoparticles as oral delivery systems for cannabinoids

    International Nuclear Information System (INIS)

    Durán-Lobato, Matilde; Martín-Banderas, Lucía; Gonçalves, Lídia M. D.; Fernández-Arévalo, Mercedes; Almeida, Antonio J.

    2015-01-01

    The cannabinoid derivative 1-naphthalenyl[4-(pentyloxy)-1-naphthalenyl]methanone (CB13) has an important therapeutic potential as analgesic in chronic pain states that respond poorly to conventional drugs. However, the incidence of its mild-to-moderate and dose-dependent adverse effects, as well as its pharmacokinetic profile, actually holds back its use in humans. Thus, the use of a suitable carrier system for oral delivery of CB13 becomes an attractive strategy to develop a valuable therapy. Polymeric poly(lactic-co-glycolic) acid (PLGA) and lipid nanoparticles (LNPs) are widely studied delivery vehicles that improve the bioavailability of lipophilic compounds and present special interest in oral delivery. Their surface can be modified to improve the adhesion of particles to the oral mucosa and increase their circulation time in blood with additives such as chitosan (CS) and polyethylene glycol (PEG), which can be feasibly incorporated onto these particles in a post-production step. In this work, CS- and PEG-modified polymeric PLGA and LNPs were successfully obtained and comparatively evaluated under the same experimental conditions as oral carriers for CB13. All the formulations presented adequate blood compatibility and absence of cytotoxicity in Caco-2 cells. Coating with CS led to a higher interaction with Caco-2 cells and a limited uptake in THP1 cells, while coating with PEG led to a limited uptake in Caco-2 cells and strongly prevented THP1 cells uptake. The performance of each formulation is discussed as a comparison of the potential of these carriers as oral delivery systems of CB13

  12. Comparative study of chitosan- and PEG-coated lipid and PLGA nanoparticles as oral delivery systems for cannabinoids

    Science.gov (United States)

    Durán-Lobato, Matilde; Martín-Banderas, Lucía; Gonçalves, Lídia M. D.; Fernández-Arévalo, Mercedes; Almeida, Antonio J.

    2015-02-01

    The cannabinoid derivative 1-naphthalenyl[4-(pentyloxy)-1-naphthalenyl]methanone (CB13) has an important therapeutic potential as analgesic in chronic pain states that respond poorly to conventional drugs. However, the incidence of its mild-to-moderate and dose-dependent adverse effects, as well as its pharmacokinetic profile, actually holds back its use in humans. Thus, the use of a suitable carrier system for oral delivery of CB13 becomes an attractive strategy to develop a valuable therapy. Polymeric poly(lactic-co-glycolic) acid (PLGA) and lipid nanoparticles (LNPs) are widely studied delivery vehicles that improve the bioavailability of lipophilic compounds and present special interest in oral delivery. Their surface can be modified to improve the adhesion of particles to the oral mucosa and increase their circulation time in blood with additives such as chitosan (CS) and polyethylene glycol (PEG), which can be feasibly incorporated onto these particles in a post-production step. In this work, CS- and PEG-modified polymeric PLGA and LNPs were successfully obtained and comparatively evaluated under the same experimental conditions as oral carriers for CB13. All the formulations presented adequate blood compatibility and absence of cytotoxicity in Caco-2 cells. Coating with CS led to a higher interaction with Caco-2 cells and a limited uptake in THP1 cells, while coating with PEG led to a limited uptake in Caco-2 cells and strongly prevented THP1 cells uptake. The performance of each formulation is discussed as a comparison of the potential of these carriers as oral delivery systems of CB13.

  13. Comparative study of chitosan- and PEG-coated lipid and PLGA nanoparticles as oral delivery systems for cannabinoids

    Energy Technology Data Exchange (ETDEWEB)

    Durán-Lobato, Matilde; Martín-Banderas, Lucía, E-mail: luciamartin@us.es [Universidad de Sevilla, Departmento Farmacia y Tecnología Farmacéutica, Facultad de Farmacia (España) (Spain); Gonçalves, Lídia M. D. [Universidade de Lisboa, Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculdade de Farmácia (Portugal); Fernández-Arévalo, Mercedes [Universidad de Sevilla, Departmento Farmacia y Tecnología Farmacéutica, Facultad de Farmacia (España) (Spain); Almeida, Antonio J. [Universidade de Lisboa, Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculdade de Farmácia (Portugal)

    2015-02-15

    The cannabinoid derivative 1-naphthalenyl[4-(pentyloxy)-1-naphthalenyl]methanone (CB13) has an important therapeutic potential as analgesic in chronic pain states that respond poorly to conventional drugs. However, the incidence of its mild-to-moderate and dose-dependent adverse effects, as well as its pharmacokinetic profile, actually holds back its use in humans. Thus, the use of a suitable carrier system for oral delivery of CB13 becomes an attractive strategy to develop a valuable therapy. Polymeric poly(lactic-co-glycolic) acid (PLGA) and lipid nanoparticles (LNPs) are widely studied delivery vehicles that improve the bioavailability of lipophilic compounds and present special interest in oral delivery. Their surface can be modified to improve the adhesion of particles to the oral mucosa and increase their circulation time in blood with additives such as chitosan (CS) and polyethylene glycol (PEG), which can be feasibly incorporated onto these particles in a post-production step. In this work, CS- and PEG-modified polymeric PLGA and LNPs were successfully obtained and comparatively evaluated under the same experimental conditions as oral carriers for CB13. All the formulations presented adequate blood compatibility and absence of cytotoxicity in Caco-2 cells. Coating with CS led to a higher interaction with Caco-2 cells and a limited uptake in THP1 cells, while coating with PEG led to a limited uptake in Caco-2 cells and strongly prevented THP1 cells uptake. The performance of each formulation is discussed as a comparison of the potential of these carriers as oral delivery systems of CB13.

  14. Insulin aspart pharmacokinetics

    DEFF Research Database (Denmark)

    Rasmussen, Christian Hove; Roge, Rikke Meldgaard; Ma, Zhulin

    2014-01-01

    Background: Insulin aspart (IAsp) is used by many diabetics as a meal-time insulin to control postprandial glucose levels. As is the case with many other insulin types, the pharmacokinetics (PK), and consequently the pharmacodynamics (PD), is associated with clinical variability, both between...... to investigate and quantify the properties of the subcutaneous depot. Data from Brange et al. (1990) are used to determine the effects of insulin chemistry in subcutis on the absorption rate. Intravenous (i.v.) bolus and infusion PK data for human insulin are used to understand and quantify the systemic...... distribution and elimination (Porksen et al., 1997; Sjostrand et al., 2002). PK and PD profiles for type 1 diabetics from Chen et al. (2005) are analyzed to demonstrate the effects of IAsp antibodies in terms of bound and unbound insulin. PK profiles from Thorisdottir et al. (2009) and Ma et al. (2012b...

  15. Safety, tolerability, pharmacokinetics, and pharmacodynamics of novel glucokinase activator HMS5552: results from a first-in-human single ascending dose study

    Directory of Open Access Journals (Sweden)

    Xu HR

    2016-05-01

    Full Text Available Hongrong Xu,1,* Lei Sheng,1,* Weili Chen,1 Fei Yuan,1 Mengjie Yang,1 Hui Li,1 Xuening Li,1 John Choi,2 Guiyu Zhao,2 Tianxin Hu,2 Yongguo Li,2 Yi Zhang,2 Li Chen2 1Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, 2Department of Clinical Research & Development, Hua Medicine, Shanghai, People’s Republic of China *These authors have contributed equally to this work Background: HMS5552, a novel fourth-generation glucokinase (GK activator, has demonstrated promising effects on glycemic control in preclinical models of type 2 diabetes. This single ascending dose study was conducted to investigate the safety, tolerability, pharmacokinetics (PK, and pharmacodynamics (PD of HMS5552 during its first-in-human exposure.Methods: Sixty healthy subjects were enrolled. In each of six dose-cohorts (5, 10, 15, 25, 35, and 50 mg, ten subjects were randomized with eight subjects receiving the same cohort-dose of HMS5552 and two receiving placebo. Plasma HMS5552 exposure, glucose, and insulin were measured repeatedly during fasting and after a standardized meal. Assessment included safety, PK, and PD endpoints.Results: HMS5552 showed dose-proportional increases in area under the curve 0 to the last quantifiable concentration (AUC0–t and maximum plasma concentration (Cmax. Slopes estimated by linear regression for AUC0–t and Cmax were ~1.0 (0.932 and 0.933, respectively. Geometric mean elimination half-life ranged from 4.48 to 7.51 hours and apparent clearance ranged from 11.5 to 13.1 L/h across all doses. No significant sex effect was observed in PK parameters. HMS5552 also demonstrated dose-related PD responses in terms of maximum glucose change from baseline (% and mean glucose area under effect curve 0–4 hours change from baseline (% (P<0.001. Fifteen adverse events were reported by nine subjects (ten with HMS5552 and five with the placebo. All adverse events were mild in intensity and resolved without any treatment

  16. A randomized two-way crossover comparative pharmacokinetic study of two different tablet formulations containing ilaprazole in healthy human Indian volunteers

    Directory of Open Access Journals (Sweden)

    Shubhasis Dan

    2014-01-01

    Full Text Available Background: Proton Pump Inhibitors (PPI are observed to be great healer in gastroesophageal reflux disorder (GERD and duodenal ulcer. Quantification of the drugs in human plasma by validated bioanalytical method are very important to determine pharmacokinetic parameters for undergoing comparative study with standard available formulations to make the newer one commercially available. Objective: The objective of this study was to determine the relative bioavailability of Ilaprazole, a novel PPI comparing the test formulation to the reference one according to standard regulatory guidelines. Materials and Methods: The bioequivalence of two tablet formulations, one as reference and other as test containing 10 mg of ilaprazole [CAS No. 172152-36-2] was studied in 12 healthy Indian volunteers. This was a single dose, twoperiod and randomized crossover study separated with a washout period of one week. Plasma samples for pharmacokinetic analysis were collected before dosing and at pre-specified time points after dosing. The concentration of ilaprazole in plasma was determined by a validated HPLC-UV method using theophylline as internal standard. The formulations were compared using the parameters Area under the plasma concentration-time curve (AUC 0-t , Area under the plasma concentration-time curve from zero to infinity (AUC 0-͵, Peak plasma concentration (C max , and time to reach peak plasma concentration (t max . Results: Mean AUC 0-t of test and reference product were calculated to be 2627.793 ± 154.989 ng h ml−1 and 2555.905 ± 225.916 ng h ml−1 , with a C max of 347.459 ± 48.175 ng h ml−1 . While mean AUC 0-͵ of test and reference product were calculated to be 2733.334 ± 242.438 ng h ml−1 and 2728.716 ± 284.408 ng h ml−1 . Conclusion: The results of this investigation indicated no statistically significant differences between the logarithmic transformed AUC 0-͵ and C max values of the two preparations. The 90% confidence

  17. Marijuana and other cannabinoids as a treatment for posttraumatic stress disorder: A literature review.

    Science.gov (United States)

    Steenkamp, Maria M; Blessing, Esther M; Galatzer-Levy, Isaac R; Hollahan, Laura C; Anderson, William T

    2017-03-01

    Posttraumatic stress disorder (PTSD) is common in the general population, yet there are limitations to the effectiveness, tolerability, and acceptability of available first-line interventions. We review the extant knowledge on the effects of marijuana and other cannabinoids on PTSD. Potential therapeutic effects of these agents may largely derive from actions on the endocannabinoid system and we review major animal and human findings in this area. Preclinical and clinical studies generally support the biological plausibility for cannabinoids' potential therapeutic effects, but underscore heterogeneity in outcomes depending on dose, chemotype, and individual variation. Treatment outcome studies of whole plant marijuana and related cannabinoids on PTSD are limited and not methodologically rigorous, precluding conclusions about their potential therapeutic effects. Reported benefits for nightmares and sleep (particularly with synthetic cannabinoid nabilone) substantiate larger controlled trials to determine effectiveness and tolerability. Of concern, marijuana use has been linked to adverse psychiatric outcomes, including conditions commonly comorbid with PTSD such as depression, anxiety, psychosis, and substance misuse. Available evidence is stronger for marijuana's harmful effects on the development of psychosis and substance misuse than for the development of depression and anxiety. Marijuana use is also associated with worse treatment outcomes in naturalistic studies, and with maladaptive coping styles that may maintain PTSD symptoms. Known risks of marijuana thus currently outweigh unknown benefits for PTSD. Although controlled research on marijuana and other cannabinoids' effects on PTSD remains limited, rapid shifts in the legal landscape may now enable such studies, potentially opening new avenues in PTSD treatment research. © 2017 Wiley Periodicals, Inc.

  18. Cannabinoid Hyperemesis Syndrome: A Paradoxical Cannabis Effect

    Directory of Open Access Journals (Sweden)

    Ivonne Marie Figueroa-Rivera

    2015-01-01

    Full Text Available Despite well-established antiemetic properties of marijuana, there has been increasing evidence of a paradoxical effect in the gastrointestinal tract and central nervous system, given rise to a new and underrecognized clinical entity called the Cannabinoid Hyperemesis Syndrome. Reported cases in the medical literature have established a series of patients exhibiting a classical triad of symptoms: cyclic vomiting, chronic marijuana use, and compulsive bathing. We present a case of a 29-year-old man whose clinical presentation strongly correlates with cannabinoid hyperemesis syndrome. Despite a diagnosis of exclusion, this syndrome should be considered plausible in the setting of a patient with recurrent intractable vomiting and a strong history of cannabis use as presented in this case.

  19. Are cannabinoids effective in multiple sclerosis?

    Directory of Open Access Journals (Sweden)

    Rodrigo Meza

    2017-03-01

    Full Text Available Resumen En el último tiempo, se han descrito diversos beneficios con el uso de cannabinoides en diferentes situaciones clínicas. Dentro de ellas se ha planteado un posible efecto en el control de la esclerosis múltiple, pero la real utilidad clínica es tema de debate. Para responder a esta pregunta utilizamos la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en múltiples bases de datos. Identificamos 25 revisiones sistemáticas que en conjunto incluyen 35 estudios que responden la pregunta de interés, entre ellos 26 estudios aleatorizados. Extrajimos los datos, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. Concluimos que el uso de cannabinoides en esclerosis múltiple no reduce la espasticidad ni el dolor, y probablemente se asocia a efectos adversos frecuentes.

  20. Pharmacokinetics of mitragynine in man

    Directory of Open Access Journals (Sweden)

    Trakulsrichai S

    2015-04-01

    Full Text Available Satariya Trakulsrichai,1,2 Korbtham Sathirakul,3,4 Saranya Auparakkitanon,5 Jatupon Krongvorakul,5 Jetjamnong Sueajai,5 Nantida Noumjad,5 Chonlaphat Sukasem,5 Winai Wananukul2,6 1Department of Emergency Medicine, Faculty of Medicine Ramathibodi Hospital, 2Ramathibodi Poison Center, Faculty of Medicine Ramathibodi Hospital, 3Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand; 4Center for Drug Research Discovery and Development, Thammasat Univerisity, Prathumthani, Thailand; 5Department of Pathology, Faculty of Medicine Ramathibodi Hospital, 6Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand Background: Kratom, known botanically as Mitragyna speciosa (Korth., is an indigenous tree in Southeast Asia. Kratom is currently easily available worldwide via special shops and the Internet to use as a drug of abuse, opioid alternative, or pain killer. So far, the pharmacokinetics of this plant has been studied only in animals, and there is no such study in humans. The major abundant active alkaloid in Kratom, mitragynine, is one of the promising new chemical substances to be developed as a new drug. The aim of this study was to examine the pharmacokinetics of mitragynine and assess the linearity in pharmacokinetics in chronic users.Methods: Since Kratom is illegal in Thailand, studies in healthy subjects would be unethical. We therefore conducted a prospective study by enrolling ten chronic, regular, healthy users. We adjusted the steady state in each subject by giving a known amount of Kratom tea for 7 days before commencement of the experiment. We admitted and gave different oral doses to subjects to confirm linearity in pharmacokinetics. The mitragynine blood concentrations at 17 times points and the urine concentrations during the 24-hour period were collected and measured by liquid chromatography-tandem mass spectrometry method. Results: Ten male subjects completed

  1. Open-label, dose escalation phase I study in healthy volunteers to evaluate the safety and pharmacokinetics of a human monoclonal antibody to Clostridium difficile toxin A.

    Science.gov (United States)

    Taylor, Claribel P; Tummala, Sanjeev; Molrine, Deborah; Davidson, Lisa; Farrell, Richard J; Lembo, Anthony; Hibberd, Patricia L; Lowy, Israel; Kelly, Ciaran P

    2008-06-25

    Recent data suggest that Clostridium difficile-associated diarrhea is becoming more severe and difficult to treat. Antibody responses to C. difficile toxin A are protective against symptomatic disease and recurrence. We examined the safety and pharmacokinetics (pk) of a novel neutralizing human monoclonal antibody against C. difficile toxin A (CDA1) in healthy adults. Five cohorts with 6 subjects each received a single intravenous infusion of CDA1 at escalating doses of 0.3, 1, 5, 10, and 20 mg/kg. Safety evaluations took place on days 1, 2, 3, 7, 14, 28, and 56 post-infusion. Samples for pk analysis were obtained before and after infusion, and at each safety evaluation. Serum CDA1 antibody concentrations and human anti-human antibody (HAHA) titers were measured with enzyme-linked immunosorbent assays. A noncompartmental model was used for pk analysis. Thirty subjects were enrolled. The median age was 27.5 yrs. There were no serious adverse events (AE) related to CDA1. Twenty-one of the 48 reported non-serious adverse events were possibly related to CDA1, and included transient blood pressure changes requiring no treatment, nasal congestion, headache, abdominal cramps, nausea, and self-limited diarrhea. Serum CDA1 concentrations increased with escalating doses: mean C(max) ranged from 6.82 microg/ml for the 0.3 mg/kg cohort to 511 microg/ml for the 20 mg/kg cohort. The geometric mean values of the half-life of CDA1 ranged between 25.3 and 31.8 days, and the volume of distribution approximated serum. No subject formed detectable HAHA titers. Administration of CDA1 as a single intravenous infusion was safe and well tolerated. C(max) increased proportionally with increasing doses. A randomized study of CDA1 in patients with C. difficile associated diarrhea is underway.

  2. Safety, pharmacokinetics, immunogenicity, and biodistribution of (186)Re-labeled humanized monoclonal antibody BIWA 4 (Bivatuzumab) in patients with early-stage breast cancer.

    Science.gov (United States)

    Koppe, Manuel; Schaijk, Frank van; Roos, Jan; Leeuwen, Paul van; Heider, Karl-Heinz; Kuthan, Hartmut; Bleichrodt, Robert

    2004-12-01

    The aim of this prospective study was to evaluate the safety, pharmacokinetics, immunogenicity, and biodistribution of (186)Re-labeled humanized anti-CD44v6 monoclonal antibody (MAb( BIWA 4 (Bivatuzumab( in 9 patients with early-stage breast cancer. Radioimmunoscintigraphy (RIS( was performed within 1, 24, and 72 hours after administration. BIWA 4 concentration in plasma (ELISA and radioactivity measurements( and the development of human antihuman antibody (HAHA( responses was determined. The biodistribution of (186)Re-BIWA 4 was determined by radioactivity measurements in tumor and normal tissue biopsies obtained during surgery 1 week after administration. Administration of (186)Re-BIWA 4 was well tolerated by all patients and no HAHA responses were observed. The mean t(1/2) in plasma of BIWA 4 (ELISA( was 81 hours (range, 67-97(, whereas the mean radioactivity t(1/2) tended to be longer, at 105 hours (range, 90-114(. RIS unmistakably showed the tumor in 3 patients. Less clear identifications were established in 3 additional patients. In 2 patients, the tumor was wrongly identified in the contralateral breast. Median tumor CD44v6 expression, as determined by immunohistochemistry, was 70% (range, 10-90%). Mean tumor uptake was 2.96% ID/kg (range, 0.92-6.27(, with no apparent correlation with either tumor CD44v6 expression, tumor-cell cellularity, or tumor diameter. Tumor-to-nontumor ratios were unfavorable for blood, bone marrow, mammary gland tissue, and skin. The (186)Re-labeled humanized MAb BIWA 4 can safely be administered to patients with early-stage breast cancer. Tumorto- nontumor ratios were unfavorable, with no apparent correlation with CD44v6 expression, tumor-cell cellularity, or tumor diameter. BIWA 4, therefore, appears to have limitations as a vehicle for radioimmunotherapy in patients with breast cancer.

  3. Linear pharmacokinetic parameters for monoclonal antibodies are similar within a species and across different pharmacological targets: A comparison between human, cynomolgus monkey and hFcRn Tg32 transgenic mouse using a population-modeling approach.

    Science.gov (United States)

    Betts, Alison; Keunecke, Anne; van Steeg, Tamara J; van der Graaf, Piet H; Avery, Lindsay B; Jones, Hannah; Berkhout, Jan

    2018-04-10

    The linear pharmacokinetics (PK) of therapeutic monoclonal antibodies (mAbs) can be considered a class property with values that are similar to endogenous IgG. Knowledge of these parameters across species could be used to avoid unnecessary in vivo PK studies and to enable early PK predictions and pharmacokinetic/pharmacodynamic (PK/PD) simulations. In this work, population-pharmacokinetic (popPK) modeling was used to determine a single set of 'typical' popPK parameters describing the linear PK of mAbs in human, cynomolgus monkey and transgenic mice expressing the human neonatal Fc receptor (hFcRn Tg32), using a rich dataset of 27 mAbs. Non-linear PK was excluded from the datasets and a 2-compartment model was applied to describe mAb disposition. Typical human popPK estimates compared well with data from comparator mAbs with linear PK in the clinic. Outliers with higher than typical clearance were found to have non-specific interactions in an affinity-capture self-interaction nanoparticle spectroscopy assay, offering a potential tool to screen out these mAbs at an early stage. Translational strategies were investigated for prediction of human linear PK of mAbs, including use of typical human popPK parameters and allometric exponents from cynomolgus monkey and Tg32 mouse. Each method gave good prediction of human PK with parameters predicted within 2-fold. These strategies offer alternative options to the use of cynomolgus monkeys for human PK predictions of linear mAbs, based on in silico methods (typical human popPK parameters) or using a rodent species (Tg32 mouse), and call into question the value of completing extensive in vivo preclinical PK to inform linear mAb PK.

  4. Quantification of Cannabinoid Content in Cannabis

    Science.gov (United States)

    Tian, Y.; Zhang, F.; Jia, K.; Wen, M.; Yuan, Ch.

    2015-09-01

    Cannabis is an economically important plant that is used in many fields, in addition to being the most commonly consumed illicit drug worldwide. Monitoring the spatial distribution of cannabis cultivation and judging whether it is drug- or fiber-type cannabis is critical for governments and international communities to understand the scale of the illegal drug trade. The aim of this study was to investigate whether the cannabinoids content in cannabis could be spectrally quantified using a spectrometer and to identify the optimal wavebands for quantifying the cannabinoid content. Spectral reflectance data of dried cannabis leaf samples and the cannabis canopy were measured in the laboratory and in the field, respectively. Correlation analysis and the stepwise multivariate regression method were used to select the optimal wavebands for cannabinoid content quantification based on the laboratory-measured spectral data. The results indicated that the delta-9-tetrahydrocannabinol (THC) content in cannabis leaves could be quantified using laboratory-measured spectral reflectance data and that the 695 nm band is the optimal band for THC content quantification. This study provides prerequisite information for designing spectral equipment to enable immediate quantification of THC content in cannabis and to discriminate drug- from fiber-type cannabis based on THC content quantification in the field.

  5. Treatment of Tourette Syndrome with Cannabinoids

    Directory of Open Access Journals (Sweden)

    Kirsten R. Müller-Vahl

    2013-01-01

    Full Text Available Cannabinoids have been used for hundred of years for medical purposes. To day, the cannabinoid delta-9-tetrahydrocannabinol (THC and the cannabis extract nabiximols are approved for the treatment of nausea, anorexia and spasticity, respectively. In Tourette syndrome (TS several anecdotal reports provided evidence that marijuana might be effective not only in the suppression of tics, but also in the treatment of associated behavioural problems. At the present time there are only two controlled trials available investigating the effect of THC in the treatment of TS. Using both self and examiner rating scales, in both studies a significant tic reduction could be observed after treatment with THC compared to placebo, without causing significant adverse effects. Available data about the effect of THC on obsessive-compulsive symptoms are inconsistent. According to a recent Cochrane review on the efficacy of cannabinoids in TS, definite conclusions cannot be drawn, because longer trials including a larger number of patients are missing. Notwithstanding this appraisal, by many experts THC is recommended for the treatment of TS in adult patients, when first line treatments failed to improve the tics. In treatment resistant adult patients, therefore, treatment with THC should be taken into consideration.

  6. Quantification of imatinib in human serum: validation of a high-performance liquid chromatography-mass spectrometry method for therapeutic drug monitoring and pharmacokinetic assays.

    Science.gov (United States)

    Rezende, Vinicius Marcondes; Rivellis, Ariane; Novaes, Mafalda Megumi Yoshinaga; de Alencar Fisher Chamone, Dalton; Bendit, Israel

    2013-01-01

    Imatinib mesylate has been a breakthrough treatment for chronic myeloid leukemia. It has become the ideal tyrosine kinase inhibitor and the standard treatment for chronic-phase leukemia. Striking results have recently been reported, but intolerance to imatinib and noncompliance with treatment remain to be solved. Molecular monitoring by quantitative real-time polymerase chain reaction is the gold standard for monitoring patients, and imatinib blood levels have also become an important tool for monitoring. A fast and cheap method was developed and validated using high-performance liquid chromatography-mass spectrometry for quantification of imatinib in human serum and tamsulosin as the internal standard. Remarkable advantages of the method includes use of serum instead of plasma, less time spent on processing and analysis, simpler procedures, and requiring reduced amounts of biological material, solvents, and reagents. Stability of the analyte was also studied. This research also intended to drive the validation scheme in clinical centers. The method was validated according to the requirements of the US Food and Drug Administration and Brazilian National Health Surveillance Agency within the range of 0.500-10.0 μg/mL with a limit of detection of 0.155 μg/mL. Stability data for the analyte are also presented. Given that the validated method has proved to be linear, accurate, precise, and robust, it is suitable for pharmacokinetic assays, such as bioavailability and bioequivalence, and is being successfully applied in routine therapeutic drug monitoring in the hospital service.

  7. Simultaneous Determination of Decursin, Decursinol Angelate, Nodakenin, and Decursinol of Angelica gigas Nakai in Human Plasma by UHPLC-MS/MS: Application to Pharmacokinetic Study

    Directory of Open Access Journals (Sweden)

    Sook-Jin Kim

    2018-04-01

    Full Text Available Coumarins in Cham-dang-gwi, the dried root of Angelica gigas Nakai (AGN, possess pharmacological effects on anemia, pain, infection, and articular rheumatism. The AGN root containes decursin (D, decursinol angelate (DA, nodakenin, and decursinol (DOH, a major metabolite of D and DA. The aim of this study was to develop a simultaneous determination method for these four coumarins in human plasma using ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS. Chromatographic separation was performed on dual columns (Kinetex® C18 column and Capcell core C18 column with mobile phase consisting of water and acetonitrile at a flow rate of 0.3 mL/min using gradient elution. Multiple reaction monitoring was operated in positive ion mode with precursors to product ion transition values of m/z 328.9→228.8, 328.9→228.9, 409.4→248.8, and 246.8→212.9 to measure D, DA, nodakenin, and DOH, respectively. Linear calibration curves were fitted over concentration range of 0.05–50 ng/mL for these four components, with correlation coefficient greater than 0.995. Inter- and intra-day accuracies were between 90.60% and 108.24%. These precisions were within 11.19% for all components. The established method was then applied to a pharmacokinetic study for the four coumarins after usual dosing in Korean subjects.

