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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. Pharmacokinetics and pharmacodynamics of cannabinoids.

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    Grotenhermen, Franjo

    2003-01-01

    Delta(9)-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for non-receptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15-30 minutes, and taper off within 2-3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30-90 minutes, reach their maximum after 2-3 hours and last for about 4-12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial

  3. Human Laboratory Studies on Cannabinoids and Psychosis.

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    Sherif, Mohamed; Radhakrishnan, Rajiv; D'Souza, Deepak Cyril; Ranganathan, Mohini

    2016-04-01

    Some of the most compelling evidence supporting an association between cannabinoid agonists and psychosis comes from controlled laboratory studies in humans. Randomized, double-blind, placebo-controlled, crossover laboratory studies demonstrate that cannabinoid agonists, including phytocannabinoids and synthetic cannabinoids, produce a wide range of positive, negative, and cognitive symptoms and psychophysiologic deficits in healthy human subjects that resemble the phenomenology of schizophrenia. These effects are time locked to drug administration, are dose related, and are transient and rarely necessitate intervention. The magnitude of effects is similar to the effects of ketamine but qualitatively distinct from other psychotomimetic drugs, including ketamine, amphetamine, and salvinorin A. Cannabinoid agonists have also been shown to transiently exacerbate symptoms in individuals with schizophrenia in laboratory studies. Patients with schizophrenia are more vulnerable than healthy control subjects to the acute behavioral and cognitive effects of cannabinoid agonists and experience transient exacerbation of symptoms despite treatment with antipsychotic medications. Furthermore, laboratory studies have failed to demonstrate any "beneficial" effects of cannabinoid agonists in individuals with schizophrenia-challenging the cannabis self-medication hypothesis. Emerging evidence suggests that polymorphisms of several genes related to dopamine metabolism (e.g., COMT, DAT1, and AKT1) may moderate the effects of cannabinoid agonists in laboratory studies. Cannabinoid agonists induce dopamine release, although the magnitude of release does not appear to be commensurate to the magnitude and spectrum of their acute psychotomimetic effects. Interactions between the endocannabinoid, gamma-aminobutyric acid, and glutamate systems and their individual and interactive effects on neural oscillations provide a plausible mechanism underlying the psychotomimetic effects of

  4. 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.

  5. Human studies of cannabinoids and medicinal cannabis.

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    Robson, P

    2005-01-01

    Cannabis has been known as a medicine for several thousand years across many cultures. It reached a position of prominence within Western medicine in the nineteenth century but became mired in disrepute and legal controls early in the twentieth century. Despite unremitting world-wide suppression, recreational cannabis exploded into popular culture in the 1960s and has remained easily obtainable on the black market in most countries ever since. This ready availability has allowed many thousands of patients to rediscover the apparent power of the drug to alleviate symptoms of some of the most cruel and refractory diseases known to humankind. Pioneering clinical research in the last quarter of the twentieth century has given some support to these anecdotal reports, but the methodological challenges to human research involving a pariah drug are formidable. Studies have tended to be small, imperfectly controlled, and have often incorporated unsatisfactory synthetic cannabinoid analogues or smoked herbal material of uncertain composition and irregular bioavailability. As a result, the scientific evaluation of medicinal cannabis in humans is still in its infancy. New possibilities in human research have been opened up by the discovery of the endocannabinoid system, a rapidly expanding knowledge of cannabinoid pharmacology, and a more sympathetic political environment in several countries. More and more scientists and clinicians are becoming interested in exploring the potential of cannabis-based medicines. Future targets will extend beyond symptom relief into disease modification, and already cannabinoids seem to offer particular promise in the treatment of certain inflammatory and neurodegenerative conditions. This chapter will begin with an outline of the development and current status of legal controls pertaining to cannabis, following which the existing human research will be reviewed. Some key safety issues will then be considered, and the chapter will conclude with

  6. In vitro and in vivo pharmacokinetics and metabolism of synthetic cannabinoids CUMYL-PICA and 5F-CUMYL-PICA.

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    Kevin, Richard C; Lefever, Timothy W; Snyder, Rodney W; Patel, Purvi R; Fennell, Timothy R; Wiley, Jenny L; McGregor, Iain S; Thomas, Brian F

    2017-01-01

    CUMYL-PICA [1-pentyl-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide] and 5F-CUMYL-PICA [1-(5-fluoropentyl)-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide] are recently identified recreationally used/abused synthetic cannabinoids, but have uncharacterized pharmacokinetic profiles and metabolic processes. This study characterized clearance and metabolism of these compounds by human and rat liver microsomes and hepatocytes, and then compared these parameters with in vivo rat plasma and urine sampling. It also evaluated hypothermia, a characteristic cannabimimetic effect. Incubation of CUMYL-PICA and 5F-CUMYL-PICA with rat and human liver microsomes suggested rapid metabolic clearance, but in vivo metabolism was prolonged, such that parent compounds remained detectable in rat plasma 24 h post-dosing. At 3 mg/kg (intraperitoneally), both compounds produced moderate hypothermic effects. Twenty-eight metabolites were tentatively identified for CUMYL-PICA and, coincidentally, 28 metabolites for 5F-CUMYL-PICA, primarily consisting of phase I oxidative transformations and phase II glucuronidation. The primary metabolic pathways for both compounds resulted in the formation of identical metabolites following terminal hydroxylation or dealkylation of the N-pentyl chain for CUMYL-PICA or of the 5-fluoropentyl chain for 5F-CUMYL-PICA. These data provide evidence that in vivo elimination of CUMYL-PICA, 5F-CUMYL-PICA and other synthetic cannabinoids is delayed compared to in vitro modeling, possibly due to sequestration into adipose tissue. Additionally, the present data underscore the need for careful selection of metabolites as analytical targets to distinguish between closely related synthetic cannabinoids in forensic settings.

  7. Vascular targets for cannabinoids: animal and human studies

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    Stanley, Christopher; O'Sullivan, Saoirse E

    2014-01-01

    Application of cannabinoids and endocannabinoids to perfused vascular beds or individual isolated arteries results in changes in vascular resistance. In most cases, the result is vasorelaxation, although vasoconstrictor responses are also observed. Cannabinoids also modulate the actions of vasoactive compounds including acetylcholine, methoxamine, angiotensin II and U46619 (thromboxane mimetic). Numerous mechanisms of action have been proposed including receptor activation, potassium channel activation, calcium channel inhibition and the production of vasoactive mediators such as calcitonin gene-related peptide, prostanoids, NO, endothelial-derived hyperpolarizing factor and hydrogen peroxide. The purpose of this review is to examine the evidence for the range of receptors now known to be activated by cannabinoids. Direct activation by cannabinoids of CB1, CBe, TRPV1 (and potentially other TRP channels) and PPARs in the vasculature has been observed. A potential role for CB2, GPR55 and 5-HT1A has also been identified in some studies. Indirectly, activation of prostanoid receptors (TP, IP, EP1 and EP4) and the CGRP receptor is involved in the vascular responses to cannabinoids. The majority of this evidence has been obtained through animal research, but recent work has confirmed some of these targets in human arteries. Vascular responses to cannabinoids are enhanced in hypertension and cirrhosis, but are reduced in obesity and diabetes, both due to changes in the target sites of action. Much further work is required to establish the extent of vascular actions of cannabinoids and the application of this research in physiological and pathophysiological situations. Linked ArticlesThis article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6 PMID:24329566

  8. 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

  9. Cannabinoids induce incomplete maturation of cultured human leukemia cells

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    Murison, G.; Chubb, C.B.H.; Maeda, S.; Gemmell, M.A.; Huberman, E.

    1987-08-01

    Monocyte maturation markers were induced in cultured human myeloblastic ML-2 leukemia cells after treatment for 1-6 days with 0.03-30 ..mu..M ..delta../sup 9/-tetrahydrocannabinol (THC), the major psychoactive component of marijuana. After a 2-day or longer treatment, 2- to 5-fold increases were found in the percentages of cells exhibiting reactivity with either the murine OKM1 monoclonal antibody of the Leu-M5 monoclonal antibody, staining positively for nonspecific esterase activity, and displaying a promonocyte morphology. The increases in these differentiation markers after treatment with 0.03-1 ..mu..M THC were dose dependent. At this dose range, THC did not cause an inhibition of cell growth. The THC-induced cell maturation was also characterized by specific changes in the patterns of newly synthesized proteins. The THC-induced differentiation did not, however, result in cells with a highly developed mature monocyte phenotype. However, treatment of these incompletely matured cells with either phorbol 12-myristate 13-acetate of 1..cap alpha..,25-dihydroxycholecalciferol, which are inducers of differentiation in myeloid leukemia cells (including ML-2 cells), produced cells with a mature monocyte morphology. The ML-2 cell system described here may be a useful tool for deciphering critical biochemical events that lead to the cannabinoid-induced incomplete cell differentiation of ML-2 cells and other related cell types. Findings obtained from this system may have important implications for studies of cannabinoid effects on normal human bone-marrow progenitor cells.