  8. Rapid, Sensitive and Validated Ultra-Performance Liquid Chromatography/Mass Spectrometric Method for the Determination of Fenofibric Acid and its Application to Human Pharmacokinetic Study

    Directory of Open Access Journals (Sweden)

    Sunil K. Dubey

    2010-01-01

    Full Text Available The first, rapid and sensitive ultra performance liquid chromatography mass spectrometric method for the determination of fenofibric acid, the active metabolite of fenofibrate, a lipid regulating agent, in human EDTA plasma has been developed and validated using fenofibric d6 acid as internal standard and Waters LC-MS/MS. Negative ions of fenofibric acid and fenofibric d6 acid were detected in multiple reaction-monitoring (MRM mode. The method was validated over a concentration range of 0.176 μg/mL to 19.837 μg/mL (r ≥ 0.99. It took only 1.5 minute to analyse a sample. Intra- and inter-run precision of fenofibric acid assay at four concentrations ranged from 0.5% to 4.3% with accuracy varied from 93.1 to 108.1% indicating good precision and accuracy. Analytical recoveries of fenofibric acid and internal standard in plasma were less than 90%. This method was successfully applied for evaluation of pharmacokinetics of fenofibric acid after a single oral dose of 145 mg fenofibrate to 10 Indian healthy volunteers

  9. Pharmacokinetics of diclofenac and inhibition of cyclooxygenases 1 and 2: no relationship to the CYP2C9 genetic polymorphism in humans

    Science.gov (United States)

    Kirchheiner, Julia; Meineke, Ingolf; Steinbach, Nadine; Meisel, Christian; Roots, Ivar; Brockmöller, Jürgen

    2003-01-01

    Aims The cytochrome P450 enzyme CYP2C9 catalyses the 4′-hydroxylation of the nonsteroidal analgesic drug diclofenac in humans. We studied the influences of the known amino acid variants, CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu), on diclofenac pharmacokinetics after a 50-mg oral dose of diclofenac in healthy volunteers. As a surrogate marker of diclofenac activity, the ex vivo formation of prostaglandin E2 and thromboxane B2, which reflects COX-2 and COX-1 activity, was measured. Methods Genotyping was performed in 516 healthy volunteers to obtain 20 participants with all allelic combinations of the two CYP2C9 variants Arg144Cys (*2) and Ile359Leu (*3). Diclofenac and 4′-hydroxydiclofenac were quantified in plasma by reversed phase h.p.l.c. after oral intake of 50 mg diclofenac. Concentrations of thromboxane B2 (TxB2) and prostaglandin E2 (PGE2) were measured by immunoassays. Results There was no evidence of impaired metabolism of oral diclofenac in heterozygous and homozygous carriers of the CYP2C9 alleles *2 and *3 compared with the wild type (mean CL/F (95% CI) 20.5 (11, 30) l h−1 for *1/*1, 29.9 (19, 40) l h−1 for *1/*2, 30.0 (4, 56) l h−1 for *2/*2, 22.6 (12, 33) l h−1 for *1/*3, 23.5 (11, 37) l h−1 for *3/*3 and 37.3 (−15, 89) l h−1 in *2/*3). Furthermore, plasma concentrations of the metabolite 4′-hydroxydiclofenac were not lower in carriers of the CYP2C9 low-activity alleles *2 and *3 compared with carriers of the CYP2C9*1/*1 genotype. Marked diclofenac mediated inhibition of COX-1- and COX-2 activity was detected in all individuals independent of CYP2C9 genotype. Conclusions Polymorphisms of the CYP2C9 gene had no discernible effect on the pharmacokinetics and pharmacodynamics of diclofenac. The question of whether enzymes other than CYP2C9 play a major role in diclofenac 4′-hydroxylation in vivo or whether 4′-hydroxylation is not a rate-limiting step in diclofenac elimination in vivo, or whether the effect of the CYP2C9

  10. A rapid, LC-MS/MS assay for quantification of piperacillin and tazobactam in human plasma and pleural fluid; application to a clinical pharmacokinetic study.

    Science.gov (United States)

    Popowicz, Natalia D; O'Halloran, Sean J; Fitzgerald, Deirdre; Lee, Y C Gary; Joyce, David A

    2018-04-01

    Piperacillin, in combination with tazobactam is a common first-line antibiotic used for the treatment of pleural infection, however its pleural pharmacokinetics and penetration has not previously been reported. The objective of this work was to develop and validate a rapid and sensitive liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay for quantification of piperacillin (PIP) and tazobactam (TAZ). PIP and TAZ were extracted from both human plasma and pleural fluid samples by protein precipitation in methanol containing the internal standards (IS) piperacillin-d 5 (PIP-d 5 ) and sulbactam (SUL). Briefly, 5 μL of sample was mixed with 125 μL of methanol containing IS, vortexed and centrifuged. Supernatant (50 μL) was diluted into 500 μL of mobile phase containing 10 mM of ammonium bicarbonate in LCMS grade water and transferred to the autosampler tray. Electrospray ionization in positive mode and multiple reaction monitoring (MRM) were used for PIP and PIP-d 5 at the transitions m/z 518.2 → 143.2 and m/z 523.2 → 148.2 respectively, and electrospray ionization in negative mode and MRM were used for TAZ and SUL at the transitions m/z 299.1 → 138.1 and m/z 232.4 → 140.1. The chromatographic separation was achieved using an Acquity BEH C-18 column with gradient elution of mobile phase containing 10 mmol/L ammonium bicarbonate in water and methanol. A linear range was observed over the concentration range of 0.25-352 mg/L and 0.25-50.5 mg/L for PIP and TAZ respectively. Complete method validation was performed according to US FDA guidelines for selectivity, specificity, precision and accuracy, LLOQ, matrix effects, recovery and stability, with all results within acceptable limits. This method was successfully applied to two patients with pleural infection and is suitable for further pharmacokinetic studies and therapeutic drug monitoring. Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.

  11. First-in-human study of the toxicity, pharmacokinetics, and pharmacodynamics of CG200745, a pan-HDAC inhibitor, in patients with refractory solid malignancies.

    Science.gov (United States)

    Kim, Kyu-pyo; Park, Seong Joon; Kim, Jeong-Eun; Hong, Yong Sang; Lee, Jae-Lyun; Bae, Kyun-Seop; Cha, Hyunju; Kwon, Sool-Ki; Ro, Seonggu; Cho, JoongMyung; Kim, Tae Won

    2015-10-01

    The aim of the present study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of single and multiple doses of intravenous CG200745, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies. Two to six patients received intravenous CG200745 according to the 2 + 4 dose-escalating method. This first-in-human trial was comprised of two parts: Part 1 was a single ascending dose, and Part 2 was multiple ascending doses weekly for 3 weeks, and then 1 week off. For the first cycle, pharmacokinetic sampling for CG200745 and pharmacodynamic sampling for acetylated histone H4 in peripheral blood mononuclear cells (PBMCs) were performed on day 1 for Part 1 and on days 1 and 15 for Part 2. Examination of acetylated histone H4 in pre- and post-biopsy samples was performed in accessible patients. In all, 28 patients were treated at 13 dose levels (1.8-250 mg/m(2)) and received a total of 71 cycles of CG200745. Hematologic toxicities included grade 3/4 neutropenia (22.2 %) that did not last a week and non-hematologic toxicities included fatigue (22.2 %) and anorexia (16.7 %) that did not exceed grade 2. No dose-limiting toxic effects were noted. Dose proportionality was observed for both the maximum concentration and area under the curve. The elimination half-life was 5.67 ± 2.69 h (mean ± standard deviation). An increase in PBMC acetylated histone H4 was observed at dose levels up to 51 mg/m(2), which plateaued at higher dose levels. At 24 h, 75 % of patients (6/8) showed higher relative acetylation in tumor tissue compared to PBMCs. Although there was no partial or complete response, 57.1 % of patients (16/28) had stable disease that lasted at least 6 weeks. CG200745 can be safely administered at effective dose levels that inhibit HDAC in PBMCs and tumor tissue. Although MTD was not reached, further escalation was not performed because acetylated histone H4 plateaued at dose

  12. A preliminary evaluation of the relationship of cannabinoid blood concentrations with the analgesic response to vaporized cannabis

    Science.gov (United States)

    Wilsey, Barth L; Deutsch, Reena; Samara, Emil; Marcotte, Thomas D; Barnes, Allan J; Huestis, Marilyn A; Le, Danny

    2016-01-01

    A randomized, placebo-controlled crossover trial utilizing vaporized cannabis containing placebo and 6.7% and 2.9% delta-9-tetrahydrocannabinol (THC) was performed in 42 subjects with central neuropathic pain related to spinal cord injury and disease. Subjects received two administrations of the study medication in a 4-hour interval. Blood samples for pharmacokinetic evaluation were collected, and pain assessment tests were performed immediately after the second administration and 3 hours later. Pharmacokinetic data, although limited, were consistent with literature reports, namely dose-dependent increase in systemic exposure followed by rapid disappearance of THC. Dose-dependent improvement in pain score was evident across all pain scale elements. Using mixed model regression, an evaluation of the relationship between plasma concentrations of selected cannabinoids and percent change in items from the Neuropathic Pain Scale was conducted. Changes in the concentration of THC and its nonpsychotropic metabolite, 11-nor-9-carboxy-THC, were related to percent change from baseline of several descriptors (eg, itching, burning, and deep pain). However, given the large number of multiple comparisons, false-discovery-rate-adjusted P-values were not significant. Plans for future work are outlined to explore the relationship of plasma concentrations with the analgesic response to different cannabinoids. Such an appraisal of descriptors might contribute to the identification of distinct pathophysiologic mechanisms and, ultimately, the development of mechanism-based treatment approaches for neuropathic pain, a condition that remains difficult to treat. PMID:27621666

  13. A preliminary evaluation of the relationship of cannabinoid blood concentrations with the analgesic response to vaporized cannabis.

    Science.gov (United States)

    Wilsey, Barth L; Deutsch, Reena; Samara, Emil; Marcotte, Thomas D; Barnes, Allan J; Huestis, Marilyn A; Le, Danny

    2016-01-01

    A randomized, placebo-controlled crossover trial utilizing vaporized cannabis containing placebo and 6.7% and 2.9% delta-9-tetrahydrocannabinol (THC) was performed in 42 subjects with central neuropathic pain related to spinal cord injury and disease. Subjects received two administrations of the study medication in a 4-hour interval. Blood samples for pharmacokinetic evaluation were collected, and pain assessment tests were performed immediately after the second administration and 3 hours later. Pharmacokinetic data, although limited, were consistent with literature reports, namely dose-dependent increase in systemic exposure followed by rapid disappearance of THC. Dose-dependent improvement in pain score was evident across all pain scale elements. Using mixed model regression, an evaluation of the relationship between plasma concentrations of selected cannabinoids and percent change in items from the Neuropathic Pain Scale was conducted. Changes in the concentration of THC and its nonpsychotropic metabolite, 11-nor-9-carboxy-THC, were related to percent change from baseline of several descriptors (eg, itching, burning, and deep pain). However, given the large number of multiple comparisons, false-discovery-rate-adjusted P-values were not significant. Plans for future work are outlined to explore the relationship of plasma concentrations with the analgesic response to different cannabinoids. Such an appraisal of descriptors might contribute to the identification of distinct pathophysiologic mechanisms and, ultimately, the development of mechanism-based treatment approaches for neuropathic pain, a condition that remains difficult to treat.

  14. Cannabinoids synergize with carfilzomib, reducing multiple myeloma cells viability and migration

    OpenAIRE

    Nabissi, Massimo; Morelli, Maria Beatrice; Offidani, Massimo; Amantini, Consuelo; Gentili, Silvia; Soriani, Alessandra; Cardinali, Claudio; Leoni, Pietro; Santoni, Giorgio

    2016-01-01

    Several studies showed a potential anti-tumor role for cannabinoids, by modulating cell signaling pathways involved in cancer cell proliferation, chemo-resistance and migration. Cannabidiol (CBD) was previously noted in multiple myeloma (MM), both alone and in synergy with the proteasome inhibitor bortezomib, to induce cell death. In other type of human cancers, the combination of CBD with ?9-tetrahydrocannabinol (THC) was found to act synergistically with other chemotherapeutic drugs suggest...

  15. Quantitation of Metformin in Human Plasma and Urine by Hydrophilic Interaction Liquid Chromatography and Application to a Pharmacokinetic Study

    DEFF Research Database (Denmark)

    Nielsen, Flemming; Hougaard Christensen, Mette Marie; Brøsen, Kim

    2014-01-01

    : We describe an analytical method for the quantification of the widely used antihyperglycemic agent, metformin, in human plasma and urine. The separation was performed using isocratic hydrophilic interaction liquid chromatography on a Luna hydrophilic interaction liquid chromatography column (125...

  16. Chiral analysis of bambuterol, its intermediate and active drug in human plasma by liquid chromatography-tandem mass spectrometry: Application to a pharmacokinetic study.

    Science.gov (United States)

    Zhou, Ting; Liu, Shan; Zhao, Ting; Zeng, Jing; He, Mingzhi; Xu, Beining; Qu, Shanshan; Xu, Ling; Tan, Wen

    2015-08-01

    A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed for simultaneous chiral analysis of an antiasthma drug bambuterol, its key intermediate monocarbamate bambuterol and its active drug terbutaline in human plasma. All samples were extracted with ethyl acetate and separated on an Astec Chirobiotic T column under isocratic elution with a mobile phase consisting of methanol and water with the addition of 20mm ammonium acetate and 0.005% (v/v) formic acid at 0.6mL/min. The analytes were detected by a Xevo TQ-S tandem mass spectrometer with positive electrospray ionization in multiple reaction monitoring mode. The established method has high sensitivity with the lower limit of quantifications of 25.00pg/mL for bambuterol enantiomers, and 50.00pg/mL for monocarbamate bambuterol and terbutaline enantiomers, respectively. The calibration curves for bambuterol enantiomers were linear in the range of 25.00-2500pg/mL, and for monocarbamate bambuterol and terbutaline enantiomers were linear in the range of 50.00-5000pg/mL. The intra- and inter-day precisions were <12.4%. All the analytes were separated in 18.0min. For the first time, the validated method was successfully applied to an enantioselective pharmacokinetic study of rac-bambuterol in 8 healthy volunteers. According to the results, this chiral LC-MS/MS assay provides a suitable and robust method for the enantioselectivity and interaction study of the prodrug bambuterol, the key intermediate monocarbamate bambuterol and its active drug terbutaline in human. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Enantioselective determination of (R)- and (S)-lansoprazole in human plasma by chiral liquid chromatography with mass spectrometry and its application to a stereoselective pharmacokinetic study.

    Science.gov (United States)

    Sun, Luning; Cao, Yang; Jiao, Huiwen; Fang, Yunqian; Yang, Zhicheng; Bian, Mingliang; Zhang, Hongwen; Gong, Xiaojian; Wang, Yongqing

    2015-11-01

    A simple and enantioselective method was developed and validated for the simultaneous determination of (R)- and (S)-lansoprazole in human plasma by chiral liquid chromatography with tandem mass spectrometry. Lansoprazole enantiomers and internal standard (esomeprazole) were extracted from plasma using acetonitrile as protein precipitating agent. Baseline chiral separation was achieved within 9.0 min on a Chiralpak IC column (150 mm × 4.6 mm, 5 μm) with the column temperature of 30°C. The mobile phase consisted of 10 mM ammonium acetate solution containing 0.05% acetic acid/acetonitrile (50:50, v/v). The mass spectrometric analysis was performed using a QTrap 5500 mass spectrometer coupled with an electrospray ionization source in positive ion mode. The multiple reactions monitoring transitions of m/z 370.1→252.1 and 346.1→198.1 were used to quantify lansoprazole enantiomers and esomeprazole, respectively. For each enantiomer, no apparent matrix effect was found, the calibration curve was linear over 5.00-3000 ng/mL, the intra- and inter-day precisions were below 10.0%, and the accuracy was -3.8 to 3.3%. Analytes were stable during the study. No chiral inversion was observed during sample storage, preparation procedure and analysis. The method was applied to the stereoselective pharmacokinetic studies in human after intravenous administration of dexlansoprazole or racemic lansoprazole. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Fast and sensitive HPLC/UV method for cefazolin quantification in plasma and subcutaneous tissue microdialysate of humans and rodents applied to pharmacokinetic studies in obese individuals.

    Science.gov (United States)

    Palma, Eduardo Celia; Laureano, João Victor; de Araújo, Bibiana Verlindo; Meinhardt, Nelson Guardiola; Stein, Airton Tetelbom; Dalla Costa, Teresa

    2018-04-14

    Antimicrobial prophylactic dosing of morbidly obese patients may differ from normal weighted individuals owing to alterations in drug tissue distribution. Drug subcutaneous tissue distribution can be investigated by microdialysis patients and animals. The need for cefazolin prophylactic dose adjustment in obese patients remains under discussion. The paper describes the validation of an HPLC-UV method for cefazolin quantification in plasma and microdialysate samples from clinical and pre-clinical studies. A C 18 column with an isocratic mobile phase was used for drug separation, with detection at 272 nm. Total and unbound cefazolin lower limit of quantitation was 5 μg/mL in human plasma, 2 μg/mL in rat plasma, and 0.5 and 0.025 μg/mL in human and rat microdialysate samples, respectively. The maximum intra- and inter-day imprecisions were 10.7 and 8.1%, respectively. The inaccuracy was <9.7%. The limit of quantitation imprecision and inaccuracy were < 15%. Cefazolin stability in the experimental conditions was confirmed. Cefazolin plasma concentrations and subcutaneous tissue penetration were determined by microdialysis in morbidly obese patients (2 g i.v. bolus) and diet-induced obese rats (30 mg/kg i.v. bolus) using the method. This method has the main advantages of easy plasma clean-up and practicability and has proven to be useful in cefazolin clinical and pre-clinical pharmacokinetic investigations. Copyright © 2018 John Wiley & Sons, Ltd.

  19. Functional role of cannabinoid receptors in urinary bladder

    Directory of Open Access Journals (Sweden)

    Pradeep Tyagi

    2010-01-01

    Full Text Available Cannabinoids, the active components of Cannabis sativa (marijuana, and their derivatives produce a wide spectrum of central and peripheral effects, some of which may have clinical applications. The discovery of specific cannabinoid receptors and a family of endogenous ligands of those receptors has attracted much attention to the general cannabinoid pharmacology. In recent years, studies on the functional role of cannabinoid receptors in bladder have been motivated by the therapeutic effects of cannabinoids on voiding dysfunction in multiple sclerosis patients. In this review, we shall summarize the literature on the expression of cannabinoid receptors in urinary bladder and the peripheral influence of locally and systemically administered cannabinoids in the bladder. The ongoing search for cannabinoid-based therapeutic strategies devoid of psychotropic effects can be complemented with local delivery into bladder by the intravesical route. A greater understanding of the role of the peripheral CB 1 and CB 2 receptor system in lower urinary tract is necessary to allow the development of new treatment for pelvic disorders.

  20. Cannabinoids in the management of spasticity associated with multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Anna Maria Malfitano

    2008-08-01

    Full Text Available Anna Maria Malfitano, Maria Chiara Proto, Maurizio BifulcoDipartimento di Scienze Farmaceutiche, Università degli Studi di SalernoAbstract: The endocannabinoid system and cannabinoid-based treatments have been involved in a wide number of diseases. In particular, several studies suggest that cannabinoids and endocannabinoids may have a key role in the pathogenesis and therapy of multiple sclerosis (MS. In this study we highlight the main findings reported in literature about the relevance of cannabinoid drugs in the management and treatment of MS. An increasing body of evidence suggests that cannabinoids have beneficial effects on the symptoms of MS, including spasticity and pain. In this report we focus on the effects of cannabinoids in the relief of spasticity describing the main findings in vivo, in the mouse experimental allergic encephalomyelitis model of MS. We report on the current treatments used to control MS symptoms and the most recent clinical studies based on cannabinoid treatments, although long-term studies are required to establish whether cannabinoids may have a role beyond symptom amelioration in MS.Keywords: cannabinoids, multiple sclerosis, spasticity

  1. Synthetic cannabinoid: prevalence, mechanisms of addiction development, mental disorders associated with the use of synthetic cannabinoid

    Directory of Open Access Journals (Sweden)

    Antsyborov A.V.

    2017-04-01

    Full Text Available according to the authors among the new psychoactive substances, the number of which is growing every year, despite the measures aimed at the obstacles to their dissemination there discovered the most frequent violations of psychotic conditions associated with use of synthetic cannabinoid in clinical practice. On the black market, they are distributed through online shops, under the guise of herbal mixtures for Smoking. When ingested, this group of drugs at the peak of intoxication raises a number of mental (different according to the depth of impaired consciousness, auditory and visual hallucinations, panic attacks, acute psychotic paranoid disorders, catatonic stupor, polar affective disorders, acute polythematic delusional symptoms and somatic disorders (disorders of heart rhythm and conduction, acute ischemic disorders, hypertension, depression of respiratory activity, violation of thermoregulation, development of acute renal failure, vomiting, expressed cephalgia, clinic of hypokalemia. In the reviewed literature and authors own observations there have been discovered some cases of mental addiction development to synthetic cannabinoids. The analysis of new literature data and own clinical observations helped the authors to compare the psychotropic effects caused by this group of drugs, relative to other known surfactants. The toxic effects of CSC on the body greatly exceeds the use of plant cannabinoids, and it has almost the same effects as the synthetic cathinone’s. The speed of formation of psychological dependence is lower compared to synthetic cathinone. Developing current strategies for diagnosis, treatment, and rehabilitation of patients who use synthetic cannabinoids remains an important task for practical healthcare.

  2. Cannabinoids and Innate Immunity: Taking a Toll on Neuroinflammation

    Directory of Open Access Journals (Sweden)

    Eric J. Downer

    2011-01-01

    Full Text Available The biologically active components of cannabis have therapeutic potential in neuroinflammatory disorders due to their anti-inflammatory propensity. Cannabinoids influence immune function in both the peripheral and the central nervous system (CNS, and the components of the cannabinoid system, the cannabinoid receptors and their endogenous ligands (endocannabinoids, have been detected on immune cells as well as in brain glia. Neuroinflammation is the complex innate immune response of neural tissue to control infection and eliminate pathogens, and Toll-like receptors (TLRs, a major family of pattern recognition receptors (PRRs that mediate innate immunity, have emerged as players in the neuroinflammatory processes underpinning various CNS diseases. This review will highlight evidence that cannabinoids interact with the immune system by impacting TLR-mediated signaling events, which may provide cues for devising novel therapeutic approaches for cannabinoid ligands.

  3. Safety Issues Concerning the Medical Use of Cannabis and Cannabinoids

    Directory of Open Access Journals (Sweden)

    Mark A Ware

    2005-01-01

    Full Text Available Safety issues are a major barrier to the use of cannabis and cannabinoid medications for clinical purposes. Information on the safety of herbal cannabis may be derived from studies of recreational cannabis use, but cannabis exposure and effects may differ widely between medical and recreational cannabis users. Standardized, quality-controlled cannabinoid products are available in Canada, and safety profiles of approved medications are available through the Canadian formulary. In the present article, the evidence behind major safety issues related to cannabis use is summarized, with the aim of promoting informed dialogue between physicians and patients in whom cannabinoid therapy is being considered. Caution is advised in interpreting these data, because clinical experience with cannabinoid use is in the early stages. There is a need for long-term safety monitoring of patients using cannabinoids for a wide variety of conditions, to further guide therapeutic decisions and public policy.

  4. Safety, pharmacokinetics, and antiviral activity of A77003, a C2 symmetry-based human immunodeficiency virus protease inhibitor

    NARCIS (Netherlands)

    Reedijk, M.; Boucher, C. A.; van Bommel, T.; Ho, D. D.; Tzeng, T. B.; Sereni, D.; Veyssier, P.; Jurriaans, S.; Granneman, R.; Hsu, A.

    1995-01-01

    A77003, an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, was administered to asymptomatic HIV-1-infected patients in a phase I trial. The drug was given by continuous intravenous infusion at dosages of 0.035, 0.07, 0.14, and 0.28 mg/kg of body weight per h. The drug was

  5. Distribution and pharmacokinetics of the prodrug daunorubicin-GA3 in nude mice bearing human ovarian cancer xenografts

    NARCIS (Netherlands)

    Houba, PHJ; Boven, E; van der Meulen-Muileman, IH; Leenders, RGG; Scheeren, JW; Pinedo, HM; Haisma, HJ

    1999-01-01

    N-[4-daunorubicin-N-carbonyl (oxymethyl)phenyl] O-beta-glucuronyl carbamate (DNR-GA3) is a glucuronide prodrug of daunorubicin (DNR) which induced a better tumor growth delay than DNR when studied at equitoxic doses in three human ovarian cancer xenografts. These results suggested that the prodrug

  6. Development and Validation of a LC/MS/MS Method for the Determination of Duloxetine in Human Plasma and Its Application to Pharmacokinetic Study

    Directory of Open Access Journals (Sweden)

    D. Chandrapal Reddy

    2012-01-01

    Full Text Available A selective, high sensitive and high throughput liquid chromatography-tandem mass spectrometry (LC-ESI-MS/MS method has been developed and validated for the chromatographic separation and quantitation of duloxetine in human EDTA plasma using fluoxetine (IS as an internal standard. Analyte and IS were extracted from human plasma by liquid-liquid extraction using MTBE-n Hexane (80:20.The eluted samples were chromatographed on X-terra RP8 (50 mmx4.6 mm, 5 μm particle size column by using mixture of 30 mM ammonium formate (pH-5.0±0.05 and acetonitrile as an isocratic mobile phase at a flow rate of 0.40 mL/min and analyzed by mass spectrometer in the multiple reaction monitoring (MRM using the respective m/z 298.08→154.0 for duloxetine and 310.02→148.07 for IS. The linearity of the response/ concentration curve was established in human plasma over the concentration range 0.100-100.017 ng/mL. The lower detection limit (LOD,S/N>3 was 0.04 ng/mL and the lower limit of quantization (LOQ,S/N>10 was 0.100 ng/mL. This LC-MS/MS method was validated with Intra-batch and Inter-batch precision of 5.21-7.02. The Intra-batch and Inter-batch accuracy was 97.14-103.50 respectively. Recovery of duloxetine in human plasma is 80.31% and ISTD recovery is 81.09%. The main pharmacokinetic parameters were Tmax (hr = (7.25±1.581, Cmax (ng/mL (44.594±18.599, AUC0→t, = (984.702±526.502 and AUC0→∞, (1027.147±572.790 respectively.

  7. Predictive model accuracy in estimating last Δ9-tetrahydrocannabinol (THC) intake from plasma and whole blood cannabinoid concentrations in chronic, daily cannabis smokers administered subchronic oral THC.

    Science.gov (United States)

    Karschner, Erin L; Schwope, David M; Schwilke, Eugene W; Goodwin, Robert S; Kelly, Deanna L; Gorelick, David A; Huestis, Marilyn A

    2012-10-01

    Determining time since last cannabis/Δ9-tetrahydrocannabinol (THC) exposure is important in clinical, workplace, and forensic settings. Mathematical models calculating time of last exposure from whole blood concentrations typically employ a theoretical 0.5 whole blood-to-plasma (WB/P) ratio. No studies previously evaluated predictive models utilizing empirically-derived WB/P ratios, or whole blood cannabinoid pharmacokinetics after subchronic THC dosing. Ten male chronic, daily cannabis smokers received escalating around-the-clock oral THC (40-120 mg daily) for 8 days. Cannabinoids were quantified in whole blood and plasma by two-dimensional gas chromatography-mass spectrometry. Maximum whole blood THC occurred 3.0 h after the first oral THC dose and 103.5h (4.3 days) during multiple THC dosing. Median WB/P ratios were THC 0.63 (n=196), 11-hydroxy-THC 0.60 (n=189), and 11-nor-9-carboxy-THC (THCCOOH) 0.55 (n=200). Predictive models utilizing these WB/P ratios accurately estimated last cannabis exposure in 96% and 100% of specimens collected within 1-5h after a single oral THC dose and throughout multiple dosing, respectively. Models were only 60% and 12.5% accurate 12.5 and 22.5h after the last THC dose, respectively. Predictive models estimating time since last cannabis intake from whole blood and plasma cannabinoid concentrations were inaccurate during abstinence, but highly accurate during active THC dosing. THC redistribution from large cannabinoid body stores and high circulating THCCOOH concentrations create different pharmacokinetic profiles than those in less than daily cannabis smokers that were used to derive the models. Thus, the models do not accurately predict time of last THC intake in individuals consuming THC daily. Published by Elsevier Ireland Ltd.

  8. Tumour localization and pharmacokinetics of iodine-125 human monoclonal IgM antibody (COU-1) and its monomeric and half-monomeric fragments analysed in nude mice grafted with human tumour

    International Nuclear Information System (INIS)

    Ditzel, H.; Erb, K.; Rasmussen, J.W.; Jensenius, J.C.