  10. The acute effects of cannabinoids on memory in humans: a review.

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    Ranganathan, Mohini; D'Souza, Deepak Cyril

    2006-11-01

    Cannabis is one of the most frequently used substances. Cannabis and its constituent cannabinoids are known to impair several aspects of cognitive function, with the most robust effects on short-term episodic and working memory in humans. A large body of the work in this area occurred in the 1970s before the discovery of cannabinoid receptors. Recent advances in the knowledge of cannabinoid receptors' function have rekindled interest in examining effects of exogenous cannabinoids on memory and in understanding the mechanism of these effects. The literature about the acute effects of cannabinoids on memory tasks in humans is reviewed. The limitations of the human literature including issues of dose, route of administration, small sample sizes, sample selection, effects of other drug use, tolerance and dependence to cannabinoids, and the timing and sensitivity of psychological tests are discussed. Finally, the human literature is discussed against the backdrop of preclinical findings. Acute administration of Delta-9-THC transiently impairs immediate and delayed free recall of information presented after, but not before, drug administration in a dose- and delay-dependent manner. In particular, cannabinoids increase intrusion errors. These effects are more robust with the inhaled and intravenous route and correspond to peak drug levels. This profile of effects suggests that cannabinoids impair all stages of memory including encoding, consolidation, and retrieval. Several mechanisms, including effects on long-term potentiation and long-term depression and the inhibition of neurotransmitter (GABA, glutamate, acetyl choline, dopamine) release, have been implicated in the amnestic effects of cannabinoids. Future research in humans is necessary to characterize the neuroanatomical and neurochemical basis of the memory impairing effects of cannabinoids, to dissect out their effects on the various stages of memory and to bridge the expanding gap between the humans and

  11. Cannabinoids inhibit cellular respiration of human oral cancer cells.

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    Whyte, Donna A; Al-Hammadi, Suleiman; Balhaj, Ghazala; Brown, Oliver M; Penefsky, Harvey S; Souid, Abdul-Kader

    2010-01-01

    The primary cannabinoids, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and Delta(8)-tetrahydrocannabinol (Delta(8)-THC) are known to disturb the mitochondrial function and possess antitumor activities. These observations prompted us to investigate their effects on the mitochondrial O(2) consumption in human oral cancer cells (Tu183). This epithelial cell line overexpresses bcl-2 and is highly resistant to anticancer drugs. A phosphorescence analyzer that measures the time-dependence of O(2) concentration in cellular or mitochondrial suspensions was used for this purpose. A rapid decline in the rate of respiration was observed when Delta(9)-THC or Delta(8)-THC was added to the cells. The inhibition was concentration-dependent, and Delta(9)-THC was the more potent of the two compounds. Anandamide (an endocannabinoid) was ineffective; suggesting the effects of Delta(9)-THC and Delta(8)-THC were not mediated by the cannabinoidreceptors. Inhibition of O(2) consumption by cyanide confirmed the oxidations occurred in the mitochondrial respiratory chain. Delta(9)-THC inhibited the respiration of isolated mitochondria from beef heart. These results show the cannabinoids are potent inhibitors of Tu183 cellular respiration and are toxic to this highly malignant tumor.

  12. Crystal Structure of the Human Cannabinoid Receptor CB1.

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    Hua, Tian; Vemuri, Kiran; Pu, Mengchen; Qu, Lu; Han, Gye Won; Wu, Yiran; Zhao, Suwen; Shui, Wenqing; Li, Shanshan; Korde, Anisha; Laprairie, Robert B; Stahl, Edward L; Ho, Jo-Hao; Zvonok, Nikolai; Zhou, Han; Kufareva, Irina; Wu, Beili; Zhao, Qiang; Hanson, Michael A; Bohn, Laura M; Makriyannis, Alexandros; Stevens, Raymond C; Liu, Zhi-Jie

    2016-10-20

    Cannabinoid receptor 1 (CB1) is the principal target of Δ9-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use. CB1 is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. Here, we present the 2.8 Å crystal structure of human CB1 in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study. The structure of the CB1-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding. In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB1 ligands, such as THC, and synthetic cannabinoids. This enhances our understanding of the molecular basis for the physiological functions of CB1 and provides new opportunities for the design of next-generation CB1-targeting pharmaceuticals. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. 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 Δ9-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

  14. Exogenous and Endogenous Cannabinoids Suppress Inhibitory Neurotransmission in the Human Neocortex

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    Kovacs, Flora E; Knop, Tim; Urbanski, Michal J; Freiman, Ilka; Freiman, Thomas M; Feuerstein, Thomas J; Zentner, Josef; Szabo, Bela

    2012-01-01

    Activation of CB1 receptors on axon terminals by exogenous cannabinoids (eg, Δ9-tetrahydrocannabinol) and by endogenous cannabinoids (endocannabinoids) released by postsynaptic neurons leads to presynaptic inhibition of neurotransmission. The aim of this study was to characterize the effect of cannabinoids on GABAergic synaptic transmission in the human neocortex. Brain slices were prepared from neocortical tissues surgically removed to eliminate epileptogenic foci. Spontaneous GABAergic inhibitory postsynaptic currents (sIPSCs) were recorded in putative pyramidal neurons using patch-clamp techniques. To enhance the activity of cannabinoid-sensitive presynaptic axons, muscarinic receptors were continuously stimulated by carbachol. The synthetic cannabinoid receptor agonist WIN55212-2 decreased the cumulative amplitude of sIPSCs. The CB1 antagonist rimonabant prevented this effect, verifying the involvement of CB1 receptors. WIN55212-2 decreased the frequency of miniature IPSCs (mIPSCs) recorded in the presence of tetrodotoxin, but did not change their amplitude, indicating that the neurotransmission was inhibited presynaptically. Depolarization of postsynaptic pyramidal neurons induced a suppression of sIPSCs. As rimonabant prevented this suppression, it is very likely that it was due to endocannabinods acting on CB1 receptors. This is the first demonstration that an exogenous cannabinoid inhibits synaptic transmission in the human neocortex and that endocannabinoids released by postsynaptic neurons suppress synaptic transmission in the human brain. Interferences of cannabinoid agonists and antagonists with synaptic transmission in the cortex may explain the cognitive and memory deficits elicited by these drugs. PMID:22048459

  15. Free and Glucuronide Whole Blood Cannabinoids' Pharmacokinetics after Controlled Smoked, Vaporized, and Oral Cannabis Administration in Frequent and Occasional Cannabis Users: Identification of Recent Cannabis Intake.

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    Newmeyer, Matthew N; Swortwood, Madeleine J; Barnes, Allan J; Abulseoud, Osama A; Scheidweiler, Karl B; Huestis, Marilyn A

    2016-12-01

    There is increasing interest in markers of recent cannabis use because following frequent cannabis intake, Δ 9 -tetrahydrocannabinol (THC) may be detected in blood for up to 30 days. The minor cannabinoids cannabidiol, cannabinol (CBN), and THC-glucuronide were previously detected for ≤2.1 h in frequent and occasional smokers' blood after cannabis smoking. Cannabigerol (CBG), Δ 9 -tetrahydrocannabivarin (THCV), and 11-nor-9-carboxy-THCV might also be recent use markers, but their blood pharmacokinetics have not been investigated. Additionally, while smoking is the most common administration route, vaporization and edibles are frequently used. We characterized blood pharmacokinetics of THC, its phase I and phase II glucuronide metabolites, and minor cannabinoids in occasional and frequent cannabis smokers for 54 (occasional) and 72 (frequent) hours after controlled smoked, vaporized, and oral cannabis administration. Few differences were observed between smoked and vaporized blood cannabinoid pharmacokinetics, while significantly greater 11-nor-9-carboxy-THC (THCCOOH) and THCCOOH-glucuronide concentrations occurred following oral cannabis. CBG and CBN were frequently identified after inhalation routes with short detection windows, but not detected following oral dosing. Implementation of a combined THC ≥5 μg/L plus THCCOOH/11-hydroxy-THC ratio tests. Clinicaltrials.gov Identifier: NCT02177513. © 2016 American Association for Clinical Chemistry.

  16. 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

    2014-01-01

    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

  17. High-resolution crystal structure of the human CB1 cannabinoid receptor.

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    Shao, Zhenhua; Yin, Jie; Chapman, Karen; Grzemska, Magdalena; Clark, Lindsay; Wang, Junmei; Rosenbaum, Daniel M

    2016-11-16

    The human cannabinoid G-protein-coupled receptors (GPCRs) CB1 and CB2 mediate the functional responses to the endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG), as well as the widely consumed plant (phyto)cannabinoid Δ(9)-tetrahydrocannabinol (THC)(1). The cannabinoid receptors have been the targets of intensive drug discovery efforts owing to the therapeutic potential of modulators for controlling pain(2), epilepsy(3), obesity(4), and other maladies. Although much progress has recently been made in understanding the biophysical properties of GPCRs, investigations of the molecular mechanisms of the cannabinoids and their receptors have lacked high-resolution structural data. We used GPCR engineering and lipidic cubic phase (LCP) crystallization to determine the structure of the human CB1 receptor bound to the inhibitor taranabant at 2.6 Å resolution. The extracellular surface of CB1, including the highly conserved membrane-proximal amino-terminal (N-terminal) region, is distinct from other lipid-activated GPCRs and forms a critical part of the ligand binding pocket. Docking studies further demonstrate how this same pocket may accommodate the cannabinoid agonist THC. Our CB1 structure provides an atomic framework for studying cannabinoid receptor function, and will aid the design and optimization of cannabinoid system modulators for therapeutic ends.

  18. A review of oral cannabinoids and medical marijuana for the treatment of chemotherapy-induced nausea and vomiting: a focus on pharmacokinetic variability and pharmacodynamics.

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    Badowski, Melissa E

    2017-09-01

    Oral cannabinoids (i.e., dronabinol, nabilone) containing the active component of marijuana, delta(Δ)9-tetrahydrocannabinol (THC), are available for the treatment of chemotherapy-induced nausea and vomiting (CINV) in patients with cancer who have failed to adequately respond to conventional antiemetic therapy. The aim of this article is to provide an overview of the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), and safety of oral cannabinoids for patients with CINV. A PubMed search of the English-language literature available through 4 January 2017 was conducted to identify relevant articles for inclusion in the review. Oral cannabinoids have been shown to have similar or improved efficacy compared with conventional antiemetics for the resolution of nausea and/or vomiting in patients with cancer. However, oral THC has high PK variability, with variability in oral dronabinol peak plasma concentrations (C max) estimated between 150 and 200%. A new oral dronabinol solution has decreased intraindividual variability (area under the curve) vs oral dronabinol capsules. Further, oral THC has a slower time to C max compared with THC administered intravenously (IV) or by smoking, and a lower systemic availability than IV or smoked THC. The PD profile (e.g., "high") of oral THC differs from that of IV or smoked THC in healthy individuals. Oral cannabinoids are associated with greater incidence of adverse effects compared with conventional antiemetic therapy or placebo (e.g., dizziness, hypotension, and dysphoria or depression). A new formulation of oral cannabinoids (i.e., dronabinol oral solution) minimized the PK/PD variability currently observed with capsule formulations.