    1992-01-01

    Human monoclonal IgM antibodies reactive with cancer-associated antigens may not have the optimal imaging capability due to their large size. Fragmentation of human IgM is less than straight-forward due to the loss of immunoreactivity. From the human monoclonal IgM antibody COU-1 we have prepared monomeric and half-monomeric fragments, which retain the ability to bind to colon cancer cells in vitro. The pharmacokinetics and tumour localization were evaluated in nude mice bearing human colon adenocarcinoma and human melanoma grafts. Faster clearance from the circulation was seen for the smaller half-monomeric fragment with a half-life (rapid phase/slow phase) of 2 h/16 h compared with the intact antibody, 4 h/25 h, and the monomeric fragment, 3 h/27 h. Intact COU-1 as well as the fragments accumulated in the colon tumour graft. Higher amounts of radioactivity were found in the colon tumour as compared to normal organs for intact COU-1 at days 4 and 6, for the monomeric fragment at day 4, and for the half-monomeric fragment at day 2 after injection. This investigation demonstrates the favourable biodistribution of the half monomeric COU-1 fragment. The fast clearance of this fragment resulted in a tumour-to-muscle ratio as high as 22 on day 2 after injection. Also, only this fragment gave a positive tumour-to-blood ratio. Normal IgM and its fragments were used as controls. Radioimmunoscintigraphy demonstrated the colon tumour discriminatory properties of each of the three iodine-labelled antibody preparations. The results compare favourably with previously reported investigations of the localization of human monoclonal antibodies and suggest that fragments of human monoclonal IgM antibodies may be useful tools for the immunodetection of cancer in patients. (orig.)

  9. Cannabinoid hyperemesis syndrome with extreme hydrophilia

    Directory of Open Access Journals (Sweden)

    Enuh HA

    2013-08-01

    Full Text Available Hilary A Enuh,1 Julia Chin,1 Jay Nfonoyim21Department of Medicine, 2Critical Care Unit, Richmond University Medical Center, Staten Island, NY, USAAbstract: Marijuana is the most widely used recreational drug in the US. Hyperemetic hydrophilic syndrome is a previously described but infrequently recognized condition of cannabinoid abuse with hyperemesis and obsessive hot showering. We present a 47-year-old male known marijuana addict with intractable abdominal pain who could not wait for physical examination, meal, or medication, because of obsessive compulsive warm baths. He had a history of epilepsy and addiction to marijuana, which he took on the day of admission. He presented to the hospital with a seizure, complicated by nausea, vomiting, and severe abdominal pain. His examination was unremarkable, except for mild epigastric tenderness. His laboratory and radiological tests were within normal limits, except for a positive urine drug screen for marijuana and opiates. He took himself immediately to the bathroom and remained under a hot shower with the exception of two 15-minute breaks for the rest of the day. He stated that it made him feel better than medication. Receiving medication and even eating was a problem because of this compulsive showering. Abstinence from marijuana during the hospital stay made the patient's nausea and vomiting resolve significantly. Cannabinoid hyperemesis is a differential diagnosis among patients with intractable nausea, vomiting, and obsessive hot bathing. The syndrome is an unmistakable indication of marijuana addiction. A thorough history and observation is very valuable. Recognition of this entity will reduce unnecessary testing and utilization of health care resources.Keywords: cannabinoid, compulsive bathing, cyclic vomiting, hyperemesis, hydrophilia, marijuana

  10. Population Pharmacokinetics of Intranasal Scopolamine

    Science.gov (United States)

    Wu, L.; Chow, D. S. L.; Putcha, L.

    2013-01-01

    Introduction: An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS).The bioavailability and pharmacokinetics (PK) was evaluated using data collected in Phase II IND protocols. We reported earlier statistically significant gender differences in PK parameters of INSCOP at a dose level of 0.4 mg. To identify covariates that influence PK parameters of INSCOP, we examined population covariates of INSCOP PK model for 0.4 mg dose. Methods: Plasma scopolamine concentrations versus time data were collected from 20 normal healthy human subjects (11 male/9 female) after a 0.4 mg dose. Phoenix NLME was employed for PK analysis of these data using gender, body weight and age as covariates for model selection. Model selection was based on a likelihood ratio test on the difference of criteria (-2LL). Statistical significance for base model building and individual covariate analysis was set at P less than 0.05{delta(-2LL)=3.84}. Results: A one-compartment pharmacokinetic model with first-order elimination best described INSCOP concentration ]time profiles. Inclusion of gender, body weight and age as covariates individually significantly reduced -2LL by the cut-off value of 3.84(P less than 0.05) when tested against the base model. After the forward stepwise selection and backward elimination steps, gender was selected to add to the final model which had significant influence on absorption rate constant (ka) and the volume of distribution (V) of INSCOP. Conclusion: A population pharmacokinetic model for INSCOP has been identified and gender was a significant contributing covariate for the final model. The volume of distribution and Ka were significantly higher in males than in females which confirm gender-dependent pharmacokinetics of scopolamine after administration of a 0.4 mg dose.

  11. Quantification of imatinib in human serum: validation of a high-performance liquid chromatography-mass spectrometry method for therapeutic drug monitoring and pharmacokinetic assays

    Directory of Open Access Journals (Sweden)

    Rezende VM

    2013-08-01

    Full Text Available Vinicius Marcondes Rezende,1 Ariane Rivellis,1 Mafalda Megumi Yoshinaga Novaes,1 Dalton de Alencar Fisher Chamone,2 Israel Bendit1,21Laboratory of Tumor Biology, 2Department of Hematology, School of Medicine, University of São Paulo, São Paulo, BrazilBackground: Imatinib mesylate has been a breakthrough treatment for chronic myeloid leukemia. It has become the ideal tyrosine kinase inhibitor and the standard treatment for chronic-phase leukemia. Striking results have recently been reported, but intolerance to imatinib and noncompliance with treatment remain to be solved. Molecular monitoring by quantitative real-time polymerase chain reaction is the gold standard for monitoring patients, and imatinib blood levels have also become an important tool for monitoring.Methods: A fast and cheap method was developed and validated using high-performance liquid chromatography-mass spectrometry for quantification of imatinib in human serum and tamsulosin as the internal standard. Remarkable advantages of the method includes use of serum instead of plasma, less time spent on processing and analysis, simpler procedures, and requiring reduced amounts of biological material, solvents, and reagents. Stability of the analyte was also studied. This research also intended to drive the validation scheme in clinical centers. The method was validated according to the requirements of the US Food and Drug Administration and Brazilian National Health Surveillance Agency within the range of 0.500–10.0 µg/mL with a limit of detection of 0.155 µg/mL. Stability data for the analyte are also presented.Conclusion: Given that the validated method has proved to be linear, accurate, precise, and robust, it is suitable for pharmacokinetic assays, such as bioavailability and bioequivalence, and is being successfully applied in routine therapeutic drug monitoring in the hospital service.Keywords: imatinib, high-performance liquid chromatography-mass spectrometry, therapeutic

  12. A Sensitive and Robust Ultra HPLC Assay with Tandem Mass Spectrometric Detection for the Quantitation of the PARP Inhibitor Olaparib (AZD2281 in Human Plasma for Pharmacokinetic Application

    Directory of Open Access Journals (Sweden)

    Jeffrey Roth

    2014-06-01

    Full Text Available Olaparib (AZD2281 is an orally active PARP-1 inhibitor, primarily effective against cancers with BRCA1/2 mutations. It is currently in Phase III development and has previously been investigated in numerous clinical trials, both as a single agent and in combination with chemotherapy. Despite this widespread testing, there is only one published method that provides assay details and stability studies for olaparib alone. A more sensitive uHPLC-MS/MS method for the quantification of olaparib in human plasma was developed, increasing the range of quantification at both ends (0.5–50,000 ng/mL compared to previously published methods (10–5,000 ng/mL. The wider range encompasses CMAX levels produced by typical olaparib doses and permits better pharmacokinetic modeling of olaparib elimination. This assay also utilizes a shorter analytical runtime, allowing for more rapid quantification and reduced use of reagents. A liquid-liquid extraction was followed by chromatographic separation on a Waters UPLC® BEH C18 column (2.1 × 50 mm, 1.7 µm and mass spectrometric detection. The mass transitions m/z 435.4→281.1 and m/z 443.2→281.1 were used for olaparib and the internal standard [2H8]-olaparib, respectively. The assay proved to be accurate (<9% deviation and precise (CV < 11%. Stability studies showed that olaparib is stable at room temperature for 24 h. in whole blood, at 4 °C for 24 h post-extraction, at −80 °C in plasma for at least 19 months, and through three freeze-thaw cycles. This method proved to be robust for measuring olaparib levels in clinical samples from a Phase I trial.

  13. Single Ascending Dose Safety and Pharmacokinetics of CDRI-97/78: First-in-Human Study of a Novel Antimalarial Drug

    Directory of Open Access Journals (Sweden)

    N. Shafiq

    2014-01-01

    Full Text Available Background. CDRI 97/78 has shown efficacy in animal models of falciparum malaria. The present study is the first in-human phase I trial in healthy volunteers. Methods. The study was conducted in 50 healthy volunteers in a single, ascending dose, randomized, placebo-controlled, double blind design. The dose ranges evaluated were from 80 mg to 700 mg. Volunteers were assessed for clinical, biochemical, haematological, radiographic, and electrocardiographic parameters for any adverse events in an in-house facility. After evaluation of safety study results, another cohort of 16 participants were administered a single oral dose of 200 mg of the drug and a detailed pharmacokinetic analysis was undertaken. Results. The compound was found to be well tolerated. MTD was not reached. The few adverse events noted were of grade 2 severity, not requiring intervention and not showing any dose response relationship. The laboratory and electrocardiographic parameters showed statistically significant differences, but all were within the predefined normal range. These parameters were not associated with symptoms/signs and hence regarded as clinically irrelevant. Mean values of T1/2, MRT, and AUC0-∞ of the active metabolite 97/63 were 11.85±1.94 h, 13.77±2.05 h, and 878.74±133.15 ng·h/mL, respectively Conclusion. The novel 1,2,4 trioxane CDRI 97/78 is safe and will be an asset in malarial therapy if results are replicated in multiple dose studies and benefit is shown in confirmatory trials.

  14. Analysis of fenretinide and its metabolites in human plasma by liquid chromatography-tandem mass spectrometry and its application to clinical pharmacokinetics.

    Science.gov (United States)

    Cho, Hwang Eui; Min, H Kang

    2017-01-05

    A simple and accurate high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the determination of N-(4-hydroxyphenyl)retinamide (fenretinide, 4-HPR) and its metabolites, 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR) and N-(4-methoxyphenyl)retinamide (4-MPR), in human plasma. Plasma samples were prepared using protein precipitation with ethanol. Chromatographic separation of the three analytes and N-(4-ethoxyphenyl)retinamide (4-EPR), an internal standard, was achieved on a Zorbax SB-C18 column (3.5μm, 50×2.1mm) using gradient elution with the mobile phase of 0.1% formic acid in water and acetonitrile (pH* 2.4) at a flow rate of 0.5mL/min. Electrospray ionization (ESI) mass spectrometry was operated in the positive ion mode with multiple reaction monitoring (MRM). The calibration curves obtained were linear over the concentration range of 0.2-50ng/mL with a lower limit of quantification of 0.2ng/mL. The relative standard deviation of intra-day and inter-day precision was below 7.64%, and the accuracy ranged from 94.92 to 105.43%. The extraction recoveries were found to be higher than 90.39% and no matrix effect was observed. The analytes were stable for the durations of the stability studies. The validated method was successfully applied to the analyses of the pharmacokinetic study for patients treated with 4-HPR in a clinical trial. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Physiologically based pharmacokinetic modeling of human exposure to perfluorooctanoic acid suggests historical non drinking-water exposures are important for predicting current serum concentrations.

    Science.gov (United States)

    Worley, Rachel Rogers; Yang, Xiaoxia; Fisher, Jeffrey

    2017-09-01

    Manufacturing of perfluorooctanoic acid (PFOA), a synthetic chemical with a long half-life in humans, peaked between 1970 and 2002, and has since diminished. In the United States, PFOA is detected in the blood of >99% of people tested, but serum concentrations have decreased since 1999. Much is known about exposure to PFOA in drinking water; however, the impact of non-drinking water PFOA exposure on serum PFOA concentrations is not well characterized. The objective of this research is to apply physiologically based pharmacokinetic (PBPK) modeling and Monte Carlo analysis to evaluate the impact of historic non-drinking water PFOA exposure on serum PFOA concentrations. In vitro to in vivo extrapolation was utilized to inform descriptions of PFOA transport in the kidney. Monte Carlo simulations were incorporated to evaluate factors that account for the large inter-individual variability of serum PFOA concentrations measured in individuals from North Alabama in 2010 and 2016, and the Mid-Ohio River Valley between 2005 and 2008. Predicted serum PFOA concentrations were within two-fold of experimental data. With incorporation of Monte Carlo simulations, the model successfully tracked the large variability of serum PFOA concentrations measured in populations from the Mid-Ohio River Valley. Simulation of exposure in a population of 45 adults from North Alabama successfully predicted 98% of individual serum PFOA concentrations measured in 2010 and 2016, respectively, when non-drinking water ingestion of PFOA exposure was included. Variation in serum PFOA concentrations may be due to inter-individual variability in the disposition of PFOA and potentially elevated historical non-drinking water exposures. Published by Elsevier Inc.

  16. Targeting Cannabinoid Signaling in the Immune System: “High”-ly Exciting Questions, Possibilities, and Challenges

    Directory of Open Access Journals (Sweden)

    Attila Oláh

    2017-11-01

    Full Text Available It is well known that certain active ingredients of the plants of Cannabis genus, i.e., the “phytocannabinoids” [pCBs; e.g., (−-trans-Δ9-tetrahydrocannabinol (THC, (−-cannabidiol, etc.] can influence a wide array of biological processes, and the human body is able to produce endogenous analogs of these substances [“endocannabinoids” (eCB, e.g., arachidonoylethanolamine (anandamide, AEA, 2-arachidonoylglycerol (2-AG, etc.]. These ligands, together with multiple receptors (e.g., CB1 and CB2 cannabinoid receptors, etc., and a complex enzyme and transporter apparatus involved in the synthesis and degradation of the ligands constitute the endocannabinoid system (ECS, a recently emerging regulator of several physiological processes. The ECS is widely expressed in the human body, including several members of the innate and adaptive immune system, where eCBs, as well as several pCBs were shown to deeply influence immune functions thereby regulating inflammation, autoimmunity, antitumor, as well as antipathogen immune responses, etc. Based on this knowledge, many in vitro and in vivo studies aimed at exploiting the putative therapeutic potential of cannabinoid signaling in inflammation-accompanied diseases (e.g., multiple sclerosis or in organ transplantation, and to dissect the complex immunological effects of medical and “recreational” marijuana consumption. Thus, the objective of the current article is (i to summarize the most recent findings of the field; (ii to highlight the putative therapeutic potential of targeting cannabinoid signaling; (iii to identify open questions and key challenges; and (iv to suggest promising future directions for cannabinoid-based drug development.

  17. Pharmacokinetics: curiosity or cure

    International Nuclear Information System (INIS)

    Notari, R.E.

    1979-01-01

    What is the fate of a drug from the time of its introduction into the body to the end of its duration. Pharmacokinetic studies are often designed to provide an answer to this question. But this question may be asked of any drug and research that is limited to answering it will remain empirical. Pharmacokinetic studies can provide answers to many other drug-related questions. In doing so pharmacokinetic research has the potential of improving drug therapy as well as the design and evaluation of drugs. While significant contributions can be cited, the future of pharmacokinetics depends upon its increased impact on clinical practice and drug design. How can a molecule be tailored for site specificity. Can chemical modification selectively alter absorption, distribution, metabolism, binding or excretion. In what new ways can pharmacokinetic information increase the predictability of drug therapy. Such questions, to which pharmacokinetics should provide answers, are numerous and easily identified. But the definitive studies are difficult both to create and conduct. Whether or not pharmacokinetics can achieve its full potential will depend upon the extent to which it can provide answers to these currently unanswered questions

  18. Lisdexamfetamine: A pharmacokinetic review.

    Science.gov (United States)

    Comiran, Eloisa; Kessler, Félix Henrique; Fröehlich, Pedro Eduardo; Limberger, Renata Pereira

    2016-06-30

    Lisdexamfetamine (LDX) is a d-amphetamine (d-AMPH) pro-drug used to treat Attention Deficit and Hyperactivity Disorder (ADHD) and Binge Eating Disorder (BED) symptoms. The in vivo pharmacodynamics of LDX is the same as that of its active product d-AMPH, although there are a few qualitative and quantitative differences due to pharmacokinetics. Due to the specific pharmacokinetics of the long-acting stimulants, this article revises the pharmacokinetic studies on LDX, the newest amphetamine pro-drug. The Medline/Pubmed, Science Direct and Biblioteca Virtual em Saúde (Lilacs and Ibecs) (2007-2016) databases were searched for articles and their list of references. As for basic pharmacokinetics studies, since LDX is a newly developed medication, there are few results concerning biotransformation, distribution and the use of different biological matrices for analysis. This is the first robust review on this topic, gathering data from all clinical pharmacokinetics studies available in the literature. The particular pharmacokinetics of LDX plays a major role in studying this pro-drug, since this knowledge was essential to understand some reports on clinical effects in literature, e.g. the small likelihood of reducing the effect by interactions, the effect of long duration use and the still questionable reduction of the potential for abuse. In general the already well-known pharmacokinetic properties of amphetamine make LDX relatively predictable, simplifying the use of LDX in clinical practice. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Immunoreactivity, stability, pharmacokinetics and biodistribution of a monoclonal antibody to human leukemic B cells after three different methods of radioiodination

    International Nuclear Information System (INIS)

    Zhenping Zhu; Ghose, T.; Kralovec, Y.; Chunzheng Yang

    1994-01-01

    Dal B02, a murine monoclonal antibody against human chronic lymphocytic leukemia (CLL) was radioiodinated using chloramine T (Chl.T), Bolton-Hunter (B-H) or N-succinimidyl-p-iodobenzoate (PIB). The preparations had comparable radiochemical purity (>97%) and immunoreactive fraction (65-80%) but the Chl.T-based product was most susceptible to deiodination and loss of immunoreactivity. After i.v. injection into CLL-xenografted nude mice, the preparations had identical patterns of clearance from the blood but the PIB-based product led to more radioactivity in liver and spleen and less in the thyroid compared to the other preparations. The Chl.T-based product showed loss of immunoreactivity in circulation and less tumor-localized radioactivity 168 h after administration. The differences between the B-H-based and PIB-based products were less impressive than between PIB-based and Chl.T-based products. (author)

  20. Are cannabinoids effective for HIV wasting syndrome?

    Directory of Open Access Journals (Sweden)

    Alejandra Núñez

    2017-12-01

    Full Text Available Resumen INTRODUCCIÓN El síndrome de emaciación (wasting en VIH/SIDA aún permanece como un problema común, constituyéndose como un factor de mortalidad en esta población. Se ha postulado el uso de cannabinoides como tratamiento de la baja de peso secundaria a la infección por VIH, lo que aún es controvertido. MÉTODOS Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios y preparamos tablas de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES Identificamos ocho revisiones sistemáticas que en conjunto incluyen 10 estudios primarios, de los cuales, seis son ensayos aleatorizados. Concluimos que no está claro si los cannabinoides aumentan el apetito o incrementan el peso en el síndrome de wasting en pacientes con VIH, y probablemente los efectos adversos son frecuentes.

  1. Effects of various cannabinoid ligands on choice behaviour in a rat model of gambling.

    Science.gov (United States)

    Gueye, Aliou B; Trigo, Jose M; Vemuri, Kiran V; Makriyannis, Alexandros; Le Foll, Bernard

    2016-04-01

    It is estimated that 0.6-1% of the population in the USA and Canada fulfil the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5) criteria for gambling disorders (GD). To date, there are no approved pharmacological treatments for GD. The rat gambling task (rGT) is a recently developed rodent analogue of the Iowa gambling task in which rats are trained to associate four response holes with different magnitudes and probabilities of food pellet rewards and punishing time-out periods. Similar to healthy human volunteers, most rats adopt the optimal strategies (optimal group). However, a subset of animals show preference for the disadvantageous options (suboptimal group), mimicking the choice pattern of patients with GD. Here, we explored for the first time the effects of various cannabinoid ligands (WIN 55,212-2, AM 4113, AM 630 and URB 597) on the rGT. Administration of the cannabinoid agonist CB1/CB2 WIN 55,212-2 improved choice strategy and increased choice latency in the suboptimal group, but only increased perseverative behaviour, when punished, in the optimal group. Blockade of CB1 or CB2 receptors or inhibition of fatty-acid amide hydrolase did not affect rGT performance. These results suggest that stimulation of cannabinoid receptors could affect gambling choice behaviours differentially in some subgroups of subjects.

  2. Case Series of Synthetic Cannabinoid Intoxication from One Toxicology Center

    Directory of Open Access Journals (Sweden)

    Kenneth D. Katz

    2016-05-01

    Full Text Available Synthetic cannabinoid use has risen at alarming rates. This case series describes 11 patients exposed to the synthetic cannabinoid, MAB-CHMINACA who presented to an emergency department with life-threatening toxicity including obtundation, severe agitation, seizures and death. All patients required sedatives for agitation, nine required endotracheal intubation, three experienced seizures, and one developed hyperthermia. One developed anoxic brain injury, rhabdomyolysis and died. A significant number were pediatric patients. The mainstay of treatment was aggressive sedation and respiratory support. Synthetic cannabinoids pose a major public health risk. Emergency physicians must be aware of their clinical presentation, diagnosis and treatment.

  3. Haloperidol, a Novel Treatment for Cannabinoid Hyperemesis Syndrome.

    Science.gov (United States)

    Witsil, Joanne C; Mycyk, Mark B

    Cannabinoid hyperemesis syndrome (CHS) is typically unresponsive to conventional pharmacologic antiemetics, and patients often require excessive laboratory and radiographic testing and hospital admission. We report 4 cases of CHS that failed standard emergency department therapy but improved significantly after treatment with haloperidol. Although the exact mechanism for CHS remains unclear, dysregulation at cannabinoid type 1 seems to play a role. Recent animal data demonstrate complex interactions between dopamine and cannabinoid type 1 signaling, a potential mechanism for haloperidol success in patients with CHS. Our success with haloperidol in these 4 patients warrants further investigation of haloperidol as an emergency department treatment for CHS.

  4. Pharmacological characterization of emerging synthetic cannabinoids in HEK293T cells and hippocampal neurons.

    Science.gov (United States)

    Costain, Willard J; Tauskela, Joseph S; Rasquinha, Ingrid; Comas, Tanya; Hewitt, Melissa; Marleau, Vincent; Soo, Evelyn C

    2016-09-05

    There has been a worldwide proliferation of synthetic cannabinoids that have become marketed as legal alternatives to cannabis (marijuana). Unfortunately, there is a dearth of information about the pharmacological effects of many of these emerging synthetic cannabinoids (ESCs), which presents a challenge for regulatory authorities that need to take such scientific evidence into consideration in order to regulate ECSs as controlled substances. We aimed to characterize the pharmacological properties of ten ESCs using two cell based assays that enabled the determination of potency and efficacy relative to a panel of well-characterized cannabinoids. Agonist-mediated inhibition of forskolin-stimulated cyclic adenosine monophosphate (cAMP) levels was monitored in live HEK293T cells transfected with human cannabinoid receptor 1 gene (CNR1) and pGloSensor-22F. Pharmacological analysis of this data indicated that all of the ESCs tested were full agonists, with the following rank order of potency: Win 55212-2≈5F-PB-22≈AB-PINACA≈EAM-2201≈MAM-2201>JWH-250≈ PB-22>AKB48 N-(5FP)>AKB-48≈STS-135>XLR-11. Assessment of agonist-stimulated depression of Ca(2+) transients was also used to confirm the efficacy of five ESCs (XLR-11, JWH-250, AB-PINACA, 5F-PB-22, and MAM-2201) in cultured primary hippocampal neurons. This work aims to help inform decisions made by regulatory agencies concerned with the profusion of these poorly characterized recreational drugs. Copyright © 2016. Published by Elsevier B.V.

  5. A mathematical model of a recombinant humanized anti-cocaine monoclonal antibody's effects on cocaine pharmacokinetics in mice.

    Science.gov (United States)

    Wetzel, Hanna N; Zhang, Tongli; Norman, Andrew B

    2017-09-01

    A recombinant humanized anti-cocaine monoclonal antibody (mAb), h2E2, is at an advanced stage of pre-clinical development as an immunotherapy for cocaine abuse. It is hypothesized that h2E2 binds to and sequesters cocaine in the blood. A three-compartment model of the effects of h2E2 on cocaine's distribution was constructed. The model assumes that h2E2 binds to cocaine and that the h2E2-cocaine complex does not enter the brain but distributes between the central and peripheral compartments. Free cocaine is eliminated from both the central and peripheral compartments, and h2E2 and the h2E2-cocaine complex are eliminated from the central compartment only. This model was tested against a new dataset measuring cocaine concentrations in the brain and plasma over 1h in the presence and absence of h2E2. The mAb significantly increased plasma cocaine concentrations with a concomitant significant decrease in brain concentration. Plasma concentrations declined over the 1-hour sampling period in both groups. With a set of parameters within reasonable physiological ranges, the three-compartment model was able to qualitatively and quantitatively simulate the increased plasma concentration in the presence of the antibody and the decreased peak brain concentration in the presence of antibody. Importantly, the model explained the decline in plasma concentrations over time as distribution of the cocaine-h2E2 complex into a peripheral compartment. This model will facilitate the targeting of ideal mAb PK/PD properties thus accelerating the identification of lead candidate anti-drug mAbs. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. HPLC method for determination of biologically active epoxy-transformers of treosulfan in human plasma: pharmacokinetic application.

    Science.gov (United States)

    Główka, Franciszek K; Romański, Michał; Teżyk, Artur; Zaba, Czesław; Wróbel, Tomasz

    2012-03-25

    Clinical trials demonstrated treosulfan (TREO) as a promising myeloablative agent prior to hematopoietic stem cell transplantation (HSCT). TREO is a specific pro-drug from which biologically active mono- (S,S-EBDM) and diepoxybutane (S,S-DEB) derivatives are formed in vitro or in vivo by a non-enzymatic pH and temperature-dependent intramolecular nucleophilic substitution. Following extraction of the plasma samples with a mixture of dichloromethane and acetonitrile, S,S-EBDM and S,S-DEB were derivatized with 3-nitrobenzenesulfonic acid (3-NBS) to UV-absorbing esters. Optimal temperature and time of derivatization as well as extraction method and also the effect of pH on TREO stability in plasma were established. Identity of the synthesized derivatives was confirmed by mass spectrometry. The post-derivatization mixture was purified from the excess of unreacted 3-NBS by extraction with water. The derivatization products and 2,2'-dinitrobiphenyl (internal standard) were separated on Nucleosil 100 C18 column using a mobile phase consisted of acetonitrile and water. The developed method was validated and demonstrated adequate accuracy and precision. Limit of quantification for both S,S-EBDM and S,S-DEB amounted to 2.5 μM. The method was applied in clinical conditions to quantify the levels of TREO activation products in plasma of children undergoing HSCT. The methodology for simultaneous determination of TREO epoxy-transformers in human plasma is described for the first time. Copyright © 2011 Elsevier B.V. All rights reserved.

  7. Determination of metabolite of nicergoline in human plasma by high-performance liquid chromatography and its application in pharmacokinetic studies

    Directory of Open Access Journals (Sweden)

    Rong Zheng

    2012-02-01

    Full Text Available A fast, simple and sensitive high performance liquid chromatographic (HPLC method has been developed for determination of 10α-methoxy-6-methyl ergoline-8β-methanol (MDL, a main metabolite of nicergoline in human plasma. One-step liquid–liquid extraction (LLE with diethyl ether was employed as the sample preparation method. Tizanidine hydrochloride was selected as the internal standard (IS. Analysis was carried out on a Diamonsil ODS column (150 mm×4.6 mm, 5 μm using acetonitrile–ammonium acetate (0.1 mol/L (15/85, v/v as mobile phase at detection wavelength of 224 nm. The calibration curves were linear over the range of 2.288–73.2 ng/mL with a lower limit of quantitation (LLOQ of 2.288 ng/mL. The intra- and inter-day precision values were below 13% and the recoveries were from 74.47% to 83.20% at three quality control levels. The method herein described was successfully applied in a randomized crossover bioequivalence study of two different nicergoline preparations after administration of 30 mg in 20 healthy volunteers. Keywords: Nicergoline, 10α-methoxy-6-methylergoline-8β-methanol (MDL, HPLC, Plasma-drug concentration, Bioequivalence study

  8. High-throughput phytochemical characterization of non-cannabinoid compounds of cannabis plant and seed, from Pakistan

    International Nuclear Information System (INIS)

    Ahmad, F.; Abbasi, T.; Farman, K.; Akrem, A.; Asif, M.; Mahmood, S.; Iqbal, M.U.

    2018-01-01

    The herbs are the natural resources for the infinite phenolic compounds that are used in pharmaceutical industry. These herbs are of significant importance due to their beneficial usage for the human health. Here, we studied a common herbs Cannabis sativa, an important member of the family Cannabaceae for phytochemical characterization. The methanol extract of whole Cannabis plant and seed was analyzed for the identification of non-cannabinoid compounds through High Performance Liquid Chromatography (HPLC) technique, because the non-cannabinoid compounds have not been much studied in C. sativa. These compounds are very useful in different diseases, used in cosmetics and as antioxidant agent. HPLC analysis revealed the presence of a variety of non-cannabinoid compounds including Quercetin, Gallic acid, p-Coumaric acid, m-Coumaric acid, Caffeic acid, Cinnamic acid, Ferulic acid, Benzoic acid and Kampferol. Furthermore, Quercetin was observed with high concentration in whole plant sample, whereas high Gallic acid and absence of m-coumaric acid was noted in the Cannabis seed. It was also observed that plant samples were with higher concentration of cinnamic acid as compared to seed. The Caffeic acid, Benzoic acid and Ferulic acid were in low concentration in both Cannabis plant and seed samples. Kampferol is another important non-cannabinoid compound that was also quantified in both samples. This research will be providing a foundation for further molecular characterization of Cannabis plant and seed for their beneficial usage. (author)

  9. Safety, pharmacokinetic, and functional effects of the nogo-a monoclonal antibody in amyotrophic lateral sclerosis: a randomized, first-in-human clinical trial.

    Directory of Open Access Journals (Sweden)

    Vincent Meininger

    Full Text Available The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in amyotrophic lateral sclerosis (ALS; it is both a potential biomarker and therapeutic target. We performed a double-blind, two-part, dose-escalation study, in subjects with ALS, assessing safety, pharmacokinetics (PK and functional effects of ozanezumab, a humanized monoclonal antibody against Nogo-A. In Part 1, 40 subjects were randomized (3∶1 to receive single dose intravenous ozanezumab (0.01, 0.1, 1, 5, or 15 mg/kg or placebo. In Part 2, 36 subjects were randomized (3∶1 to receive two repeat doses of intravenous ozanezumab (0.5, 2.5, or 15 mg/kg or placebo, approximately 4 weeks apart. The primary endpoints were safety and tolerability (adverse events [AEs], vital signs, electrocardiogram (ECG, and clinical laboratory tests. Secondary endpoints included PK, immunogenicity, functional endpoints (clinical and electrophysiological, and biomarker parameters. Overall, ozanezumab treatment (0.01-15 mg/kg was well tolerated. The overall incidence of AEs in the repeat dose 2.5 mg/kg and 15 mg/kg ozanezumab groups was higher than in the repeat dose placebo group and repeat dose 0.5 mg/kg ozanezumab group. The majority were considered not related to study drug by the investigators. Six serious AEs were reported in three subjects receiving ozanezumab; none were considered related to study drug. No study drug-related patterns were identified for ECG, laboratory, or vital signs parameters. One subject (repeat dose 15 mg/kg ozanezumab showed a weak, positive anti-ozanezumab-antibody result. PK results were generally consistent with monoclonal antibody treatments. No apparent treatment effects were observed for functional endpoints or muscle biomarkers. Immunohistochemical staining showed dose-dependent co-localization of ozanezumab with Nogo-A in skeletal muscle. In conclusion, single and repeat dose ozanezumab treatment was well tolerated and demonstrated

  10. Health Risk Behaviors With Synthetic Cannabinoids Versus Marijuana.

    Science.gov (United States)

    Clayton, Heather B; Lowry, Richard; Ashley, Carmen; Wolkin, Amy; Grant, Althea M

    2017-04-01

    Data are limited on the behavioral risk correlates of synthetic cannabinoid use. The purpose of this study was to compare the behavioral risk correlates of synthetic cannabinoid use with those among marijuana users. Data from the 2015 Youth Risk Behavior Survey, a cross-sectional survey conducted in a nationally representative sample of students in grades 9 through 12 ( N = 15 624), were used to examine the association between self-reported type of marijuana use (ie, never use of marijuana and synthetic cannabinoids, ever use of marijuana only, and ever use of synthetic cannabinoids) and self-report of 36 risk behaviors across 4 domains: substance use, injury/violence, mental health, and sexual health. Multivariable models were used to calculate adjusted prevalence ratios. Students who ever used synthetic cannabinoids had a significantly greater likelihood of engaging in each of the behaviors in the substance use and sexual risk domains compared with students who ever used marijuana only. Students who ever used synthetic cannabinoids were more likely than students who ever used marijuana only to have used marijuana before age 13 years, to have used marijuana ≥1 times during the past 30 days, and to have used marijuana ≥20 times during the past 30 days. Several injury/violence behaviors were more prevalent among students who ever used synthetic cannabinoids compared with students who ever used marijuana only. Health professionals and school-based substance use prevention programs should include strategies focused on the prevention of both synthetic cannabinoids and marijuana. Copyright © 2017 by the American Academy of Pediatrics.

  11. Efectos cardiovasculares debido al consumo de cannabinoides

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    Oscar J. León

    2018-05-01

    Full Text Available Resumen: Objetivo: dar a conocer los efectos cardiovasculares secundarios al consumo de marihuana según lo reportado en la literatura médica. Métodos: se realizó una búsqueda con los términos MESH “Cannabis”, “Marijuana smoking” y “adverse effects” en la base de datos PubMed hasta el año 2016. Se obtuvieron 265 referencias. Se excluyeron cartas de editores, protocolos de investigación en proceso, población pediátrica (menores de 18 años, embarazadas, referencias en idiomas diferentes a inglés y español y se escogieron solo referencias relacionadas con efectos cardiovasculares. Resultados: se han establecido dos tipos de receptores de cannabinoides, los CB1 y los CB2, con localizaciones a nivel del sistema nervioso central, endotelial, renal y músculo liso. En la actualidad el consumo de marihuana ha venido en aumento y los médicos poco conocen de sus efectos y los diferentes nombres comerciales para esta sustancia. Existen efectos protectores a nivel vascular con detención de la progresión de la placa aterosclerótica y a la vez múltiples efectos no deseados como taquicardia, hipotensión y bradicardia. Múltiples reportes de caso documentan la relación de la marihuana con el infarto agudo de miocardio con o sin lesión de las arterias coronarias, así como con hemorragia subaracnoidea, pero no existen mecanismos claramente descritos que expliquen una relación directa con estos desenlaces. Conclusiones: se conoce la fisiopatología y los receptores donde actúan los cannabinoides generando efectos tanto protectores como dañinos. Existe fuerte correlación con enfermedad cardiovascular, principalmente síndrome coronario agudo, pero el mecanismo fisiopatológico aún no es claro. Abstract: Objective: To determine the cardiovascular side-effects of smoking marihuana according to that reported in the medical literature. Methods: A search was performed using the MeSH terms, “Cannabis”, “Marijuana smoking” and

  12. Safety, biodistribution, pharmacokinetics, and immunogenicity of 99mTc-labeled humanized monoclonal antibody BIWA 4 (bivatuzumab) in patients with squamous cell carcinoma of the head and neck.

    Science.gov (United States)

    Colnot, David R; Roos, Jan C; de Bree, Remco; Wilhelm, Abraham J; Kummer, J Alain; Hanft, Gertraud; Heider, Karl-Heinz; Stehle, Gerd; Snow, Gordon B; van Dongen, Guus A M S

    2003-09-01

    Previous studies have shown the potential of murine and chimeric anti-CD44v6 monoclonal antibodies (MAbs) for radioimmunotherapy (RIT) of head and neck squamous cell carcinoma (HNSCC). A limitation of these MAbs, however, appeared to be their immunogenicity. Therefore, humanized monoclonal antibody BIWA 4 (bivatuzumab), with an intermediate affinity for CD44v6, was recently selected. As a prelude to RIT, we evaluated the safety, tumor-targeting potential, pharmacokinetics, and immunogenicity of technetium-99m-labeled BIWA 4 in patients undergoing operations for primary HNSCC in this study. Ten patients were treated at BIWA 4 dose levels of 25 mg (n=3), 50 mg (n=4), and 100 mg (n=3). Patients received 2 mg of 750 MBq 99mTc-BIWA 4, together with 23-, 48-, and 98-mg unlabeled BIWA 4, respectively. Radioimmunoscintigraphy (RIS) was performed within 1 h and after 21 h, and patients underwent surgery at 48 h after injection. Biodistribution of 99mTc-BIWA 4 was evaluated by radioactivity measurements in blood, bone marrow, and in biopsies of a surgical specimen obtained 48 h after injection. BIWA 4 concentration in blood was assessed by ELISA and high performance liquid chromatography and related to soluble CD44v6 levels in serum samples. The development of human anti-human antibody (HAHA) responses was determined. Administration of 99mTc-BIWA 4 was well tolerated by all patients and no HAHA responses were observed. A mean t1/2 in plasma of 54.8 +/- 11.5 h, 76.1 +/- 21.8 h, and 68.5 +/- 21.2 h was found for the 25-, 50-, and 100-mg dose group, respectively. No complex formation of BIWA 4 with soluble CD44v6 in blood was observed. RIS showed targeting of primary tumors and lymph node metastases in 8 of 10 and 1 of 5 patients, respectively. The highest tumor uptake and tumor to nontumor ratios were observed for the 50-mg dose group. Tumor uptake was 12.9 +/- 5.9, 26.2 +/- 3.1, and 15.4 +/- 1.9% of the injected dose (ID)/kg for the 25-, 50-, and 100-mg dose group

  13. Emerging Role of (EndoCannabinoids in Migraine

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    Pinja Leimuranta

    2018-04-01

    Full Text Available In this mini-review, we summarize recent discoveries and present new hypotheses on the role of cannabinoids in controlling trigeminal nociceptive system underlying migraine pain. Individual sections of this review cover key aspects of this topic, such as: (i the current knowledge on the endocannabinoid system (ECS with emphasis on expression of its components in migraine related structures; (ii distinguishing peripheral from central site of action of cannabinoids, (iii proposed mechanisms of migraine pain and control of nociceptive traffic by cannabinoids at the level of meninges and in brainstem, (iv therapeutic targeting in migraine of monoacylglycerol lipase and fatty acid amide hydrolase, enzymes which control the level of endocannabinoids; (v dual (possibly opposing actions of cannabinoids via anti-nociceptive CB1 and CB2 and pro-nociceptive TRPV1 receptors. We explore the cannabinoid-mediated mechanisms in the frame of the Clinical Endocannabinoid Deficiency (CECD hypothesis, which implies reduced tone of endocannabinoids in migraine patients. We further discuss the control of cortical excitability by cannabinoids via inhibition of cortical spreading depression (CSD underlying the migraine aura. Finally, we present our view on perspectives of Cannabis-derived (extracted or synthetized marijuana components or novel endocannabinoid therapeutics in migraine treatment.

  14. Human Microdosing with Carcinogenic Polycyclic Aromatic Hydrocarbons: In Vivo Pharmacokinetics of Dibenzo[ def,p ]chrysene and Metabolites by UPLC Accelerator Mass Spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Madeen, Erin P.; Ognibene, Ted J.; Corley, Richard A.; McQuistan, Tammie J.; Henderson, Marilyn C.; Baird, William M.; Bench, Graham; Turteltaub, Ken W.; Williams, David E.

    2016-10-17

    Metabolism is a key health risk factor following exposures to pro-carcinogenic polycyclic aromatic hydrocarbons (PAHs) such as dibenzo[def,p]chrysene (DBC), an IARC classified 2A probable human carcinogen. Human exposure to PAHs occurs primarily from the diet in non-smokers. However, little data is available on the metabolism and pharmacokinetics in humans of high molecular weight PAHs (≥4 aromatic rings), including DBC. We previously determined the pharmacokinetics of DBC in human volunteers orally administered a micro-dose (29 ng; 5 nCi) of [14C]-DBC by accelerator mass spectrometry (AMS) analysis of total [14C] in plasma and urine. In the current study, we utilized a novel “moving wire” interface between ultra-performance liquid chromatography (UPLC) and AMS to detect and quantify parent DBC and its major metabolites. The major [14C] product identified in plasma was unmetabolized [14C]-DBC itself, (Cmax= 18.5 ± 15.9 fg/mL, Tmax= 2.1 ± 1.0 h), whereas the major metabolite was identified as [14C]-(+/-)-DBC-11,12-diol (Cmax= 2.5 ± 1.3 fg/mL, Tmax= 1.8 h). Several minor species of [14C]-DBC metabolites were also detected for which no reference standards were available. Free and conjugated metabolites were detected in urine with [14C]-(+/-)-DBC-11,12,13,14-tetraol isomers identified as the major metabolites, 56.3% of which were conjugated (Cmax= 35.8 ± 23.0 pg/pool, Tmax= 6-12 h pool). [14C]-DBC-11,12-diol, of which 97.5% was conjugated, was also identified in urine (Cmax= 29.4 ± 11.6 pg/pool, Tmax= 6-12 h pool). Parent [14C]-DBC was not detected in urine. This is the first dataset to assess metabolite profiles and associated pharmacokinetics of a carcinogenic PAH in human volunteers at an environmentally relevant dose, providing the data necessary for translation of high dose animal models to humans for translation of environmental health risk assessment.

  15. Quantification of nimesulide in human plasma by high-performance liquid chromatography with ultraviolet detector (HPLC-UV): application to pharmacokinetic studies in 28 healthy Korean subjects.

    Science.gov (United States)

    Kim, Mi-Sun; Park, Yoo-Sin; Kim, Shin-Hee; Kim, Sang-Yeon; Lee, Min-Ho; Kim, Youn-Hee; Kim, Do-Wan; Yang, Seok-Chul; Kang, Ju-Seop

    2012-05-01

    Nimesulide is a selective COX-2 inhibitor that is as effective as the classical non-acidic nonsteroidal anti-inflammatory drugs in the relief of various pain and inflammatory conditions, but is better tolerated with lower incidences of adverse effects than other drugs. After oral dose of 100 mg nimesulide to western subjects, a mean maximal concentration (C(max)) of 2.86 ∼ 6.5 µg/mL was reached at 1.22 ∼ 2.75 h and mean t(1/2β) of 1.8 ∼ 4.74 h. This study developed a robust method for quantification of nimesulide for the pharmacokinetics and suitability of its dosage in Korea and compared its suitability with other racial populations. Nimesulide and internal standard were extracted from acidified samples with methyl tert-butyl ether and analyzed by high-performance liquid chromatography with ultraviolet detection (HPLC-UV). The 28 healthy volunteers took 2 tablets of 100 mg nimesulide and blood concentrations were analyzed during the 24 h post dose. Several pharmacokinetic parameters were represented: AUC(0-infinity) = 113.0 mg-h/mL, C(max) = 12.06 mg/mL, time for maximal concentrations (T(max)) = 3.19 h and t(1/2β) = 4.51 h. These were different from those of western populations as follows: AUC was 14.5% and C(max) was 28% that of of Korean subjects and T(max) and t(1/2β) were also different. The validated HPLC-UV method was successfully applied for the pharmacokinetic studies of nimesulide in Korean subjects. Because the pharmacokinetics of nimesulide were different from western populations, its dosage regimen needs to be adjusted for Koreans. © The Author [2012]. Published by Oxford University Press. All rights reserved.

  16. Steady-State pharmacokinetics and tolerability of trans-resveratrol 2000 mg twice daily with food, quercetin and alcohol (ethanol) in healthy human subjects.

    Science.gov (United States)

    la Porte, Charles; Voduc, Nha; Zhang, Guijun; Seguin, Isabelle; Tardiff, Danielle; Singhal, Neera; Cameron, D William

    2010-07-01

    Trans-resveratrol is a polyphenol, which is found in red wine and has cancer chemo-preventive properties and disease-preventive properties. The pharmacokinetics of trans-resveratrol have been investigated in single-dose studies and in studies with relatively low dosages. The present study aimed to investigate the steady-state pharmacokinetics and tolerability of trans-resveratrol 2000 mg twice daily with food, quercetin and alcohol (ethanol). This was a two-period, open-label, single-arm, within-subject control study in eight healthy subjects. The steady-state 12-hour pharmacokinetics of trans-resveratrol 2000 mg twice daily were studied with a standard breakfast, a high-fat breakfast, quercetin 500 mg twice daily and 5% alcohol 100 mL. Trans-resveratrol plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. The mean (SD) area under the plasma concentration-time curve from 0 to 12 hours (AUC(12)) and maximum plasma concentration (C(max)) of trans-resveratrol were 3558 (2195) ng * h/mL and 1274 (790) ng/mL, respectively, after the standard breakfast. The high-fat breakfast significantly decreased the AUC(12) and C(max) by 45% and 46%, respectively, when compared with the standard breakfast. Quercetin 500 mg twice daily or 5% alcohol 100 mL did not influence trans-resveratrol pharmacokinetics. Diarrhoea was reported in six of the eight subjects. Significant but not clinically relevant changes from baseline were observed in serum potassium and total bilirubin levels. Trans-resveratrol 2000 mg twice daily resulted in adequate exposure and was well tolerated by healthy subjects, although diarrhoea was frequently observed. In order to maximize trans-resveratrol exposure, it should be taken with a standard breakfast and not with a high-fat meal. Furthermore, combined intake with quercetin or alcohol did not influence trans-resveratrol exposure.

  17. Anticancer activity using positron emission tomography-computed tomography and pharmacokinetics of β-eudesmol in human cholangiocarcinoma xenografted nude mouse model.

    Science.gov (United States)

    Plengsuriyakarn, Tullayakorn; Karbwang, Juntra; Na-Bangchang, Kesara

    2015-03-01

    Cholangiocarcinoma (CCA) is an important public health problem in several parts of South East Asia, particularly in Thailand. The limited availability of effective diagnostic tools for early stage CCA, including chemotherapeutic options, constitutes a major problem for treatment and control of CCA. The aim of the present study was to assess the anti-CCA activity and pharmacokinetics of β-eudesmol in CCA-xenografted nude mouse model and healthy mice. Positron emission tomography-computed tomography (PET-CT) with (18)F-fluorodeoxyglucose was used for detecting and monitoring tumour development, and PET-CT with technetium-99m was used to investigate its pharmacokinetics property. Results support the role of PET-CT as a potential tool for detecting and monitoring the progress of lung metastasis. Tumour size and lung metastasis were significantly inhibited by 91.6% (of baseline) and 95% (of total lung mass), respectively, following treatment with high-dose β-eudesmol (100 mg/kg body weight for 30 days). Survival time was prolonged by 64.4% compared with untreated controls. Systemic clearance of the compound was rapid, particularly during the first 60 min. The compound was distributed to the vital organs at maximum levels 2 h after oral administration and 15 min after intravenous injection. Results from the present study suggest the potential of β-eudesmol as a promising candidate for further development as an anti-CCA drug with respect to its pharmacodynamics and pharmacokinetic properties. PET-CT, with radiotracers (18)F-fluorodeoxyglucose and technetium-99m, was shown to be a reliable tool in the investigation of anti-CCA and pharmacokinetic properties of β-eudesmol in CCA-xenografted and healthy mice. © 2014 Wiley Publishing Asia Pty Ltd.

  18. Availability of Acute and/or Subacute Toxicokinetic Data for Select Compounds for the Rat and Physiologically Based Pharmacokinetic (PBPK) Models for Rats and Humans for Those Compounds

    Science.gov (United States)

    2017-05-04

    DMA, and total As in urine Mouse: radioactivity in feces, liver, kidneys, lungs, and carcass (DMA), DMA in urine; after arsenate dose...radioactivity in urine, feces, liver, kidneys, lungs, skin, carcass and blood and AsV, AsIII, MMA and DMA excreted in urine; after arsenite dose, AsV, AsIII...Pharmacokinetic parameter values were taken from a variety of sources, including animal studies (e.g., oral absorption rate), in vitro kinetic

  19. Oral fluid/plasma cannabinoid ratios following controlled oral THC and smoked cannabis administration.

    Science.gov (United States)

    Lee, Dayong; Vandrey, Ryan; Milman, Garry; Bergamaschi, Mateus; Mendu, Damodara R; Murray, Jeannie A; Barnes, Allan J; Huestis, Marilyn A

    2013-09-01

    Oral fluid (OF) is a valuable biological alternative for clinical and forensic drug testing. Evaluating OF to plasma (OF/P) cannabinoid ratios provides important pharmacokinetic data on the disposition of drug and factors influencing partition between matrices. Eleven chronic cannabis smokers resided on a closed research unit for 51 days. There were four 5-day sessions of 0, 30, 60, and 120 mg oral ∆(9)-tetrahydrocannabinol (THC)/day followed by a five-puff smoked cannabis challenge on Day 5. Each session was separated by 9 days ad libitum cannabis smoking. OF and plasma specimens were analyzed for THC and metabolites. During ad libitum smoking, OF/P THC ratios were high (median, 6.1; range, 0.2-348.5) within 1 h after last smoking, decreasing to 0.1-20.7 (median, 2.1) by 13.0-17.1 h. OF/P THC ratios also decreased during 5-days oral THC dosing, and after the smoked cannabis challenge, median OF/P THC ratios decreased from 1.4 to 5.5 (0.04-245.6) at 0.25 h to 0.12 to 0.17 (0.04-5.1) at 10.5 h post-smoking. In other studies, longer exposure to more potent cannabis smoke and oromucosal cannabis spray was associated with increased OF/P THC peak ratios. Median OF/P 11-nor-9-carboxy-THC (THCCOOH) ratios were 0.3-2.5 (range, 0.1-14.7) ng/μg, much more consistent in various dosing conditions over time. OF/P THC, but not THCCOOH, ratios were significantly influenced by oral cavity contamination after smoking or oromucosal spray of cannabinoid products, followed by time-dependent decreases. Establishing relationships between OF and plasma cannabinoid concentrations is essential for making inferences of impairment or other clinical outcomes from OF concentrations.

  20. Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: A Phase 1 open-label clinical trial in healthy adults.

    Directory of Open Access Journals (Sweden)

    Martin R Gaudinski

    2018-01-01

    Full Text Available VRC01 is a human broadly neutralizing monoclonal antibody (bnMAb against the CD4-binding site of the HIV-1 envelope glycoprotein (Env that is currently being evaluated in a Phase IIb adult HIV-1 prevention efficacy trial. VRC01LS is a modified version of VRC01, designed for extended serum half-life by increased binding affinity to the neonatal Fc receptor.This Phase I dose-escalation study of VRC01LS in HIV-negative healthy adults was conducted by the Vaccine Research Center (VRC at the National Institutes of Health (NIH Clinical Center (Bethesda, MD. The age range of the study volunteers was 21-50 years; 51% of study volunteers were male and 49% were female. Primary objectives were safety and tolerability of VRC01LS intravenous (IV infusions at 5, 20, and 40 mg/kg infused once, 20 mg/kg given three times at 12-week intervals, and subcutaneous (SC delivery at 5 mg/kg delivered once, or three times at 12-week intervals. Secondary objectives were pharmacokinetics (PK, serum neutralization activity, and development of antidrug antibodies. Enrollment began on November 16, 2015, and concluded on August 23, 2017. This report describes the safety data for the first 37 volunteers who received administrations of VRC01LS. There were no serious adverse events (SAEs or dose-limiting toxicities. Mild malaise and myalgia were the most common adverse events (AEs. There were six AEs assessed as possibly related to VRC01LS administration, and all were mild in severity and resolved during the study. PK data were modeled based on the first dose of VRC01LS in the first 25 volunteers to complete their schedule of evaluations. The mean (±SD serum concentration 12 weeks after one IV administration of 20 mg/kg or 40 mg/kg were 180 ± 43 μg/mL (n = 7 and 326 ± 35 μg/mL (n = 5, respectively. The mean (±SD serum concentration 12 weeks after one IV and SC administration of 5 mg/kg were 40 ± 3 μg/mL (n = 2 and 25 ± 5 μg/mL (n = 9, respectively. Over the 5-40 mg

  1. A new fully human recombinant FSH (follitropin epsilon): two phase I randomized placebo and comparator-controlled pharmacokinetic and pharmacodynamic trials.

    Science.gov (United States)

    Abd-Elaziz, Khalid; Duijkers, Ingrid; Stöckl, Lars; Dietrich, Bruno; Klipping, Christine; Eckert, Kelvin; Goletz, Steffen

    2017-08-01

    What are the differences and similarities of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the novel recombinant human FSH follitropin epsilon expressed in the human cell line GlycoExpress compared with a Chinese hamster ovary (CHO) derived compound and a urinary derived product? Overall follitropin epsilon, with a fully human glycosylation, shows a comparable PK profile at single-dose as well as multiple-dose administration compared to recombinant CHO-derived FSH as well as urinary derived FSH, whereas the PD properties differ from product to product with follitropin epsilon being most active in PD parameters. Recombinant FSH produced in CHO and FSH obtained from the urine of postmenopausal women show comparable PK and PD properties. However, more recently a comparative study of a recombinant FSH produced in the human cell line PerC6 and a CHO-derived FSH preparation revealed differences in PK and PD properties of the molecule. Both studies were randomized, placebo- and comparator-controlled, single-blind phase I studies in healthy pituitary-suppressed female volunteers aged 18 and 40 years. The single-dose, dose escalation study included 19 women (April 2011 to September 2011) with three ascending dose levels per subject or placebo/comparators with a 14-day washout phase between dosings. The multiple-dose study included 57 women (October 2011 to April 2012) in five cohorts with three dose levels versus placebo and two comparators. Randomization to the respective treatment was performed after successful downregulation of the pituitary gland prior to Investigational Medicinal Product dosing. In the single-dose study, 12 subjects received follitropin epsilon (25, 75, 150 and 300 IU) in three of four possible ascending doses and seven subjects received one dose of two comparators (150 IU Bravelle and 150 IU Gonal-f) and placebo in random order in each treatment period. In the multiple-dose study, 30 subjects received follitropin epsilon (75 IU or

  2. Estrogenic effects of marijuana smoke condensate and cannabinoid compounds

    International Nuclear Information System (INIS)

    Lee, Soo Yeun; Oh, Seung Min; Chung, Kyu Hyuck

    2006-01-01

    Chronic exposure to marijuana produces adverse effects on the endocrine and reproductive systems in humans; however, the experimental evidence for this presented thus far has not been without controversy. In this study, the estrogenic effect of marijuana smoke condensate (MSC) was evaluated using in vitro bioassays, viz., the cell proliferation assay, the reporter gene assay, and the ER competitive binding assay. The results of these assays were compared with those of three major cannabinoids, i.e., THC, CBD, and CBN. The estrogenic effect of MSC was further confirmed by the immature female rat uterotrophic assay. MSC stimulated the estrogenicity related to the ER-mediated pathway, while neither THC, CBD, nor CBN did. Moreover, treatment with 10 and 25 mg/kg MSC induced significant uterine response, and 10 mg/kg MSC resulted in an obvious change in the uterine epithelial cell appearance. MSC also enhanced the IGFBP-1 gene expression in a dose-dependent manner. To identify the constituents of MSC responsible for its estrogenicity, the MSC fractionated samples were examined using another cell proliferation assay, and the estrogenic active fraction was analyzed using GC-MS. In the organic acid fraction that showed the strongest estrogenic activity among the seven fractions of MSC, phenols were identified. Our results suggest that marijuana abuse is considered an endocrine-disrupting factor. Furthermore, these results suggest that the phenolic compounds contained in MSC play a role in its estrogenic effect

  3. SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor.

    Science.gov (United States)

    Rinaldi-Carmona, M; Barth, F; Millan, J; Derocq, J M; Casellas, P; Congy, C; Oustric, D; Sarran, M; Bouaboula, M; Calandra, B; Portier, M; Shire, D; Brelière, J C; Le Fur, G L

    1998-02-01

    Based on both binding and functional data, this study introduces SR 144528 as the first, highly potent, selective and orally active antagonist for the CB2 receptor. This compound which displays subnanomolar affinity (Ki = 0.6 nM) for both the rat spleen and cloned human CB2 receptors has a 700-fold lower affinity (Ki = 400 nM) for both the rat brain and cloned human CB1 receptors. Furthermore it shows no affinity for any of the more than 70 receptors, ion channels or enzymes investigated (IC50 > 10 microM). In vitro, SR 144528 antagonizes the inhibitory effects of the cannabinoid receptor agonist CP 55,940 on forskolin-stimulated adenylyl cyclase activity in cell lines permanently expressing the h CB2 receptor (EC50 = 10 nM) but not in cells expressing the h CB1 (no effect at 10 microM). Furthermore, SR 144528 is able to selectively block the mitogen-activated protein kinase activity induced by CP 55,940 in cell lines expressing h CB2 (IC50 = 39 nM) whereas in cells expressing h CB1 an IC50 value of more than 1 microM is found. In addition, SR 144528 is shown to antagonize the stimulating effects of CP 55,940 on human tonsillar B-cell activation evoked by cross-linking of surface Igs (IC50 = 20 nM). In vivo, after oral administration SR 144528 totally displaced the ex vivo [3H]-CP 55,940 binding to mouse spleen membranes (ED50 = 0.35 mg/kg) with a long duration of action. In contrast, after the oral route it does not interact with the cannabinoid receptor expressed in the mouse brain (CB1). It is expected that SR 144528 will provide a powerful tool to investigate the in vivo functions of the cannabinoid system in the immune response.