  19. The behavioral profile of spice and synthetic cannabinoids in humans.

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    Müller, Helge H; Kornhuber, Johannes; Sperling, Wolfgang

    2016-09-01

    The use of synthetic cannabinoids (spice) is increasing. The number of descriptions of (new) clinical side effects is also increasing. We screened relevant publications for articles about spice with a focus on the clinical manifestations of the use of this drug. Spice creates diffuse psychiatric and somatic effects that are only partially similar to those of natural cannabinoids. Most of the observed effects are related to sympathomimetic-cardiac effects and neuropsychiatric manifestations. Clinical treatment is primarily based on intensive apparative and laboratory monitoring and supportive therapy. Because the exact active ingredients of spice are often difficult to determine with standard specific toxicology testing, the assessment and analysis of consumed substances by specialized laboratories is recommended. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. 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

  1. Failure to extinguish fear and genetic variability in the human cannabinoid receptor 1

    NARCIS (Netherlands)

    Heitland, I.; Klumpers, F.; Oosting, R.S.; Evers, D.J.; Leon Kenemans, J.; Baas, J.M.

    2012-01-01

    Failure to extinguish fear can lead to persevering anxiety and has been postulated as an important mechanism in the pathogenesis of human anxiety disorders. In animals, it is well documented that the endogenous cannabinoid system has a pivotal role in the successful extinction of fear, most

  2. 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

  3. 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

  4. 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

  5. Intravenous buprenorphine and norbuprenorphine pharmacokinetics in humans

    Science.gov (United States)

    Huestis, M.A.; Cone, E.J.; Pirnay, S.O.; Umbricht, A.; Preston, K.L.

    2013-01-01

    Background Prescribed sublingual (SL) buprenorphine is sometimes diverted for intravenous (IV) abuse, but no human pharmacokinetic data are available following high-dose IV buprenorphine. Methods Plasma was collected for 72 h after administration of placebo or 2, 4, 8, 12, or 16 mg IV buprenorphine in escalating order (single-blind, double-dummy) in 5 healthy male non-dependent opioid users. Buprenorphine and its primary active metabolite, norbuprenorphine, were quantified by liquid chromatography tandem mass spectrometry with limits of quantitation of 0.1 μg/L. Results Maximum buprenorphine concentrations (mean ± SE) were detected 10 min after 2, 4, 8, 12, 16 mg IV: 19.3±1.0, 44.5±4.8, 85.2±7.7, 124.6±16.6, and 137.7±18.8 μg/L, respectively. Maximum norbuprenorphine concentrations occurred 10–15 min (3.7±0.7 μg/L) after 16 mg IV administration. Conclusions Buprenorphine concentrations increased in a significantly linear dose-dependent manner up to 12 mg IV buprenorphine. Thus, previously demonstrated pharmacodynamic ceiling effects (over 2–16 mg) are not due to pharmacokinetic adaptations within this range, although they may play a role at doses higher than 12 mg. PMID:23246635

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

    Energy Technology Data Exchange (ETDEWEB)

    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

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

    Directory of Open Access Journals (Sweden)

    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.

  8. 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.

  9. The effects of cannabinoids on serum cortisol and prolactin in humans.

    Science.gov (United States)

    Ranganathan, Mohini; Braley, Gabriel; Pittman, Brian; Cooper, Thomas; Perry, Edward; Krystal, John; D'Souza, Deepak Cyril

    2009-05-01

    Cannabis is one of the most widely used illicit substances, and there is growing interest in the therapeutic applications of cannabinoids. While known to modulate neuroendocrine function, the precise acute and chronic dose-related effects of cannabinoids in humans are not well-known. Furthermore, the existing literature on the neuroendocrine effects of cannabinoids is limited by small sample sizes (n = 6-22), heterogeneous samples with regard to cannabis exposure (lumping users and nonusers), lack of controlling for chronic cannabis exposure, differing methodologies, and limited dose-response data. Delta-9-tetrahydrocannabinol (Delta-9-THC) was hypothesized to produce dose-related increases in plasma cortisol levels and decreases in plasma prolactin levels. Furthermore, relative to controls, frequent users of cannabis were hypothesized to show altered baseline levels of these hormones and blunted Delta-9-THC-induced changes of these hormones. Pooled data from a series of laboratory studies with multiple doses of intravenous Delta-9-THC in healthy control subjects (n = 36) and frequent users of cannabis (n = 40) was examined to characterize the acute, chronic, and acute on chronic effects of cannabinoids on plasma cortisol and prolactin levels. Hormone levels were measured before (baseline) and 70 min after administration of each dose of Delta-9-THC. Data were analyzed using linear mixed models with +70 min hormonal levels as the dependant variable and baseline hormonal level as the covariate. At socially relevant doses, Delta-9-THC raised plasma cortisol levels in a dose-dependent manner but frequent users showed blunted increases relative to healthy controls. Frequent users also had lower baseline plasma prolactin levels relative to healthy controls. These group differences may be related to the development of tolerance to the neuroendocrine effects of cannabinoids. Alternatively, these results may reflect inherent differences in neuroendocrine function in

  10. Cannabinoid receptor-independent cytotoxic effects of cannabinoids in human colorectal carcinoma cells: synergism with 5-fluorouracil.

    Science.gov (United States)

    Gustafsson, Sofia B; Lindgren, Theres; Jonsson, Maria; Jacobsson, Stig O P

    2009-03-01

    Cannabinoids (CBs) have been found to exert antiproliferative effects upon a variety of cancer cells, including colorectal carcinoma cells. However, little is known about the signalling mechanisms behind the antitumoural effect in these cells, whether the effects are shared by endogenous lipids related to endocannabinoids, or whether such effects are synergistic with treatment paradigms currently used in the clinic. The aim of this preclinical study was to investigate the effect of synthetic and endogenous CBs and their related fatty acids on the viability of human colorectal carcinoma Caco-2 cells, and to determine whether CB effects are synergistic with those seen with the pyrimidine antagonist 5-fluorouracil (5-FU). The synthetic CB HU 210, the endogenous CB anandamide, the endogenous structural analogue of anandamide, N-arachidonoyl glycine (NAGly), as well as the related polyunsaturated fatty acids arachidonic acid and eicosapentaenoic acid showed antiproliferative and cytotoxic effects in the Caco-2 cells, as measured by using [(3)H]-thymidine incorporation assay, the CyQUANT proliferation assay and calcein-AM fluorescence. HU 210 was the most potent compound examined, followed by anandamide, whereas NAGly showed equal potency and efficacy as the polyunsaturated fatty acids. Furthermore, HU 210 and 5-FU produced synergistic effects in the Caco-2 cells, but not in the human colorectal carcinoma cell lines HCT116 or HT29. The compounds examined produced cytotoxic, rather than antiproliferative effects, by a mechanism not involving CB receptors, since the CB receptor antagonists AM251 and AM630 did not attenuate the effects, nor did pertussis toxin. However, alpha-tocopherol and the nitric oxide synthase inhibitor L-NAME attenuated the CB toxicity, suggesting involvement of oxidative stress. It is concluded that the CB system may provide new targets for the development of drugs to treat colorectal cancer.

  11. 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.

  12. Cannabinoid inhibits HIV-1 Tat-stimulated adhesion of human monocyte-like cells to extracellular matrix proteins

    Science.gov (United States)

    Raborn, Erinn S.; Jamerson, Melissa; Marciano-Cabral, Francine; Cabral, Guy A.

    2014-01-01

    Aims The aim of this study was to assess the effect of select cannabinoids on human immunodeficiency virus type 1 (HIV-1) transactivating (Tat) protein-enhanced monocyte-like cell adhesion to proteins of the extracellular matrix (ECM). Main Methods Collagen IV, laminin, or an ECM gel were used to construct extracellular matrix layers. Human U937 monocyte-like cells were exposed to Tat in the presence of Δ9-tetrahydrocannabinol (THC), CP55,940, and other select cannabinoids. Cell attachment to ECM proteins was assessed using an adhesion assay. Key findings THC and CP55,940 inhibited Tat-enhanced attachment of U937 cells to ECM proteins in a mode that was linked to the cannabinoid receptor type 2 (CB2R). The cannabinoid treatment of Tat-activated U937 cells was associated with altered β1-integrin expression and distribution of polymerized actin, suggesting a modality by which these cannabinoids inhibited adhesion to the ECM. Significance The blood-brain barrier (BBB) is a complex structure that is composed of cellular elements and an extracellular matrix (ECM). HIV-1 Tat promotes transmigration of monocytes across this barrier, a process that includes interaction with ECM proteins. The results indicate that cannabinoids that activate the CB2R inhibit the ECM adhesion process. Thus, this receptor has potential to serve as a therapeutic agent for ablating neuroinflammation associated with HIV-elicited influx of monocytes across the BBB. PMID:24742657

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

    Science.gov (United States)

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

    2016-04-01

    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 different CB1 antagonists in Δ(9) -tetrahydrocannabinol (THC) challenge tests in healthy volunteer were constructed. The pharmacokinetic models of THC and four CB1 antagonists were built separately. THC-induced effects on heart rate and the visual analogue scale of feeling high in healthy volunteers and inhibitive effects of CB1 antagonists on THC-induced effects were modelled in PD models linked to the PK models. Simulations were then applied to evaluate the reduction rate of each antagonist on the reversal of the THC-induced effect in a unified simulation scenario. The final PK model of THC and antagonists was a two compartment model. An Emax model and logistic regression model were used for effect measures and the antagonist effect was added in these models in a competitive binding manner. t1/2ke0 ranged from 0.00462 to 63.7 h for heart rate and from 0.964 to 150 h for VAS. IC50 ranged from 6.42 to 202 ng ml(-1) for heart rate and from 12.1 to 376 ng ml(-1) for VAS. Benchmark simulation showed different dose-efficacy profiles of two efficacy measures for each CB1 antagonist. PK/PD modelling and simulation approach was suitable for describing and predicting heart rate and feeling high for CB1 antagonists in THC challenge tests. Direct comparison of four antagonists based on simulated efficacy profiles might be of benefit to guide future studies. © 2015 The British Pharmacological Society.