  4. Binding and Signaling Studies Disclose a Potential Allosteric Site for Cannabidiol in Cannabinoid CB2 Receptors

    Directory of Open Access Journals (Sweden)

    Eva Martínez-Pinilla

    2017-10-01

    Full Text Available The mechanism of action of cannabidiol (CBD, the main non-psychotropic component of Cannabis sativa L., is not completely understood. First assumed that the compound was acting via cannabinoid CB2 receptors (CB2Rs it is now suggested that it interacts with non-cannabinoid G-protein-coupled receptors (GPCRs; however, CBD does not bind with high affinity to the orthosteric site of any GPCR. To search for alternative explanations, we tested CBD as a potential allosteric ligand of CB2R. Radioligand and non-radioactive homogeneous binding, intracellular cAMP determination and ERK1/2 phosphorylation assays were undertaken in heterologous systems expressing the human version of CB2R. Using membrane preparations from CB2R-expressing HEK-293T (human embryonic kidney 293T cells, we confirmed that CBD does not bind with high affinity to the orthosteric site of the human CB2R where the synthetic cannabinoid, [3H]-WIN 55,212-2, binds. CBD was, however, able to produce minor but consistent reduction in the homogeneous binding assays in living cells using the fluorophore-conjugated CB2R-selective compound, CM-157. The effect on binding to CB2R-expressing living cells was different to that exerted by the orthosteric antagonist, SR144528, which decreased the maximum binding without changing the KD. CBD at nanomolar concentrations was also able to significantly reduce the effect of the selective CB2R agonist, JWH133, on forskolin-induced intracellular cAMP levels and on activation of the MAP kinase pathway. These results may help to understand CBD mode of action and may serve to revisit its therapeutic possibilities.

  5. Binding and Signaling Studies Disclose a Potential Allosteric Site for Cannabidiol in Cannabinoid CB2 Receptors.

    Science.gov (United States)

    Martínez-Pinilla, Eva; Varani, Katia; Reyes-Resina, Irene; Angelats, Edgar; Vincenzi, Fabrizio; Ferreiro-Vera, Carlos; Oyarzabal, Julen; Canela, Enric I; Lanciego, José L; Nadal, Xavier; Navarro, Gemma; Borea, Pier Andrea; Franco, Rafael

    2017-01-01

    The mechanism of action of cannabidiol (CBD), the main non-psychotropic component of Cannabis sativa L., is not completely understood. First assumed that the compound was acting via cannabinoid CB 2 receptors (CB 2 Rs) it is now suggested that it interacts with non-cannabinoid G-protein-coupled receptors (GPCRs); however, CBD does not bind with high affinity to the orthosteric site of any GPCR. To search for alternative explanations, we tested CBD as a potential allosteric ligand of CB 2 R. Radioligand and non-radioactive homogeneous binding, intracellular cAMP determination and ERK1/2 phosphorylation assays were undertaken in heterologous systems expressing the human version of CB 2 R. Using membrane preparations from CB 2 R-expressing HEK-293T (human embryonic kidney 293T) cells, we confirmed that CBD does not bind with high affinity to the orthosteric site of the human CB 2 R where the synthetic cannabinoid, [ 3 H]-WIN 55,212-2, binds. CBD was, however, able to produce minor but consistent reduction in the homogeneous binding assays in living cells using the fluorophore-conjugated CB 2 R-selective compound, CM-157. The effect on binding to CB 2 R-expressing living cells was different to that exerted by the orthosteric antagonist, SR144528, which decreased the maximum binding without changing the K D . CBD at nanomolar concentrations was also able to significantly reduce the effect of the selective CB 2 R agonist, JWH133, on forskolin-induced intracellular cAMP levels and on activation of the MAP kinase pathway. These results may help to understand CBD mode of action and may serve to revisit its therapeutic possibilities.

  6. Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB{sub 1} receptors and apoptotic cell death

    Energy Technology Data Exchange (ETDEWEB)

    Tomiyama, Ken-ichi; Funada, Masahiko, E-mail: mfunada@ncnp.go.jp

    2014-01-01

    The abuse of herbal products containing synthetic cannabinoids has become an issue of public concern. The purpose of this paper was to evaluate the acute cytotoxicity of synthetic cannabinoids on mouse brain neuronal cells. Cytotoxicity induced by synthetic cannabinoid (CP-55,940, CP-47,497, CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201, and MAM-2201) was examined using forebrain neuronal cultures. These synthetic cannabinoids induced cytotoxicity in the forebrain cultures in a concentration-dependent manner. The cytotoxicity was suppressed by preincubation with the selective CB{sub 1} receptor antagonist AM251, but not with the selective CB{sub 2} receptor antagonist AM630. Furthermore, annexin-V-positive cells were found among the treated forebrain cells. Synthetic cannabinoid treatment induced the activation of caspase-3, and preincubation with a caspase-3 inhibitor significantly suppressed the cytotoxicity. These synthetic cannabinoids induced apoptosis through a caspase-3-dependent mechanism in the forebrain cultures. Our results indicate that the cytotoxicity of synthetic cannabinoids towards primary neuronal cells is mediated by the CB{sub 1} receptor, but not by the CB{sub 2} receptor, and further suggest that caspase cascades may play an important role in the apoptosis induced by these synthetic cannabinoids. In conclusion, excessive synthetic cannabinoid abuse may present a serious acute health concern due to neuronal damage or deficits in the brain. - Highlights: • Synthetic cannabinoids (classical cannabinoids, non-classical cannabinoids, and aminoalkylindole derivatives) induce cytotoxicity in mouse forebrain cultures. • Synthetic cannabinoid-induced cytotoxicity towards forebrain cultures is mediated by the CB{sub 1} receptor, but not by the CB{sub 2} receptor, and involves caspase-dependent apoptosis. • A high concentration of synthetic cannabinoids may be toxic to neuronal cells that express CB{sub 1} receptors.

  7. Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB1 receptors and apoptotic cell death

    International Nuclear Information System (INIS)

    Tomiyama, Ken-ichi; Funada, Masahiko

    2014-01-01

    The abuse of herbal products containing synthetic cannabinoids has become an issue of public concern. The purpose of this paper was to evaluate the acute cytotoxicity of synthetic cannabinoids on mouse brain neuronal cells. Cytotoxicity induced by synthetic cannabinoid (CP-55,940, CP-47,497, CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201, and MAM-2201) was examined using forebrain neuronal cultures. These synthetic cannabinoids induced cytotoxicity in the forebrain cultures in a concentration-dependent manner. The cytotoxicity was suppressed by preincubation with the selective CB 1 receptor antagonist AM251, but not with the selective CB 2 receptor antagonist AM630. Furthermore, annexin-V-positive cells were found among the treated forebrain cells. Synthetic cannabinoid treatment induced the activation of caspase-3, and preincubation with a caspase-3 inhibitor significantly suppressed the cytotoxicity. These synthetic cannabinoids induced apoptosis through a caspase-3-dependent mechanism in the forebrain cultures. Our results indicate that the cytotoxicity of synthetic cannabinoids towards primary neuronal cells is mediated by the CB 1 receptor, but not by the CB 2 receptor, and further suggest that caspase cascades may play an important role in the apoptosis induced by these synthetic cannabinoids. In conclusion, excessive synthetic cannabinoid abuse may present a serious acute health concern due to neuronal damage or deficits in the brain. - Highlights: • Synthetic cannabinoids (classical cannabinoids, non-classical cannabinoids, and aminoalkylindole derivatives) induce cytotoxicity in mouse forebrain cultures. • Synthetic cannabinoid-induced cytotoxicity towards forebrain cultures is mediated by the CB 1 receptor, but not by the CB 2 receptor, and involves caspase-dependent apoptosis. • A high concentration of synthetic cannabinoids may be toxic to neuronal cells that express CB 1 receptors

  8. Clinical pharmacokinetics of melatonin

    DEFF Research Database (Denmark)

    Harpsøe, Nathja Groth; Andersen, Lars Peter Holst; Gögenur, Ismail

    2015-01-01

    was performed in PubMed and Embase databases. The pharmacokinetic variables included maximal plasma/serum concentration (Cmax), time to maximal plasma/serum concentration (Tmax), elimination half-life (T1/2), area-under-the-curve plasma/serum concentrations (AUC), clearance (Cl), volume of distribution (VD......) and 1602 L (4 mg, oral). Bioavailability of oral melatonin ranged from 9 to 33%. Pharmacokinetics was affected by age, caffeine, smoking, oral contraceptives, feeding status, and fluvoxamine. Critically ill patients displayed accelerated absorption and compromised elimination. CONCLUSIONS: Despite...

  9. The cannabinoid receptor type 2 as mediator of mesenchymal stromal cell immunosuppressive properties.

    Directory of Open Access Journals (Sweden)

    Francesca Rossi

    Full Text Available Mesenchymal stromal cells are non-hematopoietic, multipotent progenitor cells producing cytokines, chemokines, and extracellular matrix proteins that support hematopoietic stem cell survival and engraftment, influence immune effector cell development, maturation, and function, and inhibit alloreactive T-cell responses. The immunosuppressive properties of human mesenchymal stromal cells have attracted much attention from immunologists, stem cell biologists and clinicians. Recently, the presence of the endocannabinoid system in hematopoietic and neural stem cells has been demonstrated. Endocannabinoids, mainly acting through the cannabinoid receptor subtype 2, are able to modulate cytokine release and to act as immunosuppressant when added to activated T lymphocytes. In the present study, we have investigated, through a multidisciplinary approach, the involvement of the endocannabinoids in migration, viability and cytokine release of human mesenchymal stromal cells. We show, for the first time, that cultures of human mesenchymal stromal cells express all of the components of the endocannabinoid system, suggesting a potential role for the cannabinoid CB2 receptor as a mediator of anti-inflammatory properties of human mesenchymal stromal cells, as well as of their survival pathways and their capability to home and migrate towards endocannabinoid sources.

  10. Endogenous cannabinoid release within prefrontal-limbic pathways affects memory consolidation of emotional training

    NARCIS (Netherlands)

    Morena, M.; Roozendaal, B.; Trezza, V.; Ratano, P.; Peloso, A.; Hauer, D.; Atsak, P.; Trabace, L.; Cuomo, V.; McGaugh, J.L.; Schelling, G.; Campolongo, P.

    2014-01-01

    Previous studies have provided extensive evidence that administration of cannabinoid drugs after training modulates the consolidation of memory for an aversive experience. The present experiments investigated whether the memory consolidation is regulated by endogenously released cannabinoids. The

  11. Glycine receptors in CNS neurons as a target for nonretrograde action of cannabinoids

    NARCIS (Netherlands)

    Lozovaya, N.; Yatsenko, N.; Beketov, A.; Tsintsadze, T.; Burnashev, N.

    2005-01-01

    At many central synapses, endocannabinoids released by postsynaptic cells act retrogradely on presynaptic G-protein-coupled cannabinoid receptors to inhibit neurotransmitter release. Here, we demonstrate that cannabinoids may directly affect the functioning of inhibitory glycine receptor (GlyR)

  12. G-protein coupling of cannabinoid receptors

    International Nuclear Information System (INIS)

    Glass, M.

    2001-01-01

    Full text: Since the cloning of the cannabinoid CB1 and CB2 receptors in the early 1990's extensive research has focused on understanding their signal transduction pathways. While it has been known for sometime that both receptors can couple to intracellular signalling via pertussis toxin sensitive G-proteins (Gi/Go), the specificity and kinetics of these interactions have only recently been elucidated. We have developed an in situ reconstitution approach to investigating receptor-G-protein interactions. This approach involves chaotropic extraction of receptor containing membranes in order to inactivate or remove endogenous G-proteins. Recombinant or isolated brain G-proteins can then be added back to the receptors, and their activation monitored through the binding of [ 35 S]-GTPγS. This technique has been utilised for an extensive study of cannabinoid receptor mediated activation of G-proteins. In these studies we have established that CB1 couples with high affinity to both Gi and Go type G-proteins. In contrast, CB2 couples strongly to Gi, but has a very low affinity for Go. This finding correlated well with the previous findings that while CB1 and CB2 both couple to the inhibition of adenylate cyclase, CB1 but not CB2 could also inhibit calcium channels. We then examined the ability of a range of cannabinoid agonists to activate the Gi and Go via CB1. Conventional receptor theory suggests that a receptor is either active or inactive with regard to a G-protein and that the active receptor activates all relevant G-proteins equally. However, in this study we found that agonists could produce different degrees of activation, depending on which G-protein was present. Further studies have compared the ability of the two endocannabinoids to drive the activation of Gi or Go. These studies show that agonists can induce multiple forms of activated receptor that differ in their ability to catalyse the activation of Gi or Go. The ability of an agonist to drive a receptor

  13. Pharmacokinetics of Melatonin

    DEFF Research Database (Denmark)

    Andersen, Lars Peter Holst; Gögenur, Ismail; Rosenberg, Jacob

    2016-01-01

    Despite widespread clinical application of melatonin, several unanswered questions remain regarding the pharmacokinetics of this drug. This lack of knowledge may contribute to the inconsistency of results in previous clinical studies. Currently, a t max value of 30-45 min and a t ½elimination of ...

  14. Pharmacokinetic evaluation of pemetrexed

    DEFF Research Database (Denmark)

    Sørensen, Jens Benn

    2011-01-01

    correlates with renal function and it may be safely used with vitamin supplementation in patients with creatinine clearance ≥ 45 ml/min. The pharmacokinetics of pemetrexed is also largely unchanged in third-space fluids and can be feasibly and safely administered in combination with several other cytotoxic...

  15. Pharmacokinetic evaluation of pemetrexed

    DEFF Research Database (Denmark)

    Sørensen, Jens Benn

    2011-01-01

    correlates with renal function and it may be safely used with vitamin supplementation in patients with creatinine clearance = 45 ml/min. The pharmacokinetics of pemetrexed is also largely unchanged in third-space fluids and can be feasibly and safely administered in combination with several other cytotoxic...

  16. Spice drugs are more than harmless herbal blends: a review of the pharmacology and toxicology of synthetic cannabinoids.

    Science.gov (United States)

    Seely, Kathryn A; Lapoint, Jeff; Moran, Jeffery H; Fattore, Liana

    2012-12-03

    "K2" and "Spice" drugs (collectively hereafter referred to as Spice) represent a relatively new class of designer drugs that have recently emerged as popular alternatives to marijuana, otherwise characterized as "legal highs". These drugs are readily available on the Internet and sold in many head shops and convenience stores under the disguise of innocuous products like herbal blends, incense, or air fresheners. Although package labels indicate "not for human consumption", the number of intoxicated people presenting to emergency departments is dramatically increasing. The lack of validated and standardized human testing procedures and an endless supply of potential drugs of abuse are primary reasons why researchers find it difficult to fully characterize clinical consequences associated with Spice. While the exact chemical composition and toxicology of Spice remains to be determined, there is mounting evidence identifying several synthetic cannabinoids as causative agents responsible for psychoactive and adverse physical effects. This review provides updates of the legal status of common synthetic cannabinoids detected in Spice and analytical procedures used to test Spice products and human specimens collected under a variety of clinical circumstances. The pharmacological and toxicological consequences of synthetic cannabinoid abuse are also reviewed to provide a future perspective on potential short- and long-term implications. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. 77 FR 12508 - Schedules of Controlled Substances: Placement of Five Synthetic Cannabinoids Into Schedule I

    Science.gov (United States)

    2012-03-01

    ... constituent of marijuana. ``Synthetic cannabinoids'' are a large family of chemically unrelated structures... that is more common in current usage, ``marijuana.'' The emergence of these five synthetic cannabinoids... cannabinoids with a potential for abuse similar to the Schedule I substances marijuana and THC. These synthetic...

  18. 75 FR 71635 - Schedules of Controlled Substances: Temporary Placement of Five Synthetic Cannabinoids Into...

    Science.gov (United States)

    2010-11-24

    ... these THC-like synthetic cannabinoids are marketed as ``legal'' alternatives to marijuana and are being...] Schedules of Controlled Substances: Temporary Placement of Five Synthetic Cannabinoids Into Schedule I... intent to temporarily place five synthetic cannabinoids into the Controlled Substances Act (CSA) pursuant...

  19. Δ9-Tetrahydrocannabinol enhances MCF-7 cell proliferation via cannabinoid receptor-independent signaling

    International Nuclear Information System (INIS)

    Takeda, Shuso; Yamaori, Satoshi; Motoya, Erina; Matsunaga, Tamihide; Kimura, Toshiyuki; Yamamoto, Ikuo; Watanabe, Kazuhito

    2008-01-01

    We recently reported that Δ 9 -tetrahydrocannabinol (Δ 9 -THC) has the ability to stimulate the proliferation of human breast carcinoma MCF-7 cells. However, the mechanism of action remains to be clarified. The present study focused on the relationship between receptor expression and the effects of Δ 9 -THC on cell proliferation. RT-PCR analysis demonstrated that there was no detectable expression of CB receptors in MCF-7 cells. In accordance with this, no effects of cannabinoid 1/2 (CB1/2) receptor antagonists and pertussis toxin on cell proliferation were observed. Although MCF-7 cell proliferation is suggested to be suppressed by Δ 9 -THC in the presence of CB receptors, it was revealed that Δ 9 -THC could exert upregulation of living cells in the absence of the receptors. Interestingly, Δ 9 -THC upregulated human epithelial growth factor receptor type 2 (HER2) expression, which is known to be a predictive factor of human breast cancer and is able to stimulate cancer cells as well as MCF-7 cells. Actinomycin D-treatment interfered with the upregulation of HER2 and cell proliferation by cannabinoid. Taken together, these studies suggest that, in the absence of CB receptors, Δ 9 -THC can stimulate the proliferation of MCF-7 cells by modulating, at least in part, HER2 transcription

  20. A preliminary evaluation of the relationship of cannabinoid blood concentrations with the analgesic response to vaporized cannabis

    Directory of Open Access Journals (Sweden)

    Wilsey BL

    2016-08-01

    Full Text Available Barth L Wilsey,1,2 Reena Deutsch,3 Emil Samara,4 Thomas D Marcotte,3 Allan J Barnes,5 Marilyn A Huestis,5,6 Danny Le1,2 1VA Northern California Health Care System, Mather, CA, 2Department of Physical Medicine and Rehabilitation, University of California, Sacramento, CA, 3Department of Psychiatry, University of California, San Diego, La Jolla, CA, 4PharmaPolaris International, Davis, CA, 5Chemistry and Drug Metabolism, IRP, National Institute on Drug Abuse, Baltimore, MD, 6University of Maryland School of Medicine, Baltimore, MD, USA Abstract: A randomized, placebo-controlled crossover trial utilizing vaporized cannabis containing placebo and 6.7% and 2.9% delta-9-tetrahydrocannabinol (THC was performed in 42 subjects with central neuropathic pain related to spinal cord injury and disease. Subjects received two administrations of the study medication in a 4-hour interval. Blood samples for pharmacokinetic evaluation were collected, and pain assessment tests were performed immediately after the second administration and 3 hours later. Pharmacokinetic data, although limited, were consistent with literature reports, namely dose-dependent increase in systemic exposure followed by rapid disappearance of THC. Dose-dependent improvement in pain score was evident across all pain scale elements. Using mixed model regression, an evaluation of the relationship between plasma concentrations of selected cannabinoids and percent change in items from the Neuropathic Pain Scale was conducted. Changes in the concentration of THC and its nonpsychotropic metabolite, 11-nor-9-carboxy-THC, were related to percent change from baseline of several descriptors (eg, itching, burning, and deep pain. However, given the large number of multiple comparisons, false-discovery-rate-adjusted P-values were not significant. Plans for future work are outlined to explore the relationship of plasma concentrations with the analgesic response to different cannabinoids. Such an

  1. Quantification of hydroxyurea in human plasma by HPLC-MS/MS and its application to pharmacokinetics in patients with chronic myeloid leukaemia.

    Science.gov (United States)

    Hai, Xin; Guo, Meihua; Gao, Chunlu; Zhou, Jin

    2017-04-15

    Hydroxyurea (HU) has been used in the treatment of chronic myeloid leukaemia (CML) and other myeloproliferative malignancies. Considering patient's wide variation in clinical response to HU, a new and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to monitor patients' compliance to treatment and investigate the pharmacokinetics of HU in patients with CML. Stable isotope labeled HU- 13 C 1 , 15 N 2 was used as internal standard. Plasma samples were treated with acetonitrile to precipitate protein. The supernatant was injected directly without derivatization and separated on a hydrophilic interaction liquid chromatography column. HU was quantitatively analyzed with a mobile phase of acetonitrile-1.5mM ammonium formate (90:10, V:V) within 3min. The proposed method provided a linearity range of 1-200μg/mL. The coefficients of variation for intra- and inter-day precision were less than 2.07% and 4.28%, respectively, while the accuracy (bias) was in the range of -3.77 to 2.96%. This method was satisfactorily applied to the determination of HU in two patients with CML. It is suitable for supporting pharmacokinetic studies and clinical therapeutic monitoring. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Quantification of Photocyanine in Human Serum by High-Performance Liquid Chromatography-Tandem Mass Spectrometry and Its Application in a Pharmacokinetic Study

    Directory of Open Access Journals (Sweden)

    Bing-Tian Bi

    2014-01-01

    Full Text Available Photocyanine is a novel anticancer drug. Its pharmacokinetic study in cancer patients is therefore very important for choosing doses, and dosing intervals in clinical application. A rapid, selective and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS method was developed and validated for the determination of photocyanine in patient serum. Sample preparation involved one-step protein precipitation by adding methanol and N,N-dimethyl formamide to 0.1 mL serum. The detection was performed on a triple quadrupole tandem mass spectrometer operating in multiple reaction-monitoring (MRM mode. Each sample was chromatographed within 7 min. Linear calibration curves were obtained for photocyanine at a concentration range of 20–2000 ng/mL (r>0.995, with the lower limit of quantification (LLOQ being 20 ng/mL. The intrabatch accuracy ranged from 101.98% to 107.54%, and the interbatch accuracy varied from 100.52% to 105.62%. Stability tests showed that photocyanine was stable throughout the analytical procedure. This study is the first to utilize the HPLC-MS/MS method for the pharmacokinetic study of photocyanine in six cancer patients who had received a single dose of photocyanine (0.1 mg/kg administered intravenously.

  3. Stability of cannabinoids in urine in three storage temperatures.

    Science.gov (United States)

    Golding Fraga, S; Díaz-Flores Estévez, J; Díaz Romero, C

    1998-01-01

    Stability of cannabinoid compounds in urine samples were evaluated using several storage temperatures. Appreciable losses (> 22.4 percent) were observed in some urine samples, after being stored at room temperature for 10 days. Lower losses (8.1 percent) were observed when the urine samples were refrigerated for 4 weeks. The behavior of urine samples depended on the analyzed urine. This could be due to the different stability of the cannabinoids present in each urine sample. Important losses of 8.0 +/- 10.6, 15.8 +/- 4.2, and 19.6 +/- 6.7 percent were found when the urine samples were frozen during 40 days, 1 year, and 3 years, respectively. Average losses (> > 5 percent) can be observed after one day which could mainly be due to the decrease of the solubility of 11-nor-U9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) or adsorption process of cannabinoid molecules to the plastic storage containers.

  4. WIN 55,212-2, agonist of cannabinoid receptors, prevents amyloid β1-42 effects on astrocytes in primary culture.

    Directory of Open Access Journals (Sweden)

    Diana Aguirre-Rueda

    Full Text Available Alzheimer's disease (AD, a neurodegenerative illness involving synaptic dysfunction with extracellular accumulation of Aβ1-42 toxic peptide, glial activation, inflammatory response and oxidative stress, can lead to neuronal death. Endogenous cannabinoid system is implicated in physiological and physiopathological events in central nervous system (CNS, and changes in this system are related to many human diseases, including AD. However, studies on the effects of cannabinoids on astrocytes functions are scarce. In primary cultured astrocytes we studied cellular viability using MTT assay. Inflammatory and oxidative stress mediators were determined by ELISA and Western-blot techniques both in the presence and absence of Aβ1-42 peptide. Effects of WIN 55,212-2 (a synthetic cannabinoid on cell viability, inflammatory mediators and oxidative stress were also determined. Aβ1-42 diminished astrocytes viability, increased TNF-α and IL-1β levels and p-65, COX-2 and iNOS protein expression while decreased PPAR-γ and antioxidant enzyme Cu/Zn SOD. WIN 55,212-2 pretreatment prevents all effects elicited by Aβ1-42. Furthermore, cannabinoid WIN 55,212-2 also increased cell viability and PPAR-γ expression in control astrocytes. In conclusion cannabinoid WIN 55,212-2 increases cell viability and anti-inflammatory response in cultured astrocytes. Moreover, WIN 55,212-2 increases expression of anti-oxidant Cu/Zn SOD and is able to prevent inflammation induced by Aβ1-42 in cultured astrocytes. Further studies would be needed to assess the possible beneficial effects of cannabinoids in Alzheimer's disease patients.

  5. Beyond THC: the new generation of cannabinoid designer drugs

    Directory of Open Access Journals (Sweden)

    Liana eFattore

    2011-09-01

    Full Text Available Synthetic cannabinoids are functionally similar to delta9-tetrahydrocannabinol (THC, the psychoactive principle of cannabis, and bind to the same cannabinoid receptors in the brain and peripheral organs. From 2008, synthetic cannabinoids were detected in herbal smoking mixtures sold on websites and in head shops under the brand name of Spice Gold, Yucatan Fire, Aroma, and others. Although these products (also known as Spice drugs or legal highs do not contain tobacco or cannabis, when smoked they produce effects similar to THC. Intoxication, withdrawal, psychosis and death have been recently reported after consumption, posing difficult social, political and health challenges. More than 140 different Spice products have been identified to date. The ability to induce strong cannabis-like psychoactive effects, along with the fact that they are readily available on the Internet, still legal in many countries, marketed as natural safe substances, and undetectable by conventional drug screening tests, has rendered these drugs very popular and particularly appealing to young and drug-naïve individuals seeking new experiences. An escalating number of compounds with cannabinoid receptor activity are currently being found as ingredients of Spice, of which almost nothing is known in terms of pharmacology, toxicology and safety. Since legislation started to control the synthetic cannabinoids identified in these herbal mixtures, many new analogs have appeared on the market. New cannabimimetic compounds are likely to be synthesized in the near future to replace banned synthetic cannabinoids, leading to a dog chasing its tail situation. Spice smokers are exposed to drugs that are extremely variable in composition and potency, and are at risk of serious, if not lethal, outcomes. Social and health professionals should maintain a high degree of alertness for Spice use and its possible psychiatric effects in vulnerable people.