  14. Pharmacological actions and therapeutic uses of cannabis and cannabinoids.

    Science.gov (United States)

    Kumar, R N; Chambers, W A; Pertwee, R G

    2001-11-01

    This review highlights the pharmacology, pharmacokinetics, pharmacological actions, therapeutic uses and adverse effects of cannabinoids. The effect of cannabinoids on anaesthesia is mentioned briefly. Important advances have taken place in cannabinoid research over the last few years and have led to the discovery of novel ligands. The possible clinical applications of these ligands and the direction of future research are discussed.

  15. 76 FR 71351 - Prospective Grant of Exclusive License: Development of Cannabinoid(s) and Cannabidiol(s) Based...

    Science.gov (United States)

    2011-11-17

    ... Cannabinoid(s) and Cannabidiol(s) Based Therapeutics To Treat Hepatic Encephalopathy in Humans. AGENCY... be limited to: The development and sale of cannabinoid(s) and cannabidiol(s) based therapeutics as... chronic neurodegenerative diseases. Nonpsychoactive cannabinoids, such as Cannabidiol (CBD), are...

  16. Spicing things up: synthetic cannabinoids.

    Science.gov (United States)

    Spaderna, Max; Addy, Peter H; D'Souza, Deepak Cyril

    2013-08-01

    Recently, products containing synthetic cannabinoids, collectively referred to as Spice, are increasingly being used recreationally. The availability, acute subjective effects-including self-reports posted on Erowid-laboratory detection, addictive potential, and regulatory challenges of the Spice phenomenon are reviewed. Spice is sold under the guise of potpourri or incense. Unlike delta-9-tetrahydrocannabinol, the synthetic cannabinoids present in Spice are high-potency, high-efficacy, cannabinoid receptor full agonists. Since standard urine toxicology does not test for the synthetic cannabinoids in Spice, it is often used by those who want to avoid detection of drug use. These compounds have not yet been subjected to rigorous testing in humans. Acute psychoactive effects include changes in mood, anxiety, perception, thinking, memory, and attention. Adverse effects include anxiety, agitation, panic, dysphoria, psychosis, and bizarre behavior. Psychosis outcomes associated with Spice provide additional data linking cannabinoids and psychosis. Adverse events necessitating intervention by Poison Control Centers, law enforcement, emergency responders, and hospitals are increasing. Despite statutes prohibiting the manufacture, distribution, and sale of Spice products, manufacturers are replacing banned compounds with newer synthetic cannabinoids that are not banned. There is an urgent need for better research on the effects of synthetic cannabinoids to help clinicians manage adverse events and to better understand cannabinoid pharmacology in humans. The reported psychosis outcomes associated with synthetic cannabinoids contribute to the ongoing debate on the association between cannabinoids and psychosis. Finally, drug detection tests for synthetic cannabinoids need to become clinically available.

  17. Spicing thing up: Synthetic cannabinoids

    Science.gov (United States)

    Spaderna, Max; Addy, Peter H; D’Souza, Deepak Cyril

    2013-01-01

    Rationale Recently, products containing synthetic cannabinoids, collectively referred to as Spice, are increasingly being used recreationally. Objectives The availability, acute subjective effects—including self-reports posted on Erowid—laboratory detection, addictive potential, and regulatory challenges of the Spice phenomenon are reviewed. Results Spice is sold under the guise of potpourri or incense. Unlike THC, the synthetic cannabinoids present in Spice are high-potency, high-efficacy, cannabinoid-receptor full agonists. Since standard urine toxicology does not test for the synthetic cannabinoids in Spice, it is often used by those who want to avoid detection of drug use. These compounds have not yet been subjected to rigorous testing in humans. Acute psychoactive effects include changes in mood, anxiety, perception, thinking, memory, and attention. Adverse effects include anxiety, agitation, panic, dysphoria, psychosis, and bizarre behavior. Psychosis outcomes associated with Spice provide additional data linking cannabinoids and psychosis. Adverse events necessitating intervention by Poison Control Centers, law enforcement, emergency responders, and hospitals are increasing. Despite statutes prohibiting the manufacture, distribution, and sale of Spice products, manufacturers are replacing banned compounds with newer synthetic cannabinoids that are not banned. Conclusions There is an urgent need for better research on the effects of synthetic cannabinoids to help clinicians manage adverse events and to better understand cannabinoid pharmacology in humans. The reported psychosis outcomes associated with synthetic cannabinoids contribute to the ongoing debate on the association between cannabinoids and psychosis. Finally, drug-detection tests for synthetic cannabinoids need to become clinically available. PMID:23836028

  18. Pharmacokinetics and metabolism of rosaramicin in humans.

    Science.gov (United States)

    Lin, C C; Chung, M; Gural, R; Schuessler, D; Kim, H K; Radwanski, E; Marco, A; DiGiore, C; Symchowicz, S

    1984-01-01

    The pharmacokinetics of rosaramicin was studied in subjects receiving 500 mg of the drug (i) by 1-h intravenous infusion, (ii) in solution orally, or (iii) as tablets orally. After intravenous administration, the rosaramicin levels in serum declined rapidly with t1/2S of 0.27 h for the distribution phase and 3.28 h for the elimination phase. The apparent volume of distribution was 3.78 liter/kg, and the total body clearance was 13.41 ml/min per kg, indicating extensive tissue distribution or metabolism or both. Similar pharmacokinetic data were obtained after oral administration of the drug in solution or tablets and after intravenous dosing. The absolute bioavailability of the drug administered orally, in either tablets or solution, was 32 to 39%. The metabolism and excretion of [14C]rosaramicin administered orally were also evaluated in volunteers. The serum area under the curve (infinity) of unchanged rosaramicin was 19% of that of total radioactivity, indicating extensive metabolism of the drug. About 7.0% of the radioactivity was recovered in the urine, and 86.7% was recovered in the feces. Only a small amount of unchanged rosaramicin was present in the urine (7 to 9% of urinary radioactivity), but none was present in the feces. The major metabolite, 20-bis-ureidorosaramicin, represented 17 to 38% of the radioactivity in the urine and 26 to 29% of the radioactivity in the feces. PMID:6517543

  19. Crystal structures of agonist-bound human cannabinoid receptor CB1.

    Science.gov (United States)

    Hua, Tian; Vemuri, Kiran; Nikas, Spyros P; Laprairie, Robert B; Wu, Yiran; Qu, Lu; Pu, Mengchen; Korde, Anisha; Jiang, Shan; Ho, Jo-Hao; Han, Gye Won; Ding, Kang; Li, Xuanxuan; Liu, Haiguang; Hanson, Michael A; Zhao, Suwen; Bohn, Laura M; Makriyannis, Alexandros; Stevens, Raymond C; Liu, Zhi-Jie

    2017-07-27

    The cannabinoid receptor 1 (CB1) is the principal target of the psychoactive constituent of marijuana, the partial agonist Δ(9)-tetrahydrocannabinol (Δ(9)-THC). Here we report two agonist-bound crystal structures of human CB1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 Å and 2.95 Å resolution, respectively. The two CB1-agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state, including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G-protein-binding region. In addition, a 'twin toggle switch' of Phe200(3.36) and Trp356(6.48) (superscripts denote Ballesteros-Weinstein numbering) is experimentally observed and appears to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB1 and provide a molecular basis for predicting the binding modes of Δ(9)-THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB1 seems to be a common feature among certain class A G-protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.

  20. Characterization of CB1 cannabinoid receptor immunoreactivity in postmortem human brain homogenates.

    Science.gov (United States)

    De Jesús, M López; Sallés, J; Meana, J J; Callado, L F

    2006-06-30

    The CB1 cannabinoid receptor (CB1) is the predominant type of cannabinoid receptor in the CNS, in which it displays a unique anatomical distribution and is present at higher densities than most other known seven transmembrane domain receptors. Nevertheless, as with almost all seven transmembrane domain receptors, the tertiary and quaternary structure of this receptor is still unknown. Studies of CB1 in rat cerebral tissue are scarce, and even less is known regarding the expression of CB1 in the human brain. Thus, the aim of the present work was to characterize CB1 expression in membranes from postmortem human brain using specific antisera raised against this protein. Western blot analysis of P1 and P2 fractions, and crude plasma membrane preparations from the prefrontal cortex showed that CB1 migrated as a 60 kDa monomer under reducing conditions. These data were confirmed by blotting experiments carried out with human U373MG astrocytoma cells as a positive control for CB1 expression and wild-type CHO cells as negative control. In addition, when proteins were solubilized in the absence of dithiothreitol, the anti-human CB1 antiserum detected a new band migrating at around 120 kDa corresponding in size to a putative CB1 dimer. This band was sensitive to reducing agents (50 mM dithiothreitol) and showed sodium dodecylsulphate stability, suggesting the existence of disulfide-linked CB1 dimers in the membrane preparations. Important differences in the anatomical distribution of CB1 were observed with regard to that described previously in monkey and rat; in the human brain, CB1 levels were higher in cortex and caudate than in the cerebellum.

  1. Pharmacokinetics of bisphenol S in humans after single oral administration.

    Science.gov (United States)

    Oh, Jiwon; Choi, Jeong Weon; Ahn, Young-Ah; Kim, Sungkyoon

    2017-12-19

    Bisphenol S (BPS) has been introduced as a substitute for bisphenol A (BPA), and widely used in the manufacture of polycarbonate plastics, epoxy resins and thermal papers. Despite its adverse health outcomes and widespread exposure, pharmacokinetic data of BPS are not available for either animals or humans. The objective of the study is to describe pharmacokinetic characteristics of BPS in human body after a single oral administration with a compartmental pharmacokinetic model. Seven healthy young adults were orally exposed to 8.75μg/bw of d4-BPS, and serum and urine samples were collected for 48h. The concentrations of total and unconjugated d4-BPS in samples were measured using HPLC-MS/MS. Based on the time-concentration profiles in serum and urine, non-compartmental analysis was performed, and two-compartment model was constructed and validated. As a result of non-compartmental analysis, total d4-BPS was rapidly absorbed within 1h (0.7±0.3h) after oral administration, and excreted in urine with terminal half-life of BPS for 48h was 92±17% (67-104%) for men and 70±36% (59-77%) for women. The two-compartment model well described pharmacokinetic properties of BPS, and its parameter estimates were consistent with those from non-compartmental analysis. This study provides information on absorption, distribution, metabolism and elimination of BPS in human body, and the pharmacokinetic model can be utilized for estimating exposure dose of BPS, contributing to more realistic exposure assessment. Copyright © 2017. Published by Elsevier Ltd.