  6. Synthetic cannabinoid and marijuana exposures reported to poison centers.

    Science.gov (United States)

    Forrester, M B; Kleinschmidt, K; Schwarz, E; Young, A

    2012-10-01

    Synthetic cannabinoids have recently gained popularity as a recreational drug because they are believed to result in a marijuana-like high. This investigation compared synthetic cannabinoids and marijuana exposures reported to a large statewide poison center system. Synthetic cannabinoid and marijuana exposures reported to Texas poison centers during 2010 were identified. The distribution of exposures to the two agents with respect to various demographic and clinical factors were compared by calculating the rate ratio (RR) of the synthetic cannabinoid and marijuana percentages for each subgroup and 95% confidence interval (CI). The proportion of synthetic cannabinoid and marijuana exposures, respectively, were 87.3% and 46.5% via inhalation (RR 1.88, 95% CI 1.38-2.61), 74.9% and 65.7% in male (RR 1.14, 95% CI 0.87-1.51), 40.2% and 56.6% age ≤ 19 years (RR 0.71, 95% CI 0.52-0.98), 79.2% and 58.6% occurring at a residence (RR 1.35, 95% CI 1.02-1.82), 8.4% and 16.2% managed on-site (RR 0.52. 95% CI 0.28-1.00), and 59.3% and 41.4% with serious medical outcomes (RR 1.43, 95% CI 1.03-2.05). Compared to marijuana, synthetic cannabinoid exposures were more likely to be used through inhalation, to involve adults, to be used at a residence, and to result in serious outcomes.

  7. Direct antigonadal activity of cannabinoids: suppression of rat granulosa cell functions.

    Science.gov (United States)

    Adashi, E Y; Jones, P B; Hsueh, A J

    1983-02-01

    The direct effects of delta 9-tetrahydrocannabinol (THC) and related cannabinoids on ovarian granulosa cells were studied in vitro. Granulosa cells from immature, hypophysectomized, estrogen-treated rats were cultured for 2 days in an androstenedione-supplemented medium in the presence or absence of follicle-stimulating hormone (FSH) (10 ng/ml) with or without cannabinoids. FSH treatment increased progesterone and estrogen biosynthesis, whereas concomitant treatment with THC led to a dose-dependent inhibition of the FSH-stimulated accumulation of progesterone and estrogen with ED50 values of 3.5 +/- 0.3 X 10(-7) and 1.8 +/- 0.2 X 10(-6) M, respectively. Treatment with related but nonpsychoactive cannabinoids (cannabidiol, cannabinol, cannabigerol, or cannabichromene) was equally effective. The THC-induced inhibition of progesterone production was reversible and was associated with an inhibition of pregnenolone biosynthesis and a decrease of 3 beta-hydroxysteroid dehydrogenase activity. In addition, treatment with THC brought about a dose-dependent inhibition of the FSH-induced increase in luteinizing hormone (LH) receptors. The inhibitory effects of THC were not associated with changes in cell number, protein content, or cell viability. Thus, THC exerts direct inhibitory effects on FSH-dependent functions related to steroidogenesis and the acquisition of LH receptors, all of which are essential to follicular maturation. Because plasma concentrations of THC similar to those used in this study have been reported in human beings, repeated exposure of female users to THC may lead to ovarian dysfunction, due in part, to the direct antigonadal activity to THC.

  8. Cannabinoids and their possible use in the treatment of glaucoma

    OpenAIRE

    Zozaya Aldana, Beatriz; Medina Rodríguez, Isabel; Tamayo Pineda, Nirma

    2011-01-01

    Aunque la planta Cannabis sativa ha sido empleada desde la más remota antigüedad con fines medicinales, uno de sus derivados, la marihuana, se ha convertido en la droga de uso ilegal más consumida en el mundo. Asimismo tanto el Cannabis como sus cannabinoides se emplean como terapéutico en pocas enfermedades generalmente neurológicas. Se realizó una revisión bibliográfica para exponer el posible uso de los cannabinoides en la terapéutica del glaucoma. Para ello se tuvo en cuenta la literatura...

  9. Molecular mechanisms underlying the effects of cannabinoids in the brain

    OpenAIRE

    Puighermanal Puigvert, Emma, 1983-

    2011-01-01

    El sistema endocannabinoid és un sistema neuromodulador endogen que regula diverses funcions fisiològiques, incloent el control del moviment, la memòria, l’ansietat i el dolor, entre altres. Els compostos cannabinoids es troben principalment a la planta Cannabis sativa i exerceixen els seus efectes actuant al sistema endocannabinoid. Els cannabinoids tenen potencial terapèutic, principalment per l’esclerosi múltiple, el dolor i l’èmesi, tot i que una limitació important pel seu ús recau en el...

  10. Long-term consequences of adolescent cannabinoid exposure in adult psychopathology

    Directory of Open Access Journals (Sweden)

    Justine eRenard

    2014-11-01

    Full Text Available Marijuana is the most widely used illicit drug among adolescents and young adults. Unique cognitive, emotional, and social changes occur during this critical period of development from childhood into adulthood. The adolescent brain is in a state of transition and differs from the adult brain with respect to both anatomy (e.g., neuronal connections and morphology and neurochemistry (e.g., dopamine, GABA, and glutamate. These changes are thought to support the emergence of adult cerebral processes and behaviors. The endocannabinoid system plays an important role in development by acting on synaptic plasticity, neuronal cell proliferation, migration, and differentiation. Delta-9-tetrahydrocanabinol (THC, the principal psychoactive component in marijuana, acts as an agonist of the cannabinoid type 1 receptor (CB1R. Thus, over-activation of the endocannabinoid system by chronic exposure to CB1R agonists (e.g. THC, CP-55,940, and WIN55,212-2 during adolescence can dramatically alter brain maturation and cause long-lasting neurobiological changes that ultimately affect the function and behavior of the adult brain. Indeed, emerging evidence from both human and animal studies demonstrates that early-onset marijuana use has long-lasting consequences on cognition; moreover, in humans, this use is associated with a two-fold increase in the risk of developing a psychotic disorder. Here, we review the relationship between cannabinoid exposure during adolescence and the increased risk of neuropsychiatric disorders, focusing on both clinical and animal studies.

  11. Immunohistochemistry detected and localized cannabinoid receptor type 2 in bovine fetal pancreas at late gestation

    Directory of Open Access Journals (Sweden)

    Cecilia Dall'Aglio

    2017-03-01

    Full Text Available At present, data on the endocannabinoid system expression and distribution in the pancreatic gland appear scarce and controversial as descriptions are limited to humans and laboratory animals. Since the bovine pancreas is very similar to the human in endocrine portion development and control, studies on the fetal gland could prove to be very interesting, as an abnormal maternal condition during late pregnancy may be a predisposing trigger for adult metabolic disorders. The present investigation studied cannabinoid receptor type 2 presence and distribution in the bovine fetal pancreas towards the end of gestation. Histological analyses revealed numerous endocrinal cell clusters or islets which were distributed among exocrine adenomeri in connectival tissue. Immunohistochemistry showed that endocrine-islets contained some CB2-positive cells with a very peculiar localization that is a few primarily localized at the edges of islets and some of them also scattered in the center of the cluster. Characteristically, also the epithelium of the excretory ducts and the smooth muscle layers of the smaller arteries, in the interlobular glandular septa, tested positive for the CB2 endocannabinoid receptor. Conse - quently, the endocannabinoid system, via the cannabinoid receptor type 2, was hypothesized to play a major role in controlling pancreas function from normal fetal development to correct metabolic functioning in adulthood.

  12. Cannabinoides y su posible uso en el glaucoma Cannabinoids and their possible use in the treatment of glaucoma

    Directory of Open Access Journals (Sweden)

    Beatriz Zozaya Aldana

    2011-09-01

    Full Text Available Aunque la planta Cannabis sativa ha sido empleada desde la más remota antigüedad con fines medicinales, uno de sus derivados, la marihuana, se ha convertido en la droga de uso ilegal más consumida en el mundo. Asimismo tanto el Cannabis como sus cannabinoides se emplean como terapéutico en pocas enfermedades generalmente neurológicas. Se realizó una revisión bibliográfica para exponer el posible uso de los cannabinoides en la terapéutica del glaucoma. Para ello se tuvo en cuenta la literatura disponible sobre el tema, durante el período enero a septiembre de 2010. Se ha comprobado el efecto hipotensor ocular de los cannabinoides al disminuir la producción de humor acuoso, y aumentar la excreción de humor acuoso a través de la malla trabecular y la vía uveoescleral, efecto compatible con el hallazgo de elevadas concentraciones de receptores de cannabinoides rCB1 y rCB2; además, el tetrahidrocannabinol ha demostrado disminuir el efecto neurodegenerativo en modelos de isquemia cerebral en ratas y se evidenció también el efecto beneficioso de los cannabinoides al disminuir la degeneración secundaria asociada al glaucoma mediada por la excitotoxicidad del glutamato. Estos hallazgos sobre el efecto beneficioso de los cannabinoides como hipotensores oculares y por su efecto neuroprotector, transmiten un mensaje esperanzador sobre la función que estos podrían desempeñar en el campo del glaucoma, aunque para mayor seguridad y eficacia serían necesarios ensayos clínicos encaminados a valorar su aplicabilidad en la práctica clínica diaria.Although the Cannabis Sativa plant has been used since the most remote ancient times for medicinal purposes, one of its derivatives, marijuana, has become the most commonly used illegal drug in the world. Similarly, both Cannabis and the cannabinoids are used therapeutically in a small number of general neurological pathologies. Literature review was made to set forth the possible use of

  13. Characterisation of Population Pharmacokinetics and Endogenous Follicle Stimulating Hormone (FSH) Levels after Multiple Dosing of a Recombinant Human FSH, FE 999049, in Healthy Women

    DEFF Research Database (Denmark)

    Rose, Trine Høyer; Röshammer, Daniel; Erichsen, Lars

    2016-01-01

    : Longitudinal measurements of FSH, luteinising hormone, progesterone, estradiol, and inhibin B levels were collected after repeated subcutaneous dosing with 225 IU of FE 999049 in 24 gonadotropin downregulated healthy women. The FSH data were described using nonlinear mixed-effects modelling. Results...... increased with body weight in accordance with an allometrically scaled power exponent of 0.75 and 1, respectively. Endogenous FSH levels were lower in individuals with higher progesterone levels at baseline and were further suppressed over time with increasing inhibin B levels. Conclusions......: This characterisation of FE 999049 population pharmacokinetics after repeated dosing is in line with previous findings after single-dose administration. The results provide a basis for study design and data evaluation in the future development of recombinant FSH products, and show it can be of importance to account...

  14. Synthetic Cannabinoids-Further Evidence Supporting the Relationship Between Cannabinoids and Psychosis.

    Science.gov (United States)

    Fattore, Liana

    2016-04-01

    Consumption of synthetic mind-altering compounds, also known as "new psychoactive substances," is increasing globally at an alarming rate. Synthetic cannabinoids (SCs) are among the most commonly used new psychoactive substances. They are usually purchased as marijuana-like drugs, marketed as herbal blends and perceived as risk-free by inexperienced users. Yet, contrary to Δ(9)-tetrahydrocannabinol, SCs may lead to severe health consequences, including anxiety, tachycardia, hallucinations, violent behavior, and psychosis. This review focuses on the latest (2010-2015) evidence of psychotic symptoms induced by ingestion of products containing SCs. Reports suggesting that SCs may either exacerbate previously stable psychotic symptoms (in vulnerable individuals) or trigger new-onset psychosis (in individuals with no previous history of psychosis) are reviewed. Pharmacology and toxicology of these compounds are discussed, with particular reference to their psychoactive effects. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  15. Determination of piperphentonamine and metabolites M1 and M6 in human plasma and urine by LC/MS/MS and its application in a pharmacokinetics study in Chinese healthy volunteers.

    Science.gov (United States)

    Shi, Aixin; Hu, Xin; Li, Kexin; Li, Jian; Han, Liping; Wan, Huayin; Li, Rubing

    2012-11-01

    Piperphentonamine hydrochloride (PPTA) is a new calcium sensitizer. A liquid chromatography-tandem mass spectrometry (LC/MS/MS) method for determination of piperphentonamine and its metabolites M1 and M6 was developed for the first time and applied to a pharmacokinetics study. Protein precipitation was used for pre-treatment of plasma samples, and solid phase extraction method was used for pre-treatment of urine samples. The chromatographic separation was achieved on a C(18) column using gradient elution in this study: A: 1% acetic acid aqueous solution, and B: acetonitrile. The whole analysis lasted for 10.5min and the gradient flow rate was 0.25mL/min constantly. The detection was performed of a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via a positive electrospray ionization source. The results were that the m/z ratios of monitored precursor ions and product ions of PPTA, M1 and M6 were 354.0→191.8, 356.0→148.7 and 358.0→148.7, respectively. From the standard curve, the concentration ranges of both PPTA and M1 in blood and urine samples were 0.1-500ng/mL and 0.1-200ng/mL, respectively; the concentration ranges of M6 in blood sample and urine sample were 0.2-500ng/mL and 0.2-200ng/mL, respectively; and the correlation coefficient of standard curve was r>0.99. A total of 31 healthy Chinese subjects participated in the pharmacokinetic study of single bolus intravenous injection of piperphentonamine hydrochloride. They were divided into three dosage groups and given 0.2, 0.4 and 0.6mg/kg of PPTA. After drug administration, concentrations of PPTA, M1 and M6 in human plasma and urine samples were determined to evaluation the pharmacokinetic characteristics of PPTA and its metabolites M1 and M6. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. PHARMACOKINETICS OF PIROXICAM IN CRANES (FAMILY GRUIDAE).

    Science.gov (United States)

    Keiper, Naomi L; Cox, Sherry K; Doss, Grayson A; Elsmo, Betsy; Franzen-Klein, Dana; Hartup, Barry K

    2017-09-01

    To investigate the pharmacokinetics of the nonsteroidal anti-inflammatory drug (NSAID) piroxicam in cranes, three brolgas (Antigone rubicunda) were administered piroxicam as a single oral dose at 0.5 mg/kg and 1.0 mg/kg during separate trials. Serial blood samples were collected for quantification of piroxicam in plasma. Piroxicam was readily absorbed at both dosages, and no adverse effects were observed. Plasma concentrations peaked at 3.67 hr with a concentration of 4.00 μg/ml for the lower dosage, and at 0.83 hr at 8.77 μg/ml for the higher dosage. Piroxicam may exhibit linear kinetics and dose proportionality in brolgas, but will require further study. Mean peak plasma concentrations in brolgas were comparable to concentrations demonstrated to be analgesic in humans. To the authors' knowledge, this study represents the first pharmacokinetic investigation of piroxicam in an avian species.

  17. Pharmacokinetics of Alternative Administration Routes of Melatonin

    DEFF Research Database (Denmark)

    Zetner, D.; Andersen, L. P.H.; Rosenberg, J.

    2016-01-01

    Background: Melatonin is traditionally administered orally but has a poor and variable bioavailability. This study aims to present an overview of studies investigating the pharmacokinetics of alternative administration routes of melatonin. Methods: A systematic literature search was performed...... and included experimental or clinical studies, investigating pharmacokinetics of alternative administration routes of melatonin in vivo. Alternative administration routes were defined as all administration routes except oral and intravenous. Results: 10 studies were included in the review. Intranasal....... Subcutaneous injection of melatonin displayed a rapid absorption rate compared to oral administration. Conclusion: Intranasal administration of melatonin has a large potential, and more research in humans is warranted. Transdermal application of melatonin has a possible use in a local application, due to slow...

  18. Clinical pharmacology of cannabinoids in early phase drug development

    NARCIS (Netherlands)

    Zuurman, Hillie Henka

    2008-01-01

    Although cannabis is especially known for its recreational use as a ‘soft drug’, its potential therapeutic properties have been recognized for hundreds of years. Since the isolation of THC from Cannabis sativa L, the discovery of cannabinoid receptors and their natural ligands (endocannabinoids) the

  19. Cannabinoids: New Promising Agents in the Treatment of Neurological Diseases

    Directory of Open Access Journals (Sweden)

    Sabrina Giacoppo

    2014-11-01

    Full Text Available Nowadays, Cannabis sativa is considered the most extensively used narcotic. Nevertheless, this fame obscures its traditional employ in native medicine of South Africa, South America, Turkey, Egypt and in many regions of Asia as a therapeutic drug. In fact, the use of compounds containing Cannabis and their introduction in clinical practice is still controversial and strongly limited by unavoidable psychotropic effects. So, overcoming these adverse effects represents the main open question on the utilization of cannabinoids as new drugs for treatment of several pathologies. To date, therapeutic use of cannabinoid extracts is prescribed in patients with glaucoma, in the control of chemotherapy-related vomiting and nausea, for appetite stimulation in patients with anorexia-cachexia syndrome by HIV, and for the treatment of multiple sclerosis symptoms. Recently, researcher efforts are aimed to employ the therapeutic potentials of Cannabis sativa in the modulation of cannabinoid receptor activity within the central nervous system, particularly for the treatment of neurodegenerative diseases, as well as psychiatric and non-psychiatric disorders. This review evaluates the most recent available data on cannabinoids utilization in experimental and clinical studies, and highlights their beneficial effects in the prevention of the main neurological diseases and for the clinical treatment of symptoms with them correlated.

  20. Drug- and cue-induced reinstatement of cannabinoid-seeking behaviour in male and female rats: influence of ovarian hormones.

    Science.gov (United States)

    Fattore, L; Spano, M S; Altea, S; Fadda, P; Fratta, W

    2010-06-01

    Animal and human studies have shown that sex and hormones are key factors in modulating addiction. Previously, we have demonstrated that self-administration of the cannabinoid CB(1) receptor agonist WIN55,212-2 (WIN; 12.5 microg.kg(-1) per infusion) is dependent on sex, intact female rats being more sensitive than males to the reinforcing properties of cannabinoids, and on the oestrous cycle, ovariectomized (OVX) females being less responsive than intact females. This follow-up study investigated whether sex and ovarian function also affect reinstatement of cannabinoid-seeking in rats after exposure to drug or cue priming. After priming with 0.15 or 0.3 mg.kg(-1) WIN, intact female rats exhibited stronger reinstatement than males and OVX females. Responses of intact female rats were higher than those of male and OVX rats even after priming with a drug-associated visual (Light) or auditory (Tone) cue, or a WIN + Light combination. However, latency to the first response did not differ between intact and OVX female rats, and males showed the longest latency to initiate lever-pressing activity. Our study provides compelling evidence for a pivotal role of sex and the oestrous cycle in modulating cannabinoid-seeking, with ovariectomy diminishing drug and cue-induced reinstatement. However, it is possible that sex differences during self-administration training are responsible for sex differences in reinstatement. Finding that not only drug primings but also acute exposure to drug-associated cues can reinstate responding in rats could have significant implications for the development of pharmacological and behavioural treatments of abstinent female and male marijuana smokers.

  1. Development and validation of a sensitive liquid chromatographic-tandem mass spectrometric method for the simultaneous analysis of granisetron and 7-hydroxy granisetron in human plasma and urine samples: application in a clinical pharmacokinetic study in pregnant subject.

    Science.gov (United States)

    Zhao, Yang; Chen, Hui-Jun; Caritis, Steve; Venkataramanan, Raman

    2016-02-01

    A liquid chromatography-tandem mass spectrometric method for the quantification of granisetron and its major metabolite, 7-hydroxy granisetron in human plasma and urine samples was developed and validated. Respective stable isotopically labeled granisetron and 7-hydroxy granisetron were used as internal standards (IS). Chromatography was performed using an Xselect HSS T3 analytical column with a mobile phase of 20% acetonitrile in water (containing 0.2 mM ammonium formate and 0.14% formic acid, pH 4) delivered in an isocratic mode. Tandem mass spectrometry operating in positive electrospray ionization mode with multiple reaction monitoring was used for quantification. The standard curves were linear in the concentration ranges of 0.5-100 ng/mL for granisetron and 0.1-100 ng/mL for 7-hydroxy granisetron in human plasma samples, and 2-2000 ng/mL for granisetron and 2-1000 ng/mL for 7-hydroxy granisetron in human urine samples, respectively. The accuracies were >85% and the precision as determined by the coefficient of variations was granisetron or 7-hydroxy granisetron in either plasma or urine samples. Granisetron was stable under various storage and experimental conditions. This validated method was successfully applied to a pharmacokinetic study after intravenous administration of 1 mg granisetron to a pregnant subject. Copyright © 2015 John Wiley & Sons, Ltd.

  2. New designer drugs (synthetic cannabinoids and synthetic cathinones): review of literature.

    Science.gov (United States)

    Cottencin, Olivier; Rolland, Benjamin; Karila, Laurent

    2014-01-01

    New designer drugs (synthetic cannabinoids and synthetic cathinones) are new "legal highs" that are sold online for recreational public or private use. Synthetic cannabinoids are psychoactive herbal and chemical products that mimic the effects of cannabis when used. These drugs are available on the Internet or in head shops as incense or air fresheners to circumvent the law. Cathinone is a naturally occurring beta-ketone amphetamine analog found in the leaves of the Catha edulis plant. Synthetic cathinones are phenylalkylamine derivatives that may possess amphetamine-like properties. These drugs are sold online as bath salts. Designer drugs are often labeled as "not for human consumption" to circumvent drug abuse legislation. The absence of legal risks, the ease of obtaining these drugs, the moderate cost, and the availability via the Internet are the main features that attract users, but the number of intoxicated people presenting with emergencies is increasing. There is evidence that negative health and social consequences may affect recreational and chronic users. The addictive potential of designer drugs is not negligible.

  3. CYP3A4 Mediates Oxidative Metabolism of the Synthetic Cannabinoid AKB-48.

    Science.gov (United States)

    Holm, Niels Bjerre; Nielsen, Line Marie; Linnet, Kristian

    2015-09-01

    Synthetic cannabinoid designer drugs have emerged as drugs of abuse during the last decade, and acute intoxication cases are documented in the scientific literature. Synthetic cannabinoids are extensively metabolized, but our knowledge of the involved enzymes is limited. Here, we investigated the metabolism of N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (AKB-48), a compound identified in herbal blends from 2012 and onwards. We screened for metabolite formation using a panel of nine recombinant cytochrome P450 (CYP) enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4) and compared the formed metabolites to human liver microsomal (HLM) incubations with specific inhibitors against CYP2D6, 2C19, and 3A4, respectively. The data reported here demonstrate CYP3A4 to be the major CYP enzyme responsible for the oxidative metabolism of AKB-48, preferentially performing the oxidation on the adamantyl moiety. Genetic polymorphisms are likely not important with regard to toxicity given the major involvement of CYP3A4. Adverse drug-drug interactions (DDIs) could potentially occur in cases with co-intake of strong CYP3A4 inhibitors, e.g., HIV antivirals and azole antifungal agents.

  4. Serum-dependent effects of tamoxifen and cannabinoids upon C6 glioma cell viability.

    Science.gov (United States)

    Jacobsson, S O; Rongård, E; Stridh, M; Tiger, G; Fowler, C J

    2000-12-15

    In the present study, the effects of the combination of tamoxifen ((Z)-2[p-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylamine citrate) and three cannabinoids (Delta(9)-tetrahydrocannabinol [Delta(9)-THC], cannabidiol, and anandamide [AEA]) upon the viability of C6 rat glioma cells was assessed at different incubation times and using different culturing concentrations of foetal bovine serum (FBS). Consistent with previous data for human glioblastoma cells, the tamoxifen sensitivity of the cells was increased as the FBS content of the culture medium was reduced from 10 to 0.4 and 0%. The cells expressed protein kinase C alpha and calmodulin (the concentration of which did not change significantly as the FBS concentration was reduced), but did not express estrogen receptors. Delta(9)-THC and cannabidiol, but not AEA, produced a modest reduction in cell viability after 6 days of incubation in serum-free medium, whereas no effects were seen in 10% FBS-containing medium. There was no observed synergy between the effects of tamoxifen and the cannabinoids upon cell viability.

  5. Lack of Exposure in a First-in-Man Study Due to Aldehyde Oxidase Metabolism: Investigated by Use of 14C-microdose, Humanized Mice, Monkey Pharmacokinetics, and In Vitro Methods.

    Science.gov (United States)

    Jensen, Klaus Gjervig; Jacobsen, Anne-Marie; Bundgaard, Christoffer; Nilausen, Dorrit Østergaard; Thale, Zia; Chandrasena, Gamini; Jørgensen, Martin

    2017-01-01

    Inclusion of a microdose of 14 C-labeled drug in the first-in-man study of new investigational drugs and subsequent analysis by accelerator mass spectrometry has become an integrated part of drug development at Lundbeck. It has been found to be highly informative with regard to investigations of the routes and rates of excretion of the drug and the human metabolite profiles according to metabolites in safety testing guidance and also when additional metabolism-related issues needed to be addressed. In the first-in-man study with the NCE Lu AF09535, contrary to anticipated, surprisingly low exposure was observed when measuring the parent compound using conventional bioanalysis. Parallel accelerator mass spectrometry analysis revealed that the low exposure was almost exclusively attributable to extensive metabolism. The metabolism observed in humans was mediated via a human specific metabolic pathway, whereas an equivalent extent of metabolism was not observed in preclinical species. In vitro, incubation studies in human liver cytosol revealed involvement of aldehyde oxidase (AO) in the biotransformation of Lu AF09535. In vivo, substantially lower plasma exposure of Lu AF09535 was observed in chimeric mice with humanized livers compared with control animals. In addition, Lu AF09535 exhibited very low oral bioavailability in monkeys despite relatively low clearance after intravenous administration in contrast to the pharmacokinetics in rats and dogs, both showing low clearance and high bioavailability. The in vitro and in vivo methods applied were proved useful for identifying and evaluating AO-dependent metabolism. Different strategies to integrate these methods for prediction of in vivo human clearance of AO substrates were evaluated. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  6. Clinical Pharmacokinetics of Paclitaxel Monotherapy

    DEFF Research Database (Denmark)

    Stage, Tore B; Bergmann, Troels K; Kroetz, Deanna L

    2018-01-01

    Paclitaxel is an anticancer agent efficacious in the treatment of ovarian, breast, and lung cancer. Due to a strong link between the pharmacokinetics and therapeutic efficacy of paclitaxel, we reviewed the literature on paclitaxel pharmacokinetics. Systematic data mining was performed to extract ...

  7. Stimulation of cannabinoid receptor 2 (CB2 suppresses microglial activation

    Directory of Open Access Journals (Sweden)

    Fernandez Francisco

    2005-12-01

    Full Text Available Abstract Background Activated microglial cells have been implicated in a number of neurodegenerative disorders, including Alzheimer's disease (AD, multiple sclerosis (MS, and HIV dementia. It is well known that inflammatory mediators such as nitric oxide (NO, cytokines, and chemokines play an important role in microglial cell-associated neuron cell damage. Our previous studies have shown that CD40 signaling is involved in pathological activation of microglial cells. Many data reveal that cannabinoids mediate suppression of inflammation in vitro and in vivo through stimulation of cannabinoid receptor 2 (CB2. Methods In this study, we investigated the effects of a cannabinoid agonist on CD40 expression and function by cultured microglial cells activated by IFN-γ using RT-PCR, Western immunoblotting, flow cytometry, and anti-CB2 small interfering RNA (siRNA analyses. Furthermore, we examined if the stimulation of CB2 could modulate the capacity of microglial cells to phagocytise Aβ1–42 peptide using a phagocytosis assay. Results We found that the selective stimulation of cannabinoid receptor CB2 by JWH-015 suppressed IFN-γ-induced CD40 expression. In addition, this CB2 agonist markedly inhibited IFN-γ-induced phosphorylation of JAK/STAT1. Further, this stimulation was also able to suppress microglial TNF-α and nitric oxide production induced either by IFN-γ or Aβ peptide challenge in the presence of CD40 ligation. Finally, we showed that CB2 activation by JWH-015 markedly attenuated CD40-mediated inhibition of microglial phagocytosis of Aβ1–42 peptide. Taken together, these results provide mechanistic insight into beneficial effects provided by cannabinoid receptor CB2 modulation in neurodegenerative diseases, particularly AD.

  8. Limited Sampling Strategy for Accurate Prediction of Pharmacokinetics of Saroglitazar: A 3-point Linear Regression Model Development and Successful Prediction of Human Exposure.