  2. 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.

  3. Pyrolysis of UR-144, a synthetic cannabinoid, augments an affinity to human CB1receptor and cannabimimetic effects in mice.

    Science.gov (United States)

    Kaizaki-Mitsumoto, Asuka; Hataoka, Kyoko; Funada, Masahiko; Odanaka, Yuki; Kumamoto, Hiroki; Numazawa, Satoshi

    2017-01-01

    Drug abusers most often smoke 'herbal incense' as a cigarette or inhale it using a smoking tool. Smoking may cause pyrolysis of the drug and produce decomposed products of which biological effect has never been investigated. The synthetic cannabinoid UR-144 is known to undergo thermal degradation, giving a ring-opened isomer, so-called UR-144 degradant. The present study demonstrates by using UR-144 as a model drug that the smoke of burned UR-144 contains the UR-144 degradant. The UR-144 degradant showed approximately four fold higher agonist activity to human CB 1 receptor and augmented hypothermic and akinetic actions in mice compared to UR-144. These results indicate that smoking behavior may increase psychological actions of the certain synthetic cannabinoids.

  4. Metabolite profiling of RCS-4, a novel synthetic cannabinoid designer drug, using human hepatocyte metabolism and TOF-MS

    Science.gov (United States)

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

    2014-01-01

    Background Since 2009, scheduling legislation of synthetic cannabinoids prompted new compound emergence to circumvent legal restrictions. 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4) is a potent cannabinoid receptor agonist sold in herbal smoking blends. Absence of parent synthetic cannabinoids in urine suggests the importance of metabolite identification for detecting RCS-4 consumption in clinical and forensic investigations. Materials & methods & Results With 1 h human hepatocyte incubation and TOF high-resolution MS, we identified 18 RCS-4 metabolites, many not yet reported. Most metabolites were hydroxylated with or without demethylation, carboxylation and dealkylation followed by glucuronidation. One additional sulfated metabolite was also observed. O-demethylation was the most common biotransformation and generated the major metabolite. Conclusion For the first time, we present a metabolic scheme of RCS-4 obtained from human hepatocytes, including Phase I and II metabolites. Metabolite structural information and associated high-resolution mass spectra can be employed for developing clinical and forensic laboratory RCS-4 urine screening methods. PMID:25046048

  5. The activation of cannabinoid CB2 receptors stimulates in situ and in vitro beta-amyloid removal by human macrophages.

    Science.gov (United States)

    Tolón, Rosa María; Núñez, Estefanía; Pazos, María Ruth; Benito, Cristina; Castillo, Ana Isabel; Martínez-Orgado, José Antonio; Romero, Julián

    2009-08-04

    The endocannabinoid system is a promising therapeutic target in a wide variety of diseases. However, the non-desirable psychotropic effects of natural and synthetic cannabinoids have largely counteracted their clinical usefulness. These effects are mostly mediated by cannabinoid receptors of the CB(1) type, that exhibit a wide distribution in neuronal elements of the CNS. Thus, the presence of other elements of this system in the CNS, such as CB(2) receptors, may open new possibilities for the development of cannabinoid-based therapies. These receptors are almost absent from the CNS in normal conditions but are up-regulated in glial cells under chronic neuroinflammatory stimuli, as has been described in Alzheimer's disease. To understand the functional role of these receptors, we tested their role in the process of beta-amyloid removal, that is currently considered as one of the most promising experimental approaches for the treatment of this disease. Our results show that a CB(2) agonist (JWH-015) is capable of inducing the removal of native beta-amyloid removal from human frozen tissue sections as well as of synthetic pathogenic peptide by a human macrophage cell line (THP-1). Remarkably, this effect was achieved at low doses (maximum effect at 10 nM) and was specific for this type of cells, as U373MG astrocytoma cells did not respond to the treatment. The effect was CB(2)-mediated, at least partially, as the selective CB(2) antagonist SR144528 prevented the JWH-015-induced plaque removal in situ. These data corroborate the possible therapeutic interest of CB(2) cannabinoid specific chemicals in the treatment of Alzheimer's disease.

  6. Ligand-specific homology modeling of human cannabinoid (CB1) receptor.

    Science.gov (United States)

    Ai, Rizi; Chang, Chia-en A

    2012-09-01

    Cannabinoid (CB1) receptor is a therapeutic drug target, and its structure and conformational changes after ligand binding are of great interest. To study the protein conformations in ligand bound state and assist in drug discovery, CB1 receptor homology models are needed for computer-based ligand screening. The known CB1 ligands are highly diverse structurally, so CB1 receptor may undergo considerable conformational changes to accept different ligands, which is challenging for molecular docking methods. To account for the flexibility of CB1 receptor, we constructed four CB1 receptor models based on four structurally distinct ligands, HU-210, ACEA, WIN55212-2 and SR141716A, using the newest X-ray crystal structures of human β₂ adrenergic receptor and adenosine A(2A) receptor as templates. The conformations of these four CB1-ligand complexes were optimized by molecular dynamics (MD) simulations. The models revealed interactions between CB1 receptor and known binders suggested by experiments and could successfully discriminate known ligands and non-binders in our docking assays. MD simulations were used to study the most flexible ligand, ACEA, in its free and bound states to investigate structural mobility achieved by the rearrangement of the fatty acid chain. Our models may capture important conformational changes of CB1 receptor to help improve accuracy in future CB1 drug screening. Copyright © 2012 Elsevier Inc. All rights reserved.

  7. Incretin secretion in humans is under the influence of cannabinoid receptors.

    Science.gov (United States)

    Chia, Chee W; Carlson, Olga D; Liu, David D; González-Mariscal, Isabel; Santa-Cruz Calvo, Sara; Egan, Josephine M

    2017-09-01

    The mechanisms regulating incretin secretion are not fully known. Human obesity is associated with altered incretin secretion and elevated endocannabinoid levels. Since cannabinoid receptors (CBRs) are expressed on incretin-secreting cells in rodents, we hypothesized that endocannabinoids are involved in the regulation of incretin secretion. We compared plasma glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) responses during oral glucose tolerance test (OGTT) in 20 lean and 20 obese participants from the Baltimore Longitudinal Study of Aging (BLSA). Next, we recruited 20 healthy men to evaluate GIP and GLP-1 responses during OGTT after administering placebo or nabilone (CBR agonist) in a randomized, double-blind, crossover fashion. Compared with the BLSA lean group, the BLSA obese group had significantly higher fasting and post-OGTT GIP levels, but similar fasting GLP-1 and significantly lower post-OGTT GLP-1 levels. In the nabilone vs. placebo study, when compared with placebo, nabilone resulted in significantly elevated post-dose fasting GIP levels and post-OGTT GIP levels, but no change in post-dose fasting GLP-1 levels together with significantly lower post-OGTT GLP-1 levels. Glucose levels were not different with both interventions. We conclude that elevated GIP levels in obesity are likely a consequence of increased endocannabinoid levels. CBRs exert tonic control over GIP secretion, which may have a homeostatic effect in suppressing GLP-1 secretion. This raises the possibility that gut hormones are influenced by endocannabinoids.

  8. Evaluation of anti-invasion effect of cannabinoids on human hepatocarcinoma cells.

    Science.gov (United States)

    Pourkhalili, Nazila; Ghahremani, Mohammad Hossein; Farsandaj, Narges; Tavajohi, Shohreh; Majdzadeh, Maryam; Parsa, Maliheh; Lavasani, Nasir Jafar; Ostad, Seyed Nasser

    2013-02-01

    Cancer is a disease characterized by abnormal growth of cells. One of the most common types of liver cancers is called hepatocellular carcinoma (HCC) which is highly metastatic. As most of cannabinoids have shown anticancer effect against different cell lines in a number of reports, a biological investigation of two cannabinoids, CB65 (CB2 receptor agonist) and ACEA (CB1 receptor agonist) was carried out in this study. In an attempt to find natural products as a new solution of cancer, this study was designed to investigate the potential antitumoral and anti-invasive activity of cannabinoids on HepG2 cells and the possible roles of matrix metalloproteinase-2 (MMP-2) and MMP-9 in its action. The researchers examined the effect of various concentrations of CB65 (CB2 receptor agonist) and ACEA (CB1 receptor agonist), on the cell proliferation, viability, and invasion as well as expression of MMP-2 and MMP-9 in HepG2 cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay, matrigel invasion assay, and western blotting method. The results revealed that both cannabinoids reduce cell viability, cell invasion as well as MMP-2 and MMP-9 expression in higher dose of 20 nM. Furthermore, higher concentrations of examined cannabinoids were more effective. These data suggest ACEA and CB65 as an option for novel treatment of hepatocellular cancer. Our findings may contribute to design of new therapeutic strategies for the management of HCC.

  9. Cannabis Edibles: Blood and Oral Fluid Cannabinoid Pharmacokinetics and Evaluation of Oral Fluid Screening Devices for Predicting Δ9-Tetrahydrocannabinol in Blood and Oral Fluid following Cannabis Brownie Administration.

    Science.gov (United States)

    Newmeyer, Matthew N; Swortwood, Madeleine J; Andersson, Maria; Abulseoud, Osama A; Scheidweiler, Karl B; Huestis, Marilyn A

    2017-03-01

    Roadside oral fluid (OF) Δ9-tetrahydrocannabinol (THC) detection indicates recent cannabis intake. OF and blood THC pharmacokinetic data are limited and there are no on-site OF screening performance evaluations after controlled edible cannabis. We reviewed OF and blood cannabinoid pharmacokinetics and performance evaluations of the Draeger DrugTest®5000 (DT5000) and Alere™ DDS®2 (DDS2) on-site OF screening devices. We also present data from a controlled oral cannabis administration session. OF THC maximum concentrations (Cmax) were similar in frequent as compared to occasional smokers, while blood THC Cmax were higher in frequent [mean (range) 17.7 (8.0-36.1) μg/L] smokers compared to occasional [8.2 (3.2-14.3) μg/L] smokers. Minor cannabinoids Δ9-tetrahydrocannabivarin and cannabigerol were never detected in blood, and not in OF by 5 or 8 h, respectively, with 0.3 μg/L cutoffs. Recommended performance (analytical sensitivity, specificity, and efficiency) criteria for screening devices of ≥80% are difficult to meet when maximizing true positive (TP) results with confirmation cutoffs below the screening cutoff. TPs were greatest with OF confirmation cutoffs of THC ≥1 and ≥2 μg/L, but analytical sensitivities were 80% with an OF THC ≥5 μg/L cutoff. Performance criteria also were >80% with a blood THC ≥5 μg/L confirmation cutoff; however, positive OF screening results might not confirm due to the time required to collect blood after a crash or police stop. OF confirmation is recommended for roadside OF screening.ClinicalTrials.gov identification number: NCT02177513. © 2016 American Association for Clinical Chemistry.

  10. The Synthetic Cannabinoids Phenomenon.

    Science.gov (United States)

    Karila, Laurent; Benyamina, Amine; Blecha, Lisa; Cottencin, Olivier; Billieux, Joël

    2016-01-01

    « Spice » is generally used to describe the diverse types of herbal blends that encompass synthetic cannabinoids on the market. The emergence of smokable herbal products containing synthetic cannabinoids, which mimic the effects of cannabis, appears to become increasingly popular, in the new psychoactive substances landscape. In 2014, the existence of 134 different types of synthetic cannabinoids were reported by the European Union Early Warning System. These drugs are mainly sold online as an alternative to controlled and regulated psychoactive substances. They appear to have a life cycle of about 1-2 years before being replaced by a next wave of products. Legislation controlling these designer drugs has been introduced in many countries with the objective to limit the spread of existing drugs and control potential new analogs. The majority of the synthetic cannabinoids are full agonists at the CB1 receptor and do not contain tobacco or cannabis. They are becoming increasingly popular in adolescents, students and clubbers as an abused substance. Relatively high incidence of adverse effects associated with synthetic cannabinoids use has been documented in the literature. Numerous fatalities linked with their use and abuse have been reported. In this paper, we will review the available data regarding the use and effects of synthetic cannabinoids in humans in order to highlight their impact on public health. To reach this objective, a literature search was performed on two representative databases (Pubmed, Google Scholar), the Erowid Center website (a US non-profit educational organization that provides information about psychoactive plants and chemicals), and various governmental websites. The terms used for the database search were: "synthetic cannabinoids", "spice", "new psychoactive substances", and/or "substance use disorder", and/or "adverse effects", and/or "fatalities". The search was limited to years 2005 to 2016 due to emerging scientific literature at

  11. Development of a Human Physiologically Based Pharmacokinetics (PBPK) Model For Dermal Permeability for Lindane

    Science.gov (United States)

    Lindane is a neurotoxicant used for the treatment of lice and scabies present on human skin. Due to its pharmaceutical application, an extensive pharmacokinetic database exists in humans. Mathematical diffusion models allow for calculation of lindane skin permeability coefficient...

  12. Variation in the human cannabinoid receptor CNR1 gene modulates gaze duration for happy faces

    Directory of Open Access Journals (Sweden)

    Chakrabarti Bhismadev

    2011-06-01

    Full Text Available Abstract Background From an early age, humans look longer at preferred stimuli and also typically look longer at facial expressions of emotion, particularly happy faces. Atypical gaze patterns towards social stimuli are common in autism spectrum conditions (ASC. However, it is unknown whether gaze fixation patterns have any genetic basis. In this study, we tested whether variations in the cannabinoid receptor 1 (CNR1 gene are associated with gaze duration towards happy faces. This gene was selected because CNR1 is a key component of the endocannabinoid system, which is involved in processing reward, and in our previous functional magnetic resonance imaging (fMRI study, we found that variations in CNR1 modulate the striatal response to happy (but not disgust faces. The striatum is involved in guiding gaze to rewarding aspects of a visual scene. We aimed to validate and extend this result in another sample using a different technique (gaze tracking. Methods A total of 30 volunteers (13 males and 17 females from the general population observed dynamic emotional expressions on a screen while their eye movements were recorded. They were genotyped for the identical four single-nucleotide polymorphisms (SNPs in the CNR1 gene tested in our earlier fMRI study. Results Two SNPs (rs806377 and rs806380 were associated with differential gaze duration for happy (but not disgust faces. Importantly, the allelic groups associated with a greater striatal response to happy faces in the fMRI study were associated with longer gaze duration at happy faces. Conclusions These results suggest that CNR1 variations modulate the striatal function that underlies the perception of signals of social reward, such as happy faces. This suggests that CNR1 is a key element in the molecular architecture of perception of certain basic emotions. This may have implications for understanding neurodevelopmental conditions marked by atypical eye contact and facial emotion processing

  13. Retracted: Physiologically based pharmacokinetic predictions of intestinal BCRP-mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans.

    Science.gov (United States)

    Bae, Soo Hyeon; Park, Wan-Su; Han, Seunghoon; Park, Gab-Jin; Lee, Jongtae; Hong, Taegon; Jeon, Sangil; Yim, Dong-Seok

    2017-07-01

    'Physiologically based pharmacokinetic predictions of intestinal BCRP-mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans' by Soo Hyeon Bae, Wan-Su Park, Seunghoon Han, Gab-jin Park, Jongtae Lee, Taegon Hong, Sangil Jeon and Dong-Seok Yim The above article, published online on 06 February 2017 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor in Chief, K. Sandy Pang, and John Wiley & Sons, Ltd. The authors retracted the paper due to errors associated with use of log D vs. log P of telmisartan as inputs of the PBPK model. The authors concluded that there are too many changes in the article to be resolved by an Erratum, and had requested a retraction. Reference Bae, S. H., Park, W.-S., Han, S., Park, G., Lee, J., Hong, T., Jeon, S., and Yim, D.-S. (2016) Physiologically based pharmacokinetic predictions of intestinal BCRP-mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans. Biopharm. Drug Dispos., doi: 10.1002/bdd.2060. Copyright © 2016 John Wiley & Sons, Ltd.

  14. Cannabinoids in health and disease

    Science.gov (United States)

    Kogan, Natalya M.; Mechoulam, Raphael

    2007-01-01

    Cannabis sativa L. preparations have been used in medicine for millenia. However, concern over the dangers of abuse led to the banning of the medicinal use of marijuana in most countries in the 1930s. Only recently, marijuana and individual natural and synthetic cannabinoid receptor agonists and antagonists, as well as chemically related compounds, whose mechanism of action is still obscure, have come back to being considered of therapeutic value. However, their use is highly restricted. Despite the mild addiction to cannabis and the possible enhancement of addiction to other substances of abuse, when combined with cannabis, the therapeutic value of cannabinoids is too high to be put aside. Numerous diseases, such as anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Tourette's syndrome, Alzheimer's disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders, to name just a few, are being treated or have the potential to be treated by cannabinoid agonists/antagonists/cannabinoid-related compounds. In view of the very low toxicity and the generally benign side effects of this group of compounds, neglecting or denying their clinical potential is unacceptable - instead, we need to work on the development of more selective cannabinoid receptor agonists/antagonists and related compounds, as well as on novel drugs of this family with better selectivity, distribution patterns, and pharmacokinetics, and - in cases where it is impossible to separate the desired clinical action and the psychoactivity - just to monitor these side effects carefully. PMID:18286801

  15. 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.

  16. Prediction of Human Pharmacokinetics of Ulixertinib, a Novel ERK1/2 Inhibitor from Mice, Rats, and Dogs Pharmacokinetics.

    Science.gov (United States)

    Suresh, Ponnayyan Sulochana; Jairam, Ravi Kumar; Chandrasekhar, Devaraj V; Vinod, Anera Balakrishna; Hiremath, Rakesh A; Raj, Anusha; Zainuddin, Mohd; Bhamidipati, Ravi Kanth; Mullangi, Ramesh

    2018-02-22

    Ulixertinib (BVD-523) is a novel and selective reversible inhibitor of ERK1/ERK2. The primary objectives of the study were to evaluate the pharmacokinetics of ulixertinib in mice, rats, and dogs followed by prediction of human pharmacokinetic profile by allometric equations with/without correction factors. Oral and intravenous pharmacokinetic profiles of ulixertinib were generated in mice, rats, and dogs. The human intravenous pharmacokinetics profiles [volume of distribution (V ss ) and clearance (CL)] were predicted employing simple allometry and using correction factors [maximum life span potential (MLP) and brain weight (BW)]. Pharmacokinetic data obtained from dogs were used to simulate human oral profile [area under the curve (AUC) and maximum plasma concentrations (C max )]. Post-intravenous administration the CL was moderate in dogs (15.5 mL/min/kg) and low in mice (6.24 mL/min/kg) and rats (1.67 mL/min/kg). V ss was 0.56, 0.36, and 1.61 L/kg in mice, rats, and dogs, respectively. The half-life (t ½ ) of ulixertinib ranged between 1.0 and 2.5 h across the animal species. Following oral administration ulixertinib attained maximum concentration in plasma (T max ) within 0.50-0.75 h in mice and rats, indicating that absorption was rapid; however, in dogs, T max attained at 2 h. Absolute oral bioavailability in mice and rats was > 92%; however, in dogs, it was 34%. By different allometric approaches, simple method and brain weight correction factor shown clear improvement in the prediction efficiency of allometric scaling for V ss (1.34-1.70 L/kg) and CL (4.18-6.09 mL/min/kg), respectively, comparing with the MLP method and simple method for CL. Similarly, simulation of oral human profile was attained from scaled values and dog data to predict reported human profile (AUC and C max ). The derived pharmacokinetic parameters (AUC and C max at 600 mg dose) and simulated plasma concentration-time profiles of ulixertinib in humans were predicted with good