    Science.gov (United States)

    Joshi, Shuchi N; Srinivas, Nuggehally R; Parmar, Deven V

    2018-03-01

    Our aim was to develop and validate the extrapolative performance of a regression model using a limited sampling strategy for accurate estimation of the area under the plasma concentration versus time curve for saroglitazar. Healthy subject pharmacokinetic data from a well-powered food-effect study (fasted vs fed treatments; n = 50) was used in this work. The first 25 subjects' serial plasma concentration data up to 72 hours and corresponding AUC 0-t (ie, 72 hours) from the fasting group comprised a training dataset to develop the limited sampling model. The internal datasets for prediction included the remaining 25 subjects from the fasting group and all 50 subjects from the fed condition of the same study. The external datasets included pharmacokinetic data for saroglitazar from previous single-dose clinical studies. Limited sampling models were composed of 1-, 2-, and 3-concentration-time points' correlation with AUC 0-t of saroglitazar. Only models with regression coefficients (R 2 ) >0.90 were screened for further evaluation. The best R 2 model was validated for its utility based on mean prediction error, mean absolute prediction error, and root mean square error. Both correlations between predicted and observed AUC 0-t of saroglitazar and verification of precision and bias using Bland-Altman plot were carried out. None of the evaluated 1- and 2-concentration-time points models achieved R 2 > 0.90. Among the various 3-concentration-time points models, only 4 equations passed the predefined criterion of R 2 > 0.90. Limited sampling models with time points 0.5, 2, and 8 hours (R 2 = 0.9323) and 0.75, 2, and 8 hours (R 2 = 0.9375) were validated. Mean prediction error, mean absolute prediction error, and root mean square error were prediction of saroglitazar. The same models, when applied to the AUC 0-t prediction of saroglitazar sulfoxide, showed mean prediction error, mean absolute prediction error, and root mean square error model predicts the exposure of

  9. Pharmacokinetics, biodistribution and dosimetry of sup 99 Tc sup m (V)DMSA in humans with squamous cell carcinoma. [Dimercaptosuccinic acid

    Energy Technology Data Exchange (ETDEWEB)

    Watkinson, J.C.; Allen, S.; Lazarus, C.R.; Sinclair, J.; Blake, G.M.; Clarke, S.E.M. (Guy' s Hospital, London (UK))

    1990-05-01

    Technetium-99m ({sup 99}Tc{sup m})(V) dimercaptosuccinic acid (DMSA) is a new tumour imaging agent which has been used to evaluate squamous carcinoma (SCC) of the head and neck. This study evaluated the pharmacokinetics and biodistribution of {sup 99}Tc{sup m}(V)DMSA in patients with SCC and calculated the bone mass of a New Zealand White (NZW) rabbit. This data was then used to calculate the effective dose equivalent in man. A total of 16 patients were studied (5 with no tumour, 11 with tumour). {sup 99}Tc{sup m}(V)DMSA had a fast bi-exponential blood clearance in patients with no tumour (30 and 401 min) and patients with tumour (30 and 387 min) with no significant difference (p > 0.05) between the two groups. {sup 99}Tc{sup m}(V)DMSA had a fast cumulative urine excretion with mean half-times in non-tumour and tumour patients of 183 min and 244 min respectively. There was no significant difference (p > 0.05) between these two latter groups. The effective dose equivalent of {sup 99}Tc{sup m}(V)DMSA in man is 5.1 {mu}Sv/MBq. (author).

  10. Relative contributions of the major human CYP450 to the metabolism of icotinib and its implication in prediction of drug-drug interaction between icotinib and CYP3A4 inhibitors/inducers using physiologically based pharmacokinetic modeling.

    Science.gov (United States)

    Chen, Jia; Liu, Dongyang; Zheng, Xin; Zhao, Qian; Jiang, Ji; Hu, Pei

    2015-06-01

    Icotinib is an anticancer drug, but relative contributions of CYP450 have not been identified. This study was carried out to identify the contribution percentage of CYP450 to icotinib and use the results to develop a physiologically based pharmacokinetic (PBPK) model, which can help to predict drug-drug interaction (DDI). Human liver microsome (HLM) and supersome using relative activity factor (RAF) were employed to determine the relative contributions of the major human P450 to the net hepatic metabolism of icotinib. These values were introduced to develop a PBPK model using SimCYP. The model was validated by the observed data in a Phase I clinical trial in Chinese healthy subjects. Finally, the model was used to simulate the DDI with ketoconazole or rifampin. Final contribution of CYP450 isoforms determined by HLM showed that CYP3A4 provided major contributions to the metabolism of icotinib. The percentage contributions of the P450 to the net hepatic metabolism of icotinib were determined by HLM inhibition assay and RAF. The AUC ratio under concomitant use of ketoconazole and rifampin was 3.22 and 0.55, respectively. Percentage of contribution of CYP450 to icotinib metabolism was calculated by RAF. The model has been proven to fit the observed data and is used in predicting icotinib-ketoconazole/rifampin interaction.

  11. The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation

    Science.gov (United States)

    Bow, Eric W.; Rimoldi, John M.

    2016-01-01

    The cannabinoids are members of a deceptively simple class of terpenophenolic secondary metabolites isolated from Cannabis sativa highlighted by (−)-Δ9-tetrahydrocannabinol (THC), eliciting distinct pharmacological effects mediated largely by cannabinoid receptor (CB1 or CB2) signaling. Since the initial discovery of THC and related cannabinoids, synthetic and semisynthetic classical cannabinoid analogs have been evaluated to help define receptor binding modes and structure–CB1/CB2 functional activity relationships. This perspective will examine the classical cannabinoids, with particular emphasis on the structure–activity relationship of five regions: C3 side chain, phenolic hydroxyl, aromatic A-ring, pyran B-ring, and cyclohexenyl C-ring. Cumulative structure–activity relationship studies to date have helped define the critical structural elements required for potency and selectivity toward CB1 and CB2 and, more importantly, ushered the discovery and development of contemporary nonclassical cannabinoid modulators with enhanced physicochemical and pharmacological profiles. PMID:27398024

  12. Microdosing of a Carbon-14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages

    NARCIS (Netherlands)

    Vlaming, M.L.; Duijn, E. van; Dillingh, M.R.; Brands, R.; Windhorst, A.D.; Hendrikse, N.H.; Bosgra, S.; Burggraaf, J.; Koning, M.C. de; Fidder, A.; Mocking, J.A.; Sandman, H.; Ligt, R.A. de; Fabriek, B.O.; Pasman, W.J.; Seinen, W.; Alves, T.; Carrondo, M.; Peixoto, C.; Peeters, P.A.; Vaes, W.H.

    2015-01-01

    Preclinical development of new biological entities (NBEs), such as human protein therapeutics, requires considerable expenditure of time and costs. Poor prediction of pharmacokinetics in humans further reduces net efficiency. In this study, we show for the first time that pharmacokinetic data of

  13. Drugs in space: Pharmacokinetics and pharmacodynamics in astronauts.

    Science.gov (United States)

    Kast, Johannes; Yu, Yichao; Seubert, Christoph N; Wotring, Virginia E; Derendorf, Hartmut

    2017-11-15

    Space agencies are working intensely to push the current boundaries of human spaceflight by sending astronauts deeper into space than ever before, including missions to Mars and asteroids. Spaceflight alters human physiology due to fluid shifts, muscle and bone loss, immune system dysregulation, and changes in the gastrointestinal tract and metabolic enzymes. These alterations may change the pharmacokinetics and/or pharmacodynamics of medications used by astronauts and subsequently might impact drug efficacy and safety. Most commonly, medications are administered during space missions to treat sleep disturbances, allergies, space motion sickness, pain, and sinus congestion. These medications are administered under the assumption that they act in a similar way as on Earth, an assumption that has not been investigated systematically yet. Few inflight pharmacokinetic data have been published, and pharmacodynamic and pharmacokinetic/pharmacodynamic studies during spaceflight are also lacking. Therefore, bed-rest models are often used to simulate physiological changes observed during microgravity. In addition to pharmacokinetic/pharmacodynamic changes, decreased drug and formulation stability in space could also influence efficacy and safety of medications. These alterations along with physiological changes and their resulting pharmacokinetic and pharmacodynamic effects must to be considered to determine their ultimate impact on medication efficacy and safety during spaceflight. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Comparison of high-pressure liquid chromatography and microbiological assay for determination of ciprofloxacin tablets in human plasma employed in bioequivalence and pharmacokinetics study.

    Science.gov (United States)

    Khan, Muhammad Khalid; Khan, Muhammad Farid; Mustafa, Ghulam; Sualah, Mohammed

    2012-01-01

    Ciprofloxacin was given orally to 28 healthy male volunteers for single oral dose of 500mg; Plasma samples were collected at different time's interval between 0 and 12h and analyzed both by high pressure liquid chromatography and by a microbiological assay. The detection limits (LOD) were 0.02μg/ml and 0.1μg/ml, for both methods respectively. For each method, coefficients of variation (R(2)) were 0.9995 and 0.9918 in plasma and limit of quantitation (LOQ).02 and 0.5μg/ml. The Comparison of means maximum concentration 2.68 μg/ml at 1.5 hr for test and 2.43 μg/ml are attain in HPLC method of Reference at 2hrs respectively. The plasma concentrations measured by microbiological assay of reference tablet are 3.95μg/ml (mean ± SE) at 1 hour and 3.80μg/ml (mean ± SE) at 1 hour. The concentrations in plasma measured by microbiological method were markedly higher than the high-pressure liquid chromatography values which indicates the presence of antimicrobially active metabolites. The mean ± SE values of pharmacokinetic parameters calculated by HPLC method, for total area under the curve (AUC 0-oo) were 13.11, and 11.91 h.mg/l for both test and reference tablets respectively. The mean ± SE values of clearance measured in l/h were 44.91 and 48.42 respectively. The elimination rate constant Kel [l/h] showed 0.17 l/h for test and 0.15 l/h reference tablets and likewise, absorption half-life expressed in hours shown 0.67 h for test and 1.04 h for reference respectively. The Mean Residence Time for test is 5.48 h and 5.49 h for reference. The mean ± SE values of pharmacokinetic parameters (Microbiological assay) for total area under the curve (AUC 0-oo) were 22.11 and 19.33 h.mg/l for both test and reference tablets respectively. The mean ± SE values of clearance measured in l/h were 29.02 and 31.63 respectively. The elimination rate constant Kel [l/h] showed 0.21 l/h for test and 0.20 l/h reference tablets and likewise, absorption half-life expressed in hours shown

  15. Assessing human variability in kinetics for exposures to multiple environmental chemicals: a physiologically based pharmacokinetic modeling case study with dichloromethane, benzene, toluene, ethylbenzene, and m-xylene.

    Science.gov (United States)

    Valcke, Mathieu; Haddad, Sami

    2015-01-01

    The objective of this study was to compare the magnitude of interindividual variability in internal dose for inhalation exposure to single versus multiple chemicals. Physiologically based pharmacokinetic models for adults (AD), neonates (NEO), toddlers (TODD), and pregnant women (PW) were used to simulate inhalation exposure to "low" (RfC-like) or "high" (AEGL-like) air concentrations of benzene (Bz) or dichloromethane (DCM), along with various levels of toluene alone or toluene with ethylbenzene and xylene. Monte Carlo simulations were performed and distributions of relevant internal dose metrics of either Bz or DCM were computed. Area under the blood concentration of parent compound versus time curve (AUC)-based variability in AD, TODD, and PW rose for Bz when concomitant "low" exposure to mixtures of increasing complexities occurred (coefficient of variation (CV) = 16-24%, vs. 12-15% for Bz alone), but remained unchanged considering DCM. Conversely, AUC-based CV in NEO fell (15 to 5% for Bz; 12 to 6% for DCM). Comparable trends were observed considering production of metabolites (AMET), except for NEO's CYP2E1-mediated metabolites of Bz, where an increased CV was observed (20 to 71%). For "high" exposure scenarios, Cmax-based variability of Bz and DCM remained unchanged in AD and PW, but decreased in NEO (CV= 11-16% to 2-6%) and TODD (CV= 12-13% to 7-9%). Conversely, AMET-based variability for both substrates rose in every subpopulation. This study analyzed for the first time the impact of multiple exposures on interindividual variability in toxicokinetics. Evidence indicates that this impact depends upon chemical concentrations and biochemical properties, as well as the subpopulation and internal dose metrics considered.

  16. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials

    OpenAIRE

    Lynch, Mary E; Campbell, Fiona

    2011-01-01

    Effective therapeutic options for patients living with chronic pain are limited. The pain relieving effect of cannabinoids remains unclear. A systematic review of randomized controlled trials (RCTs) examining cannabinoids in the treatment of chronic non-cancer pain was conducted according to the PRISMA statement update on the QUORUM guidelines for reporting systematic reviews that evaluate health care interventions. Cannabinoids studied included smoked cannabis, oromucosal extracts of cannabi...

  17. Cannabinoid-Induced Changes in the Activity of Electron Transport Chain Complexes of Brain Mitochondria.

    Science.gov (United States)

    Singh, Namrata; Hroudová, Jana; Fišar, Zdeněk

    2015-08-01

    The aim of this study was to investigate changes in the activity of individual mitochondrial respiratory chain complexes (I, II/III, IV) and citrate synthase induced by pharmacologically different cannabinoids. In vitro effects of selected cannabinoids on mitochondrial enzymes were measured in crude mitochondrial fraction isolated from pig brain. Both cannabinoid receptor agonists, Δ(9)-tetrahydrocannabinol, anandamide, and R-(+)-WIN55,212-2, and antagonist/inverse agonists of cannabinoid receptors, AM251, and cannabidiol were examined in pig brain mitochondria. Different effects of these cannabinoids on mitochondrial respiratory chain complexes and citrate synthase were found. Citrate synthase activity was decreased only by Δ(9)-tetrahydrocannabinol and AM251. Significant increase in the complex I activity was induced by anandamide. At micromolar concentration, all the tested cannabinoids inhibited the activity of electron transport chain complexes II/III and IV. Stimulatory effect of anandamide on activity of complex I may participate on distinct physiological effects of endocannabinoids compared to phytocannabinoids or synthetic cannabinoids. Common inhibitory effect of cannabinoids on activity of complex II/III and IV confirmed a non-receptor-mediated mechanism of cannabinoid action on individual components of system of oxidative phosphorylation.

  18. Are cannabinoids effective for Parkinson’s disease?

    Directory of Open Access Journals (Sweden)

    Gonzalo A Bravo-Soto

    2017-06-01

    Full Text Available Resumen Se postula que los cannabinoides pudieran tener beneficios en la enfermedad de Parkinson. No obstante, su real efectividad clínica aún es discutida. Para responder a esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Identificamos seis revisiones sistemáticas que en conjunto incluyen ocho estudios, de los cuales cuatro corresponden a ensayos aleatorizados. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios y preparamos tablas de resumen de los resultados utilizando el método GRADE. Concluimos que los cannabinoides probablemente no disminuyen los síntomas ni las discinesias, y se asocian a efectos adversos frecuentes en pacientes con enfermedad de Parkinson

  19. The Wide and Unpredictable Scope of Synthetic Cannabinoids Toxicity

    Directory of Open Access Journals (Sweden)

    Jose Orsini

    2015-01-01

    Full Text Available Drug use and abuse continue to be a large public health concern worldwide. Over the past decade, novel or atypical drugs have emerged and become increasingly popular. In the recent past, compounds similar to tetrahydrocannabinoid (THC, the active ingredient of marijuana, have been synthetically produced and offered commercially as legal substances. Since the initial communications of their abuse in 2008, few case reports have been published illustrating the misuse of these substances with signs and symptoms of intoxication. Even though synthetic cannabinoids have been restricted, they are still readily available across USA and their use has been dramatically increasing, with a concomitant increment in reports to poison control centers and emergency department (ED visits. We describe a case of acute hypoxemic/hypercapnic respiratory failure as a consequence of acute congestive heart failure (CHF developed from myocardial stunning resulting from a non-ST-segment elevation myocardial infarction (MI following the consumption of synthetic cannabinoids.

  20. Endogenous and Synthetic Cannabinoids as Therapeutics in Retinal Disease

    Directory of Open Access Journals (Sweden)

    Despina Kokona

    2016-01-01

    Full Text Available The functional significance of cannabinoids in ocular physiology and disease has been reported some decades ago. In the early 1970s, subjects who smoked Cannabis sativa developed lower intraocular pressure (IOP. This led to the isolation of phytocannabinoids from this plant and the study of their therapeutic effects in glaucoma. The main treatment of this disease to date involves the administration of drugs mediating either the decrease of aqueous humour synthesis or the increase of its outflow and thus reduces IOP. However, the reduction of IOP is not sufficient to prevent visual field loss. Retinal diseases, such as glaucoma and diabetic retinopathy, have been defined as neurodegenerative diseases and characterized by ischemia-induced excitotoxicity and loss of retinal neurons. Therefore, new therapeutic strategies must be applied in order to target retinal cell death, reduction of visual acuity, and blindness. The aim of the present review is to address the neuroprotective and therapeutic potential of cannabinoids in retinal disease.

  1. Loss of cannabinoid receptor CB1 induces preterm birth.

    Directory of Open Access Journals (Sweden)

    Haibin Wang

    2008-10-01

    Full Text Available Preterm birth accounting approximate 10% of pregnancies in women is a tremendous social, clinical and economic burden. However, its underlying causes remain largely unknown. Emerging evidence suggests that endocannabinoid signaling via cannabinoid receptor CB1 play critical roles in multiple early pregnancy events in both animals and humans. Since our previous studies demonstrated that loss of CB1 defers the normal implantation window in mice, we surmised that CB1 deficiency would influence parturition events.Exploiting mouse models with targeted deletion of Cnr1, Cnr2 and Ptgs1 encoding CB1, CB2 and cyclooxygenase-1, respectively, we examined consequences of CB1 or CB2 silencing on the onset of parturition. We observed that genetic or pharmacological inactivation of CB1, but not CB2, induced preterm labor in mice. Radioimmunoassay analysis of circulating levels of ovarian steroid hormones revealed that premature birth resulting from CB1 inactivation is correlated with altered progesterone/estrogen ratios prior to parturition. More strikingly, the phenotypic defects of prolonged pregnancy length and parturition failure in mice missing Ptgs1 were corrected by introducing CB1 deficiency into Ptgs1 null mice. In addition, loss of CB1 resulted in aberrant secretions of corticotrophin-releasing hormone and corticosterone during late gestation. The pathophysiological significance of this altered corticotrophin-releasing hormone-driven endocrine activity in the absence of CB1 was evident from our subsequent findings that a selective corticotrophin-releasing hormone antagonist was able to restore the normal parturition timing in Cnr1 deficient mice. In contrast, wild-type females receiving excessive levels of corticosterone induced preterm birth.CB1 deficiency altering normal progesterone and estrogen levels induces preterm birth in mice. This defect is independent of prostaglandins produced by cyclooxygenase-1. Moreover, CB1 inactivation resulted in

  2. Marijuana and cannabinoid regulation of brain reward circuits

    OpenAIRE

    Lupica, Carl R; Riegel, Arthur C; Hoffman, Alexander F

    2004-01-01

    The reward circuitry of the brain consists of neurons that synaptically connect a wide variety of nuclei. Of these brain regions, the ventral tegmental area (VTA) and the nucleus accumbens (NAc) play central roles in the processing of rewarding environmental stimuli and in drug addiction. The psychoactive properties of marijuana are mediated by the active constituent, Δ9-THC, interacting primarily with CB1 cannabinoid receptors in a large number of brain areas. However, it is the activation o...

  3. Rhabdomyolysis and Renal Insufficiency Due to Synthetic Cannabinoid Intoxication

    Directory of Open Access Journals (Sweden)

    Semiha Orhan

    2017-12-01

    Full Text Available Bonsai is the street name of synthetic marijuana, which is a psychoactive substance. Since synthetic cannabinoids are easily accessible and cheap, their use is becoming widespread day by day. It can cause not only various clinical symptoms but also severe rhabdomyolysis. In this case, with severe rhabdomyolysis, we tried to discuss the treatment challenges of the patient examined in intensive care unit with the history of bonsai use.

  4. Multiple sleep alterations in mice lacking cannabinoid type 1 receptors.

    Directory of Open Access Journals (Sweden)

    Alessandro Silvani

    Full Text Available Cannabinoid type 1 (CB1 receptors are highly expressed in the brain and play a role in behavior control. Endogenous cannabinoid signaling is modulated by high-fat diet (HFD. We investigated the consequences of congenital lack of CB1 receptors on sleep in mice fed standard diet (SD and HFD. CB1 cannabinoid receptor knock-out (KO and wild-type (WT mice were fed SD or HFD for 4 months (n = 9-10 per group. Mice were instrumented with electroencephalographic (EEG and electromyographic electrodes. Recordings were performed during baseline (48 hours, sleep deprivation (gentle handling, 6 hours, sleep recovery (18 hours, and after cage switch (insomnia model paradigm, 6 hours. We found multiple significant effects of genotype on sleep. In particular, KO spent more time awake and less time in non-rapid-eye-movement sleep (NREMS and rapid-eye-movement sleep (REMS than WT during the dark (active period but not during the light (rest period, enhancing the day-night variation of wake-sleep amounts. KO had slower EEG theta rhythm during REMS. REMS homeostasis after sleep deprivation was less effective in KO than in WT. Finally, KO habituated more rapidly to the arousing effect of the cage-switch test than WT. We did not find any significant effects of diet or of diet x genotype interaction on sleep. The occurrence of multiple sleep alterations in KO indicates important roles of CB1 cannabinoid receptors in limiting arousal during the active period of the day, in sleep regulation, and in sleep EEG in mice.

  5. Overvej cannabinoid hyperemesis-syndrom ved recidiverende opkastninger

    DEFF Research Database (Denmark)

    Nordholm-Carstensen, Andreas

    2014-01-01

    Cannabinoid hyperemesis syndrome (CHS) is characterised by unrelenting nausea, recurrent vomiting, abdominal pain and compulsive, hot bathing behaviour. The symptoms contrast the traditional effects associated with cannabis use. We report a "textbook example" of a 26-year-old man with CHS. CHS...... is an important differential diagnosis to consider in patients with similar symptoms and the distinctive symptom relief in hot water. Early recognition may prevent extensive, unnecessary medical examinations and frequent hospital admissions....

  6. Simultaneous quantification of acetaminophen and five acetaminophen metabolites in human plasma and urine by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry: Method validation and application to a neonatal pharmacokinetic study.

    Science.gov (United States)

    Cook, Sarah F; King, Amber D; van den Anker, John N; Wilkins, Diana G

    2015-12-15

    Drug metabolism plays a key role in acetaminophen (paracetamol)-induced hepatotoxicity, and quantification of acetaminophen metabolites provides critical information about factors influencing susceptibility to acetaminophen-induced hepatotoxicity in clinical and experimental settings. The aims of this study were to develop, validate, and apply high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) methods for simultaneous quantification of acetaminophen, acetaminophen-glucuronide, acetaminophen-sulfate, acetaminophen-glutathione, acetaminophen-cysteine, and acetaminophen-N-acetylcysteine in small volumes of human plasma and urine. In the reported procedures, acetaminophen-d4 and acetaminophen-d3-sulfate were utilized as internal standards (IS). Analytes and IS were recovered from human plasma (10μL) by protein precipitation with acetonitrile. Human urine (10μL) was prepared by fortification with IS followed only by sample dilution. Calibration concentration ranges were tailored to literature values for each analyte in each biological matrix. Prepared samples from plasma and urine were analyzed under the same HPLC-ESI-MS/MS conditions, and chromatographic separation was achieved through use of an Agilent Poroshell 120 EC-C18 column with a 20-min run time per injected sample. The analytes could be accurately and precisely quantified over 2.0-3.5 orders of magnitude. Across both matrices, mean intra- and inter-assay accuracies ranged from 85% to 112%, and intra- and inter-assay imprecision did not exceed 15%. Validation experiments included tests for specificity, recovery and ionization efficiency, inter-individual variability in matrix effects, stock solution stability, and sample stability under a variety of storage and handling conditions (room temperature, freezer, freeze-thaw, and post-preparative). The utility and suitability of the reported procedures were illustrated by analysis of pharmacokinetic samples

  7. Trace analysis of three antihistamines in human urine by on-line single drop liquid-liquid-liquid microextraction coupled to sweeping micellar electrokinetic chromatography and its application to pharmacokinetic study.

    Science.gov (United States)

    Gao, Wenhua; Chen, Yunsheng; Chen, Gaopan; Xi, Jing; Chen, Yaowen; Yang, Jianying; Xu, Ning

    2012-09-01

    A rapid and efficient dual preconcentration method of on-line single drop liquid-liquid-liquid microextraction (SD-LLLME) coupled to sweeping micellar electrokinetic chromatography (MEKC) was developed for trace analysis of three antihistamines (mizolastine, chlorpheniramine and pheniramine) in human urine. Three analytes were firstly extracted from donor phase (4 mL urine sample) adjusted to alkaline condition (0.5 M NaOH). The unionized analytes were subsequently extracted into a drop of n-octanol layered over the urine sample, and then into a microdrop of acceptor phase (100 mM H(3)PO(4)) suspended from a capillary inlet. The enriched acceptor phase was on-line injected into capillary with a height difference and then analyzed directly by sweeping MEKC. Good linear relationships were obtained for all analytes in a range of 6.25 × 10(-6) to 2.5 × 10(-4)g/L with correlation coefficients (r) higher than 0.987. The proposed method achieved limits of detections (LOD) varied from 1.2 × 10(-7) to 9.5 × 10(-7)g/L based on a signal-to-noise of 3 (S/N=3) with 751- to 1372-fold increases in detection sensitivity for analytes, and it was successfully applied to the pharmacokinetic study of three antihistamines in human urine after an oral administration. The results demonstrated that this method was a promising combination for the rapid trace analysis of antihistamines in human urine with the advantages of operation simplicity, high enrichment factor and little solvent consumption. Copyright © 2012 Elsevier B.V. All rights reserved.

  8. Pharmacokinetics of clomipramine during pregnancy

    NARCIS (Netherlands)

    Ter Horst, P G J; Proost, J H; Smit, J P; Vries, M T; de Jong-van den Berg, Lolkje; Wilffert, B

    2015-01-01

    Clomipramine is one of the drugs for depression during pregnancy; however, pharmacokinetic data of clomipramine and its active metabolite desmethylclomipramine in this vulnerable period are lacking. In this study, we describe clomipramine and desmethylclomipramine concentrations including their

  9. A comparative pharmacokinetic study of a fixed dose combination for essential hypertensive patients: a randomized crossover study in healthy human volunteers.

    Science.gov (United States)

    Gorain, B; Choudhury, H; Halder, D; Sarkar, A K; Sarkar, P; Biswas, E; Ghosh, B; Pal, T K

    2013-04-01

    This study was aimed to investigate the relative bioavailability of fixed-dose-combination (FDC) product of amlodipine, telmisartan and hydrochlorothiazide with individual marketed products in healthy male volunteers. Control of blood pressure with fixed dose combination of the above drugs acting through different mechanism have a benefit of convenient dosing in terms of compliance, lower the dose and subsequently reduce the side effects. The authors investigated the relative bioavailability under a fasting state of the 3 drugs in a randomized, open-label, 2-treatment, 2-period, 2-sequence, crossover bioequivalence study with a washout period of 21 days. Plasma concentration of the analytes were assayed in timed samples with a simple, highly sensitive and rapid validated method using HPLC coupled to tandem mass spectrometry that had a lower limit of quantification of 1 ng/mL for all the 3 components. Test and reference formulations gave a mean Cmax of 5.234±0.914 ng/mL and 4.991±0.563 ng/mL, 108.839±13.601 ng/mL and 114.783±12.315 ng/mL and 97.814±10.779 ng/mL and 93.731±10.018 ng/mL for amlodipine, telmisartan and hydrochlorothiazide respectively. The AUC0-t of amlodipine, telmisartan and hydrochlorothiazide was 161.484 ng.h/mL, 1 917.644 ng.h/mL and 822.847 ng.h/mL for test formulation and 162.108 ng.h/mL, 2 014.764 ng.h/mL and 829.323 ng.h/mL for reference in the fasting state. The 90% confidence intervals for the test/reference ratio of the pharmacokinetic parameters in fasting state (mean Cmax, AUC0-t, and AUC0-∞) were within the acceptable range of 80.00-125.00. Thus, these findings clearly indicate that the FDC product is bioequivalent with the individual marketed products in terms of rate and extent of drug absorption and is well tolerated with no significant adverse reactions. © Georg Thieme Verlag KG Stuttgart · New York.