  17. Pharmacokinetics and leukocyte responses of recombinant human interleukin-10.

    Science.gov (United States)

    Radwanski, E; Chakraborty, A; Van Wart, S; Huhn, R D; Cutler, D L; Affrime, M B; Jusko, W J

    1998-12-01

    To study the pharmacokinetics and ex vivo leukocyte responses of recombinant human IL-10 (rHuIL-10) following single s.c. and i.v. dosing. A randomized two-way cross-over study was undertaken in 17 healthy volunteers in which rHuIL-10 was administered as 25 microg/kg s.c. and i.v. doses. Blood samples were collected for 48 hr after dosing to determine serum IL-10 concentrations. Inhibitory activity of IL-10 on ex vivo production of inflammatory cytokines (TNF-alpha and IL-1beta) by LPS-treated peripheral blood cells were measured over 96 hr. A physiologically-relevant modeling approach was developed to determine the pharmacokinetics for two routes of administration (s.c. and i.v.). The i.v. dose showed polyexponential disposition with CL of 65 mL/kg/hr, Vss of 70 mL/kg, and t1/2 of 1.94 hr. Absolute bioavailability averaged 42% for s.c. dosing which produced lower but sustained concentrations. Substantial and prolonged suppression of TNF-alpha and IL-1beta production was achieved during IL-10 treatment. The Hill Function was used to account for the joint concentration-dependent immunosuppressive action of rHuIL-10 after both i.v. and s.c. doses. The IC50 values were about 0.03 ng/ml and Imax values were about 0.85 for both TNF-alpha and IL-1beta suppression. The degree of change as well as the duration of leukocyte response was greater after s.c. administration than after i.v. administration. rHuIL-10 shows favorable PKPD characteristics especially by the s.c. route of administration which produced prolonged suppression of cytokine production (ex vivo) which may be applicable in various immune-related disorders.

  18. Application of in silico, in vitro and preclinical pharmacokinetic data for the effective and efficient prediction of human pharmacokinetics.

    Science.gov (United States)

    Grime, Kenneth H; Barton, Patrick; McGinnity, Dermot F

    2013-04-01

    In the present age of pharmaceutical research and development, focused delivery of decision making data is more imperative than ever before. Resulting from several years' success, failure and consequential learning, this article also proffers advice and guidance on which in vitro and in vivo experiments to perform to facilitate efficient and cost-effective pursuit of candidate drugs with acceptable human pharmacokinetic profiles. Predictive in silico models are important in directing design toward compounds with the highest probability of having suitable DMPK properties rather than in predicting human pharmacokinetics per se, and the value and utility of such approaches are reviewed with the intention of providing direction to DMPK scientists. Relating to absorption, distribution, elimination and effective half-life, strategies are described to provide direction in commonly encountered scenarios.

  19. Human urine and plasma concentrations of bisphenol A extrapolated from pharmacokinetics established in in vivo experiments with chimeric mice with humanized liver and semi-physiological pharmacokinetic modeling.

    Science.gov (United States)

    Miyaguchi, Takamori; Suemizu, Hiroshi; Shimizu, Makiko; Shida, Satomi; Nishiyama, Sayako; Takano, Ryohji; Murayama, Norie; Yamazaki, Hiroshi

    2015-06-01

    The aim of this study was to extrapolate to humans the pharmacokinetics of estrogen analog bisphenol A determined in chimeric mice transplanted with human hepatocytes. Higher plasma concentrations and urinary excretions of bisphenol A glucuronide (a primary metabolite of bisphenol A) were observed in chimeric mice than in control mice after oral administrations, presumably because of enterohepatic circulation of bisphenol A glucuronide in control mice. Bisphenol A glucuronidation was faster in mouse liver microsomes than in human liver microsomes. These findings suggest a predominantly urinary excretion route of bisphenol A glucuronide in chimeric mice with humanized liver. Reported human plasma and urine data for bisphenol A glucuronide after single oral administration of 0.1mg/kg bisphenol A were reasonably estimated using the current semi-physiological pharmacokinetic model extrapolated from humanized mice data using algometric scaling. The reported geometric mean urinary bisphenol A concentration in the U.S. population of 2.64μg/L underwent reverse dosimetry modeling with the current human semi-physiological pharmacokinetic model. This yielded an estimated exposure of 0.024μg/kg/day, which was less than the daily tolerable intake of bisphenol A (50μg/kg/day), implying little risk to humans. Semi-physiological pharmacokinetic modeling will likely prove useful for determining the species-dependent toxicological risk of bisphenol A. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. 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

  1. Endogenous cannabinoids and appetite.

    Science.gov (United States)

    Kirkham, T C; Williams, C M

    2001-06-01

    Since pre-history, Cannabis sativa has been exploited for its potent and manifold pharmacological actions. Amongst the most renowned of these actions is a tendency to provoke ravenous eating. The characterization of the psychoactive principals in cannabis (exogenous cannabinoids) and, more recently, the discovery of specific brain cannabinoid receptors and their endogenous ligands (endocannabinoids) has stimulated research into the physiological roles of endocannabinoid systems. In this review, we critically discuss evidence from the literature that describe studies on animals and human subjects to support endocannabinoid involvement in the control of appetite. We describe the hyperphagic actions of the exogenous cannabinoid, Delta9-tetrahydrocannabinol, and the endogenous CB1 ligands, anandamide and 2-arachidonylglycerol, and present evidence to support a specific role of endocannabinoid systems in appetitive processes related to the incentive and reward properties of food. A case is made for more comprehensive and systematic analyses of cannabinoid actions on eating, in the anticipation of improved therapies for disorders of appetite and body weight, and a better understanding of the biopsychological processes underlying hunger.

  2. 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.

  3. The Endocannabinoid/Endovanilloid N-Arachidonoyl Dopamine (NADA) and Synthetic Cannabinoid WIN55,212-2 Abate the Inflammatory Activation of Human Endothelial Cells*

    Science.gov (United States)

    Wilhelmsen, Kevin; Khakpour, Samira; Tran, Alphonso; Sheehan, Kayla; Schumacher, Mark; Xu, Fengyun; Hellman, Judith

    2014-01-01

    Although cannabinoids, such as Δ9-tetrahydrocannabinol, have been studied extensively for their psychoactive effects, it has become apparent that certain cannabinoids possess immunomodulatory activity. Endothelial cells (ECs) are centrally involved in the pathogenesis of organ injury in acute inflammatory disorders, such as sepsis, because they express cytokines and chemokines, which facilitate the trafficking of leukocytes to organs, and they modulate vascular barrier function. In this study, we find that primary human ECs from multiple organs express the cannabinoid receptors CB1R, GPR18, and GPR55, as well as the ion channel transient receptor potential cation channel vanilloid type 1. In contrast to leukocytes, CB2R is only minimally expressed in some EC populations. Furthermore, we show that ECs express all of the known endocannabinoid (eCB) metabolic enzymes. Examining a panel of cannabinoids, we demonstrate that the synthetic cannabinoid WIN55,212-2 and the eCB N-arachidonoyl dopamine (NADA), but neither anandamide nor 2-arachidonoylglycerol, reduce EC inflammatory responses induced by bacterial lipopeptide, LPS, and TNFα. We find that endothelial CB1R/CB2R are necessary for the effects of NADA, but not those of WIN55,212-2. Furthermore, transient receptor potential cation channel vanilloid type 1 appears to counter the anti-inflammatory properties of WIN55,212-2 and NADA, but conversely, in the absence of these cannabinoids, its inhibition exacerbates the inflammatory response in ECs activated with LPS. These data indicate that the eCB system can modulate inflammatory activation of the endothelium and may have important implications for a variety of acute inflammatory disorders that are characterized by EC activation. PMID:24644287

  4. The endocannabinoid/endovanilloid N-arachidonoyl dopamine (NADA) and synthetic cannabinoid WIN55,212-2 abate the inflammatory activation of human endothelial cells.

    Science.gov (United States)

    Wilhelmsen, Kevin; Khakpour, Samira; Tran, Alphonso; Sheehan, Kayla; Schumacher, Mark; Xu, Fengyun; Hellman, Judith

    2014-05-09

    Although cannabinoids, such as Δ(9)-tetrahydrocannabinol, have been studied extensively for their psychoactive effects, it has become apparent that certain cannabinoids possess immunomodulatory activity. Endothelial cells (ECs) are centrally involved in the pathogenesis of organ injury in acute inflammatory disorders, such as sepsis, because they express cytokines and chemokines, which facilitate the trafficking of leukocytes to organs, and they modulate vascular barrier function. In this study, we find that primary human ECs from multiple organs express the cannabinoid receptors CB1R, GPR18, and GPR55, as well as the ion channel transient receptor potential cation channel vanilloid type 1. In contrast to leukocytes, CB2R is only minimally expressed in some EC populations. Furthermore, we show that ECs express all of the known endocannabinoid (eCB) metabolic enzymes. Examining a panel of cannabinoids, we demonstrate that the synthetic cannabinoid WIN55,212-2 and the eCB N-arachidonoyl dopamine (NADA), but neither anandamide nor 2-arachidonoylglycerol, reduce EC inflammatory responses induced by bacterial lipopeptide, LPS, and TNFα. We find that endothelial CB1R/CB2R are necessary for the effects of NADA, but not those of WIN55,212-2. Furthermore, transient receptor potential cation channel vanilloid type 1 appears to counter the anti-inflammatory properties of WIN55,212-2 and NADA, but conversely, in the absence of these cannabinoids, its inhibition exacerbates the inflammatory response in ECs activated with LPS. These data indicate that the eCB system can modulate inflammatory activation of the endothelium and may have important implications for a variety of acute inflammatory disorders that are characterized by EC activation.