  10. Pharmacokinetics and brain distribution in non human primate of R(-)[123I]DOI, A 5HT2A/2C serotonin agonist

    International Nuclear Information System (INIS)

    Zea-Ponce, Yolanda; Kegeles, Lawrence S.; Guo, Ningning; Raskin, Leonid; Bakthavachalam, Venkatesalu; Laruelle, Marc

    2002-01-01

    Our goal was to synthesize with high specific activity R(-)-1-(2,5-Dimethoxy-4-[ 123 I]iodophenyl)-2-aminopropane [R(-)[ 123 I]DOI], an in vitro potent and selective 5-HT 2A/2C serotonin agonist, and study in vivo its plasma pharmacokinetics and brain distribution in baboon by SPECT. The purpose was to evaluate this radiotracer as a potential tool in discerning the role of the agonist high affinity state of 5-HT 2 receptors in depression and other neurological disorders. The radiotracer was prepared by electrophilic radioiodination of the N-trifluoroacetyl precursor of R(-)-1-(2,5-Dimethoxyphenyl)-2-aminopropane [R(-)DMA-TFA] with high-purity sodium [ 123 I]iodide in the presence of chloramine-T, followed by amino deprotection with KOH in isopropanol (labeling yield: 73%, radiochemical yield: 62%, radiochemical purity: 99%). In vivo studies in baboon showed high accumulation of radioactivity in thalamus, the frontoparietal cortex, temporal, occipital and the striatum regions, with slightly lower accumulation in the midbrain and cerebellum. Ketanserin did not displaced the radioactivity in any of these brain regions. Plasma metabolite analysis was performed using methanol protein precipitation, the methanol fractions contained from 68% to 92% of the mixture of a labeled metabolite and parent compound. The recovery coefficient of unmetabolized R(-)[ 123 I]DOI was 68%. The percent parent compound present in the extracted fraction, measured by HPLC, decreased gradually with time from 99.8% to 0.3% still present after 4.7 hours post injection whereas the percentage of the only one detected metabolite increased conversely. Free fraction determination (f 1 ), was 31±0.9% (n=3). For comparison purposes, ex-vivo brain distribution, displacement and metabolite analysis was also carried out in rodents. Although R(-)[ 123 I]DOI displayed good brain uptake and localized in serotonergic areas of the brain, its target to non target ratio and its insensitivity to ketanserin

  11. Cannabinoids and glucocorticoids modulate emotional memory after stress.

    Science.gov (United States)

    Akirav, Irit

    2013-12-01

    Bidirectional and functional relationships between glucocorticoids and the endocannabinoid system have been demonstrated. Here, I review the interaction between the endocannabinoid and glucocorticoid/stress systems. Specifically, stress is known to produce rapid changes in endocannabinoid signaling in stress-responsive brain regions. In turn, the endocannabinoid system plays an important role in the downregulation and habituation of hypothalamic-pituitary-adrenocortical (HPA) axis activity in response to stress. Glucocorticoids also recruit the endocannabinoid system to exert rapid negative feedback control of the HPA axis during stress. It became increasingly clear, however, that cannabinoid CB1 receptors are also abundantly expressed in the basolateral amygdala (BLA) and other limbic regions where they modulate emotional arousal effects on memory. Enhancing cannabinoids signaling using exogenous CB1 receptor agonists prevent the effects of acute stress on emotional memory. I propose a model suggesting that the ameliorating effects of exogenously administered cannabinoids on emotional learning after acute stress are mediated by the decrease in the activity of the HPA axis via GABAergic mechanisms in the amygdala. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. Pharmacological effects of cannabinoids on learning and memory in Lymnaea.

    Science.gov (United States)

    Sunada, Hiroshi; Watanabe, Takayuki; Hatakeyama, Dai; Lee, Sangmin; Forest, Jeremy; Sakakibara, Manabu; Ito, Etsuro; Lukowiak, Ken

    2017-09-01

    Cannabinoids are hypothesized to play an important role in modulating learning and memory formation. Here, we identified mRNAs expressed in Lymnaea stagnalis central nervous system that encode two G-protein-coupled receptors ( Lymnaea CBr-like 1 and 2) that structurally resemble mammalian cannabinoid receptors (CBrs). We found that injection of a mammalian CBr agonist WIN 55,212-2 (WIN 55) into the snail before operant conditioning obstructed learning and memory formation. This effect of WIN 55 injection persisted for at least 4 days following its injection. A similar obstruction of learning and memory occurred when a severe traumatic stimulus was delivered to L. stagnalis In contrast, injection of a mammalian CBr antagonist AM 251 enhanced long-term memory formation in snails and reduced the duration of the effects of the severe traumatic stressor on learning and memory. Neither WIN 55 nor AM 251 altered normal homeostatic aerial respiratory behaviour elicited in hypoxic conditions. Our results suggest that putative cannabinoid receptors mediate stressful stimuli that alter learning and memory formation in Lymnaea This is also the first demonstration that putative CBrs are present in Lymnaea and play a key role in learning and memory formation. © 2017. Published by The Company of Biologists Ltd.

  13. A Modified Method for Determination of Lumefantrine in Human Plasma by HPLC-UV and Combination of Protein Precipitation and Solid-Phase Extraction: Application to a Pharmacokinetic Study

    Directory of Open Access Journals (Sweden)

    Liusheng Huang

    2010-03-01

    Full Text Available An HPLC-UV method was developed and validated for the determination of lumefantrine in human plasma. Lumefantrine and its internal standard halofantrine were extracted from plasma samples using protein precipitation with acetonitrile (0.2% perchloric acid followed by solid-phase extraction with Hypersep C8 cartridges. Chromatographic separation was performed on a Zorbax SB-CN HPLC column (3.0 × 150 mm, 3.5 μm with water/methanol (0.1% TFA as the mobile phases in a gradient elution mode. Detection was performed using UV/vis detector at λ = 335 nm. The method showed to be linear over a range of 50–10,000 ng/mL with acceptable intra- and inter-day precision and accuracy. The mean recoveries were 88.2% for lumefatrine and 84.5% for the I.S. The internal standard halofantrine is readily available from commercial sources. This method was successfully applied to a pharmacokinetic interaction study between a first-line antimalarial combination (artemether—lumefantrine and antiretroviral therapy.

  14. Simultaneous determination and pharmacokinetics of danshensu, protocatechuic aldehyde, 4-hydroxy-3-methyloxyphenyl lactic acid and protocatechuic acid in human plasma by LC-MS/MS after oral administration of Compound Danshen Dripping Pills.

    Science.gov (United States)

    Li, Wei; Zhou, Hongjie; Chu, Yang; Wang, Xiangyang; Luo, Ruizhi; Yang, Liu; Polachi, Navaneethakrishnan; Li, Xiao; Chen, Min; Huang, Luqi; Yan, Xueying; Guo, Zhixin; Sun, He

    2017-10-25

    Compound Danshen Dripping Pills (CDDP), a herbal patent medicine, is widely used in China for the prevention and treatment of cardiovascular diseases. A simple, sensitive and reliable method for simultaneous determination of danshensu (DSS), protocatechuic aldehyde (PCA), and their related metabolites, 4-hydroxy-3-methyloxyphenyl lactic acid (HMLA) and protocatechuic acid (PAA) in human plasma was developed and validated based on liquid chromatography tandem mass spectrometry (LC-MS/MS). The analytes and internal standard (IS), vanillic acid (VAA), were extracted from plasma with ethyl acetate and separated on a C 18 column by using the mobile phase consisted of methanol-0.1% formic acid via gradient elution. The electrospray ionization (ESI) source was applied and operated under the multiple reaction monitoring (MRM) mode. The linear calibration curves were obtained at the concentration ranges of 0.46-1000ng/mL for DSS and PAA, and 1.38-1000ng/mL for PCA and HMLA, respectively. The inter- and intra-day precisions (RSD%) were less than 13.5%, and the accuracy (±RE%) was within 13.4%. The described method was successfully applied for the clinical pharmacokinetics of CDDP in Chinese healthy volunteers. Copyright © 2017. Published by Elsevier B.V.

  15. Whole body [O-15]water pharmacokinetics measured in blood

    NARCIS (Netherlands)

    Maguire, RP; Spyrou, NM; Leenders, KL

    A simple pharmacokinetic model to explain the time course of [0-15]water in human whole blood after bolus injection is described. The model has been derived from measurements in twelve healthy volunteers who were measured repeatedly, resulting in 67 datasets, made in the context of PET blood flow

  16. Comparative Pharmacokinetics of Perfluorononanoic acid in Rats and Mice*.

    Science.gov (United States)

    Perfluorononanoic acid (PFNA), a member of the perfluoroalkyl acids (PFAAs) is found at low concentrations in the environment, but is also detectable in humans and wildlife. Previous studies have examined the pharmacokinetics (PK) of lower carbon-chain PFAAs, such as perfluorobut...

  17. Analysis of Cannabinoids and Their Metabolites in Human Urine

    OpenAIRE

    Wei, Binnian; Wang, Lanqing; Blount, Benjamin C.

    2015-01-01

    Biologically monitoring marijuana exposure from active and passive use requires both a wide linear range and sensitive detection. We have developed and validated a multifunctional method using ultrahigh performance liquid chromatography coupled with tandem mass spectrometry (UHPLC–MS/MS) for analysis of urinary Δ9-tetrahydrocannabinol (THC), cannabidiol and cannabinol, and two major metabolites of THC, 11-nor-9-carboxy-THC and 11-hydroxy-THC, in active users and particularly in people exposed...

  18. PHARMACOKINETIC RESEARCHES AND PRACTICAL MEDICINE

    Directory of Open Access Journals (Sweden)

    V. G. Belolipetskaya

    2015-12-01

    Full Text Available An article gives in a comprehensive manner the main idea of pharmacokinetics, as the science about rules of substances behavior in the internal environment of the organism, as well as of main parameters of pharmacokinetic researches. The article provides vivid and very  persuasive examples of high practical importance of this science both for creating new medical forms of drugs and for choosing the optimal of therapy regime.

  19. PHARMACOKINETIC RESEARCHES AND PRACTICAL MEDICINE

    Directory of Open Access Journals (Sweden)

    V. G. Belolipetskaya

    2005-01-01

    Full Text Available An article gives in a comprehensive manner the main idea of pharmacokinetics, as the science about rules of substances behavior in the internal environment of the organism, as well as of main parameters of pharmacokinetic researches. The article provides vivid and very  persuasive examples of high practical importance of this science both for creating new medical forms of drugs and for choosing the optimal of therapy regime.

  20. PK/DB: database for pharmacokinetic properties and predictive in silico ADME models.

    Science.gov (United States)

    Moda, Tiago L; Torres, Leonardo G; Carrara, Alexandre E; Andricopulo, Adriano D

    2008-10-01

    The study of pharmacokinetic properties (PK) is of great importance in drug discovery and development. In the present work, PK/DB (a new freely available database for PK) was designed with the aim of creating robust databases for pharmacokinetic studies and in silico absorption, distribution, metabolism and excretion (ADME) prediction. Comprehensive, web-based and easy to access, PK/DB manages 1203 compounds which represent 2973 pharmacokinetic measurements, including five models for in silico ADME prediction (human intestinal absorption, human oral bioavailability, plasma protein binding, blood-brain barrier and water solubility). http://www.pkdb.ifsc.usp.br

  1. Cannabinoid Type 1 Receptor (CB1) Ligands with Therapeutic Potential for Withdrawal Syndrome in Chemical Dependents of Cannabis sativa.

    Science.gov (United States)

    Ferreira, Jaderson V; Chaves, Gisele A; Marino, Bianca L B; Sousa, Kessia P A; Souza, Lucilene R; Brito, Maiara F B; Teixeira, Hueldem R C; da Silva, Carlos H T P; Santos, Cleydson B R; Hage-Melim, Lorane I S

    2017-08-22

    Cannabis sativa withdrawal syndrome is characterized mainly by psychological symptoms. By using computational tools, the aim of this study was to propose drug candidates for treating withdrawal syndrome based on the natural ligands of the cannabinoid type 1 receptor (CB1). One compound in particular, 2-n-butyl-5-n-pentylbenzene-1,3-diol (ZINC1730183, also known as stemphol), showed positive predictions as a human CB1 ligand and for facile synthetic accessibility. Therefore, ZINC1730183 is a favorable candidate scaffold for further research into pharmacotherapeutic alternatives to treat C. sativa withdrawal syndrome. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Selective Cannabinoid 2 Receptor Stimulation Reduces Tubular Epithelial Cell Damage after Renal Ischemia-Reperfusion Injury.

    Science.gov (United States)

    Pressly, Jeffrey D; Mustafa, Suni M; Adibi, Ammaar H; Alghamdi, Sahar; Pandey, Pankaj; Roy, Kuldeep K; Doerksen, Robert J; Moore, Bob M; Park, Frank

    2018-02-01

    Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI), which is an increasing problem in the clinic and has been associated with elevated rates of mortality. Therapies to treat AKI are currently not available, so identification of new targets that can be modulated to ameliorate renal damage upon diagnosis of AKI is essential. In this study, a novel cannabinoid receptor 2 (CB2) agonist, SMM-295 [3'-methyl-4-(2-(thiophen-2-yl)propan-2-yl)biphenyl-2,6-diol], was designed, synthesized, and tested in vitro and in silico. Molecular docking of SMM-295 into a CB2 active-state homology model showed that SMM-295 interacts well with key amino acids to stabilize the active state. In human embryonic kidney 293 cells, SMM-295 was capable of reducing cAMP production with 66-fold selectivity for CB2 versus cannabinoid receptor 1 and dose-dependently increased mitogen-activated protein kinase and Akt phosphorylation. In vivo testing of the CB2 agonist was performed using a mouse model of bilateral IRI, which is a common model to mimic human AKI, where SMM-295 was immediately administered upon reperfusion of the kidneys after the ischemia episode. Histologic damage assessment 48 hours after reperfusion demonstrated reduced tubular damage in the presence of SMM-295. This was consistent with reduced plasma markers of renal dysfunction (i.e., creatinine and neutrophil gelatinase-associated lipocalin) in SMM-295-treated mice. Mechanistically, kidneys treated with SMM-295 were shown to have elevated activation of Akt with reduced terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling (TUNEL)-positive cells compared with vehicle-treated kidneys after IRI. These data suggest that selective CB2 receptor activation could be a potential therapeutic target in the treatment of AKI. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

  3. Pharmacokinetics of BMEDA after Intravenous Administration in Beagle Dogs

    Directory of Open Access Journals (Sweden)

    Chih-Hsien Chang

    2014-01-01

    Full Text Available The pharmacokinetics of N,N-bis(2-mercapatoethly-N',N'-diethylenediamine (BMEDA, a molecule that can form a chelate with rhenium-188 (188Re to produce the 188Re-BMEDA-liposomes, was studied. In this work, beagles received a single injection of BMEDA, at doses of 1, 2, or 5 mg/kg; the concentration of BMEDA in the beagles’ plasma was then analyzed and determined by liquid chromatography-mass spectrometry/mass spectrometry. Based on the pharmacokinetic parameters of BMEDA, we found that male and female animals shared similar patterns indicating that the pharmacokinetics of BMEDA is independent of gender differences. In addition, the pharmacokinetics of BMEDA was seen to be non-linear because the increase of mean AUC0–t and AUC0–∞ values tend to be greater than dose proportional while the mean Vss and CL values of BMEDA appeared to be dose dependent. The information on the pharmacokinetics of BMEDA generated from this study will serve as a basis to design appropriate pharmacology and toxicology studies for future human use.

  4. Efecto neuroprotector de los cannabinoides en las enfermedades neurodegenerativas

    Directory of Open Access Journals (Sweden)

    Carlos Suero-García

    2015-01-01

    Full Text Available Objetivos: Se analiza la situación actual de las investigaciones relacionadas con las sustancias cannabinoides, así como su interacción con el organismo, clasificación, efectos terapéuticos y su uso en las enfermedades neurodegenerativas. Métodos: Se realiza una exhaustiva revisión bibliográfica relacionada con las sustancias cannabinoides y sus derivados sintéticos, haciendo especial hincapié en la forma de interactuar con el organismo y los efectos que provocan dichas interacciones. Concretamente, se estudiarán sus efectos neuroantiinflamatorio y analgésico lo que conlleva al efecto neuroprotector en enfermedades neurodegenerativas tales como Alzheimer, Parkinson, Huntington, esclerosis múltiple y esclerosis lateral amiotrófica. Resultados: Desde hace miles de años la planta Cannabis Sativa ha sido utilizada por muchas culturas con distintos fines, de ocio, textiles, analgésicos, pero no es hasta finales del siglo XX cuando se empieza a incentivar los estudios científicos relacionados con ésta. La planta posee una mezcla de unos 400 componentes, de los cuales 60 pertenecen al grupo de los cannabinoides siendo los principales el cannabinol, cannabidiol y tetrahidrocannabinol. Con el descubrimiento de las sustancias cannabinoides, sus derivados, y los receptores que interactúan, se amplían las posibilidades terapéuticas teniendo un especial interés el efecto neuroprotector que estas sustancias contienen. Conclusiones. Se ha demostrado el gran potencial de los cannabinoides como sustancias terapéuticas más allá de su uso analgésico o antiemético, esto es, en enfermedades neurodegenerativas en las que pueden no solo disminuir los síntomas, sino frenar el proceso de la enfermedad. Otra posible aplicación puede ser en el campo oncológico, siendo particularmente intensa la actividad investigadora realizada en los últimos 15 años.

  5. A Gut Gone to Pot: A Case of Cannabinoid Hyperemesis Syndrome due to K2, a Synthetic Cannabinoid

    Directory of Open Access Journals (Sweden)

    Anene Ukaigwe

    2014-01-01

    Full Text Available Cannabinoid Hyperemesis Syndrome (CHS was first described in 2004. Due to its novelty, CHS is often unrecognized by clinicians leading to expensive workup of these patients with cyclical symptoms. It may take up to 9 years to diagnose CHS. CHS is characterized by cyclical nausea and vomiting, abdominal pain, and an unusual compulsion to take hot showers in the presence of chronic use of cannabinoids. Cannabicyclohexanol is a synthetic cannabinoid, popularly known as K2 spice. It is a popular marijuana alternative among teenagers and young adults since it is readily available as herbal incense. Unlike marijuana, many users know that K2 is not detected in conventional urine drug screens, allowing those users to conceal their intake from typical detection methods. Serum or urine gas chromatography mass spectrophotometry is diagnostic, though not widely available. Thus, it is imperative for clinicians to recognize CHS, even with negative UDS, to provide cost-effective care. We present a 38-year-old man with a 10-year history of cannabis, and 1-year history of K2 abuse admitted with 1-week history of episodes of nausea, vomiting of clear fluids, and epigastric discomfort. Symptoms are relieved only by hot showers. Extensive laboratory, radiologic, and endoscopic evaluation was unrevealing. CHS was diagnosed, based on proposed criteria by Simonetti et al.

  6. AM-2201 Inhibits Multiple Cytochrome P450 and Uridine 5′-Diphospho-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes

    Directory of Open Access Journals (Sweden)

    Ju-Hyun Kim

    2017-03-01

    Full Text Available AM-2201 is a synthetic cannabinoid that acts as a potent agonist at cannabinoid receptors and its abuse has increased. However, there are no reports of the inhibitory effect of AM-2201 on human cytochrome P450 (CYP or uridine 5′-diphospho-glucuronosyltransferase (UGT enzymes. We evaluated the inhibitory effect of AM-2201 on the activities of eight major human CYPs (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 and six major human UGTs (1A1, 1A3, 1A4, 1A6, 1A9, and 2B7 enzymes in pooled human liver microsomes using liquid chromatography–tandem mass spectrometry to investigate drug interaction potentials of AM-2201. AM-2201 potently inhibited CYP2C9-catalyzed diclofenac 4′-hydroxylation, CYP3A4-catalyzed midazolam 1′-hydroxylation, UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-glucuronidation, and UGT2B7-catalyzed naloxone 3-glucuronidation with IC50 values of 3.9, 4.0, 4.3, and 10.0 μM, respectively, and showed mechanism-based inhibition of CYP2C8-catalyzed amodiaquine N-deethylation with a Ki value of 2.1 μM. It negligibly inhibited CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, UGT1A1, UGT1A4, UGT1A6, and UGT1A9 activities at 50 μM in human liver microsomes. These in vitro results indicate that AM-2201 needs to be examined for potential pharmacokinetic drug interactions in vivo due to its potent inhibition of CYP2C8, CYP2C9, CYP3A4, UGT1A3, and UGT2B7 enzyme activities.

  7. Metabolomics and bioanalysis of terpenoid derived secondary metabolites : Analysis of Cannabis sativa L. metabolite production and prenylases for cannabinoid production

    NARCIS (Netherlands)

    Muntendam, Remco

    2015-01-01

    Cannabinoid research has gained a renenewed interest by both the public and scientist. Focus is mainly directed to the medicinal activities, as reported for various cannabinoid structures. This thesis focusses on prenyl-derived secondary metabolites with main focus on cannabinoids. Firstly the

  8. 76 FR 11075 - Schedules of Controlled Substances: Temporary Placement of Five Synthetic Cannabinoids Into...

    Science.gov (United States)

    2011-03-01

    ... constituent of marijuana. ``Synthetic cannabinoids'' are a large family of chemically unrelated structures functionally (biologically) similar to THC, the active principle of marijuana. Two of the five synthetic...-like synthetic cannabinoids are perceived as ``legal'' alternatives to marijuana despite the fact that...

  9. Cannabinoids for Medical Use A Systematic Review and Meta-analysis

    NARCIS (Netherlands)

    Whiting, Penny F.; Wolff, Robert F.; Deshpande, Sohan; Di Nisio, Marcello; Duffy, Steven; Hernandez, Adrian V.; Keurentjes, J. Christiaan; Lang, Shona; Misso, Kate; Ryder, Steve; Schmidlkofer, Simone; Westwood, Marie; Kleijnen, Jos

    2015-01-01

    IMPORTANCE Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear. OBJECTIVE To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids. DATA SOURCES Twenty-eight databases from

  10. Novelty-induced emotional arousal modulates cannabinoid effects on recognition memory and adrenocortical activity

    NARCIS (Netherlands)

    Campolongo, P.; Morena, M.; Scaccianoce, S.; Trezza, V.; Chiarotti, F.; Schelling, G.; Cuomo, V.; Roozendaal, B.

    2013-01-01

    Although it is well established that cannabinoid drugs can influence cognitive performance, the findings-describing both enhancing and impairing effects-have been ambiguous. Here, we investigated the effects of posttraining systemic administration of the synthetic cannabinoid agonist WIN55,212-2

  11. The Antitumor Activity of Plant-Derived Non-Psychoactive Cannabinoids.

    Science.gov (United States)

    McAllister, Sean D; Soroceanu, Liliana; Desprez, Pierre-Yves

    2015-06-01

    As a therapeutic agent, most people are familiar with the palliative effects of the primary psychoactive constituent of Cannabis sativa (CS), Δ(9)-tetrahydrocannabinol (THC), a molecule active at both the cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor subtypes. Through the activation primarily of CB1 receptors in the central nervous system, THC can reduce nausea, emesis and pain in cancer patients undergoing chemotherapy. During the last decade, however, several studies have now shown that CB1 and CB2 receptor agonists can act as direct antitumor agents in a variety of aggressive cancers. In addition to THC, there are many other cannabinoids found in CS, and a majority produces little to no psychoactivity due to the inability to activate cannabinoid receptors. For example, the second most abundant cannabinoid in CS is the non-psychoactive cannabidiol (CBD). Using animal models, CBD has been shown to inhibit the progression of many types of cancer including glioblastoma (GBM), breast, lung, prostate and colon cancer. This review will center on mechanisms by which CBD, and other plant-derived cannabinoids inefficient at activating cannabinoid receptors, inhibit tumor cell viability, invasion, metastasis, angiogenesis, and the stem-like potential of cancer cells. We will also discuss the ability of non-psychoactive cannabinoids to induce autophagy and apoptotic-mediated cancer cell death, and enhance the activity of first-line agents commonly used in cancer treatment.

  12. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System

    Directory of Open Access Journals (Sweden)

    Shenglong Zou

    2018-03-01

    Full Text Available The biological effects of cannabinoids, the major constituents of the ancient medicinal plant Cannabis sativa (marijuana are mediated by two members of the G-protein coupled receptor family, cannabinoid receptors 1 (CB1R and 2. The CB1R is the prominent subtype in the central nervous system (CNS and has drawn great attention as a potential therapeutic avenue in several pathological conditions, including neuropsychological disorders and neurodegenerative diseases. Furthermore, cannabinoids also modulate signal transduction pathways and exert profound effects at peripheral sites. Although cannabinoids have therapeutic potential, their psychoactive effects have largely limited their use in clinical practice. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, focusing on the CB1R and the CNS, with emphasis on recent breakthroughs in the field. We aim to define several potential roles of cannabinoid receptors in the modulation of signaling pathways and in association with several pathophysiological conditions. We believe that the therapeutic significance of cannabinoids is masked by the adverse effects and here alternative strategies are discussed to take therapeutic advantage of cannabinoids.

  13. Understanding the Growing Threat of Synthetic Cannabinoids and Its Implications on University-Based Counselors

    Science.gov (United States)

    Golubovic, Nedeljko; Dew, Brian J.

    2017-01-01

    The rise in synthetic cannabinoid use has been one of the nation's most alarming drug-related trends. Considering the popularity of use among young adults, college counselors are likely to be among the 1st professionals to treat clients who use these drugs. In this article, the unique aspects of synthetic cannabinoids are reviewed, implications…

  14. Pharmacokinetic studies of neuromuscular blocking agents: Good Clinical Research Practice (GCRP)

    DEFF Research Database (Denmark)

    Viby-Mogensen, J.; Østergaard, D.; Donati, F.

    2000-01-01

    Good Clinical Research Practice (GCRP), neuromuscular blocking agents, pharmacokinetics, pharmacokinetic/pharmacodynamic modeling, population pharmacokinetics, statistics, study design......Good Clinical Research Practice (GCRP), neuromuscular blocking agents, pharmacokinetics, pharmacokinetic/pharmacodynamic modeling, population pharmacokinetics, statistics, study design...

  15. Modelling delays in pharmacokinetics

    International Nuclear Information System (INIS)

    Farooqi, Z.H.; Lambrecht, R.M.

    1990-01-01

    Linear system analysis has come to form the backbone of pharmacokinetics. Natural systems usually involve time delays, thus models incorporating them would be an order closer approximation to the real world compared to those that do not. Delays may be modelled in several ways. The approach considered in this study is to have a discrete-time delay dependent rate with the delay respresenting the duration between the entry of a drug into a compartment and its release in some form (may be as a metabolite) from the compartment. Such a delay may be because of one or more of several physiological reasons, like, formation of a reservoir, slow metabolism, or receptor binding. The mathematical structure this gives rise to is a system of delay-differential equations. Examples are given of simple one and two compartment systems with drugs like bumetanide, carbamazepine, and quinolone-caffeine interaction. In these examples generally a good fit is obtained and the suggested models form a good approximation. 21 refs., 6 figs

  16. Determination of telmisartan in human blood plasma: Part II: Liquid chromatography-tandem mass spectrometry method development, comparison to immunoassay and pharmacokinetic study

    NARCIS (Netherlands)

    Hempen, C.M.; Gläsle-Schwarz, Liane; Kunz, Ulrich; Karst, U.

    2006-01-01

    A new liquid chromatography/atmospheric pressure chemical ionization-tandem mass spectrometry (LC/APCI-MS/MS) method with on-line sample clean-up for the determination of telmisartan in human blood plasma is presented. This technique is compared to a previously introduced enzyme-linked immunosorbent

  17. Anti-inflammatory Properties of Cannabidiol, a Nonpsychotropic Cannabinoid, in Experimental Allergic Contact Dermatitis.

    Science.gov (United States)

    Petrosino, Stefania; Verde, Roberta; Vaia, Massimo; Allarà, Marco; Iuvone, Teresa; Di Marzo, Vincenzo

    2018-06-01

    Phytocannabinoids modulate inflammatory responses by regulating the production of cytokines in several experimental models of inflammation. Cannabinoid type-2 (CB 2 ) receptor activation was shown to reduce the production of the monocyte chemotactic protein-2 (MCP-2) chemokine in polyinosinic-polycytidylic acid [poly-(I:C)]-stimulated human k