  5. Cannabinoid receptor localization in brain

    Energy Technology Data Exchange (ETDEWEB)

    Herkenham, M.; Lynn, A.B.; Little, M.D.; Johnson, M.R.; Melvin, L.S.; de Costa, B.R.; Rice, K.C. (National Institute of Mental Health, Bethesda, MD (USA))

    1990-03-01

    (3H)CP 55,940, a radiolabeled synthetic cannabinoid, which is 10-100 times more potent in vivo than delta 9-tetrahydrocannabinol, was used to characterize and localize a specific cannabinoid receptor in brain sections. The potencies of a series of natural and synthetic cannabinoids as competitors of (3H)CP 55,940 binding correlated closely with their relative potencies in several biological assays, suggesting that the receptor characterized in our in vitro assay is the same receptor that mediates behavioral and pharmacological effects of cannabinoids, including human subjective experience. Autoradiography of cannabinoid receptors in brain sections from several mammalian species, including human, reveals a unique and conserved distribution; binding is most dense in outflow nuclei of the basal ganglia--the substantia nigra pars reticulata and globus pallidus--and in the hippocampus and cerebellum. Generally high densities in forebrain and cerebellum implicate roles for cannabinoids in cognition and movement. Sparse densities in lower brainstem areas controlling cardiovascular and respiratory functions may explain why high doses of delta 9-tetrahydrocannabinol are not lethal.

  6. Pharmacokinetics and anti-HIV-1 efficacy of negatively charged human serum albumins in mice

    NARCIS (Netherlands)

    Kuipers, M E; Swart, P J; Schutten, Martin; Smit, C; Proost, J H; Osterhaus, A D; Meijer, D K

    Negatively charged albumins (NCAs, with the prototypes succinylated human serum albumin (Suc-HSA) and aconitylated human serum albumin (Aco-HSA)), modified proteins with a potent anti-human immunodeficiency virus type 1 (anti-HIV-1) activity in vitro, were studied for their pharmacokinetic behaviour

  7. Pharmacokinetics and bioavailability of quercetin glycosides in humans.

    Science.gov (United States)

    Graefe, E U; Wittig, J; Mueller, S; Riethling, A K; Uehleke, B; Drewelow, B; Pforte, H; Jacobasch, G; Derendorf, H; Veit, M

    2001-05-01

    Due to its potentially beneficial impact on human health, the polyphenol quercetin has come into the focus of medicinal interest. However, data on the bioavailability of quercetin after oral intake are scarce and contradictory. Previous investigations indicate that the disposition of quercetin may depend on the sugar moiety of the glycoside or the plant matrix. To determine the influence of the sugar moiety or matrix on the absorption of quercetin, two isolated quercetin glycosides and two plant extracts were administered to 12 healthy volunteers in a four-way crossover study. Each subject received an onion supplement or quercetin-4'-O-glucoside (both equivalent to 100 mg quercetin), as well as quercetin-3-O-rutinoside and buckwheat tea (both equivalent to 200 mg quercetin). Samples were analyzed by HPLC with a 12-channel coulometric array detector. In human plasma, only quercetin glucuronides, but no free quercetin, could be detected. There was no significant difference in the bioavailability and pharmacokinetic parameters between the onion supplement and quercetin-4'-O-glucoside. Peak plasma concentrations were 2.3 +/- 1.5 microg x mL(-1) and 2.1 +/- 1.6 microg x mL(-1) (mean +/- SD) and were reached after 0.7 +/- 0.2 hours and 0.7 +/- 0.3 hours, respectively. After administration of buckwheat tea and rutin, however, peak plasma levels were--despite the higher dose-only 0.6 +/- 0.7 microg x mL(-1) and 0.3 +/- 0.3 microg x mL(-1), respectively. Peak concentrations were reached 4.3 +/- 1.8 hours after administration of buckwheat tea and 7.0 +/- 2.9 hours after ingestion of rutin. The terminal elimination half-life was about 11 hours for all treatments. Thus, the disposition of quercetin in humans primarily depends on the sugar moiety. To a minor extent, the plant matrix influences both the rate and extent of absorption in the case of buckwheat tea administration compared with the isolated compound. The site of absorption seems to be different for quercetin-4'-O

  8. 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, 6...

  9. 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

  10. Cannabinoid Hyperemesis

    Directory of Open Access Journals (Sweden)

    Stephen Sullivan

    2010-01-01

    Full Text Available Cannabinoid hyperemesis syndrome is characterized by chronic, heavy use of cannabis, recurrent episodes of severe nausea and intractable vomiting, and abdominal pain. Temporary relief of symptoms is achieved by taking a hot bath or shower, and resolution of the problem when cannabis use is stopped. Failure to recognize the syndrome leads to misdiagnoses such as psychogenic vomiting, the cyclic vomiting syndrome, an eating disorder or ‘drug-seeking behaviour’, and may lead to extensive, expensive and unproductive investigations, psychiatric referrals and ineffective treatments. Other than stopping cannabis use, there is no proven treatment. Why a substance known for its antiemetic properties should cause such a syndrome is unknown.

  11. 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.

  12. Simulation of amoxicillin pharmacokinetics in humans for the prevention of streptococcal endocarditis in rats.

    OpenAIRE

    Fluckiger, U.; Moreillon, P.; Blaser, J.; Bickle, M.; Glauser, M P; Francioli, P.

    1994-01-01

    The pharmacokinetic determinants of successful antibiotic prophylaxis of endocarditis are not precisely known. Differences in half-lives of antibiotics between animals and humans preclude extrapolation of animal results to human situations. To overcome this limitation, we have mimicked in rats the amoxicillin kinetics in humans following a 3-g oral dose (as often used for prophylaxis of endocarditis) by delivering the drug through a computerized pump. Rats with catheter-induced vegetations we...

  13. Fatty acid-modified gapmer antisense oligonucleotide and human serum albumin constructs for pharmacokinetic modulation

    DEFF Research Database (Denmark)

    Hvam, Michael Lykke; Cai, Yunpeng; Dagnæs-Hansen, Frederik

    2017-01-01

    oligonucleotides (ASOs)/albumin constructs. We show by an electrophoretic mobility assay that fatty acid-modified gapmer and human serum albumin (HSA) can self-assemble into constructs that offer favorable pharmacokinetics. The interaction was dependent on fatty acid type (either palmitic or myristic acid), number...

  14. Endo-cannabinoids system and the toxicity of cannabinoids with a biotechnological approach

    Science.gov (United States)

    Niaz, Kamal; Khan, Fazlullah; Maqbool, Faheem; Momtaz, Saeideh; Ismail Hassan, Fatima; Nobakht-Haghighi, Navid; Rahimifard, Mahban; Abdollahi, Mohammad

    2017-01-01

    Cannabinoids have shown diverse and critical effects on the body systems, which alter the physiological functions. Synthetic cannabinoids are comparatively innovative misuse drugs with respect to their nature of synthesis. Synthetic cannabinoids therapy in healthy, chain smokers, and alcoholic individuals cause damage to the immune and nervous system, eventually leading to intoxication throughout the body. Relevant studies were retrieved using major electronic databases such as PubMed, EMBASE, Medline, Scopus, and Google Scholar. The extensive use of Cannabis Sativa L. (C. Sativa) and its derivatives/analogues such as the nonpsychoactive dimethyl heptyl homolog (CBG-DMH), and tetrahydrocannabivarin (THCV) amongst juveniles and adults have been enhanced in recent years. Cannabinoids play a crucial role in the induction of respiratory, reproductive, immune and carcinogenic effects; however, potential data about mutagenic and developmental effects are still insufficient. The possible toxicity associated with the prolong use of cannabinoids acts as a tumor promoter in animal models and humans. Particular synthetic cannabinoids and analogues have low affinity for CB1 or CB2 receptors, while some synthetic members like Δ9-THC have high affinity towards these receptors. Cannabinoids and their derivatives have a direct or indirect association with acute and long-term toxicity. To reduce/attenuate cannabinoids toxicity, pharmaceutical biotechnology and cloning methods have opened a new window to develop cannabinoids encoding the gene tetrahydrocannabinolic acid (THCA) synthase. Plant revolution and regeneration hindered genetic engineering in C. Sativa. The genetic culture suspension of C. Sativa can be transmuted by the use of Agrobacterium tumefaciens to overcome its toxicity. The main aim of the present review was to collect evidence of the endo-cannabinoid system (ECS), cannabinoids toxicity, and the potential biotechnological approach of cannabinoids synthesis. PMID

  15. Cannabinoids in the Cardiovascular System.

    Science.gov (United States)

    Ho, Wing S V; Kelly, Melanie E M

    2017-01-01

    Cannabinoids are known to modulate cardiovascular functions including heart rate, vascular tone, and blood pressure in humans and animal models. Essential components of the endocannabinoid system, namely, the production, degradation, and signaling pathways of endocannabinoids have been described not only in the central and peripheral nervous system but also in myocardium, vasculature, platelets, and immune cells. The mechanisms of cardiovascular responses to endocannabinoids are often complex and may involve cannabinoid CB1 and CB2 receptors or non-CB1/2 receptor targets. Preclinical and some clinical studies have suggested that targeting the endocannabinoid system can improve cardiovascular functions in a number of pathophysiological conditions, including hypertension, metabolic syndrome, sepsis, and atherosclerosis. In this chapter, we summarize the local and systemic cardiovascular effects of cannabinoids and highlight our current knowledge regarding the therapeutic potential of endocannabinoid signaling and modulation. © 2017 Elsevier Inc. All rights reserved.

  16. Cannabinoid receptor binding and messenger RNA expression in human brain: an in vitro receptor autoradiography and in situ hybridization histochemistry study of normal aged and Alzheimer's brains.

    Science.gov (United States)

    Westlake, T M; Howlett, A C; Bonner, T I; Matsuda, L A; Herkenham, M

    1994-12-01

    The distribution and density of cannabinoid receptor binding and messenger RNA expression in aged human brain were examined in several forebrain and basal ganglia structures. In vitro binding of [3H]CP-55,940, a synthetic cannabinoid, was examined by autoradiography in fresh frozen brain sections from normal aged humans (n = 3), patients who died with Alzheimer's disease (n = 5) and patients who died with other forms of cortical pathology (n = 5). In the structures examined--hippocampal formation, neocortex, basal ganglia and parts of the brainstem--receptor binding showed a characteristic pattern of high densities in the dentate gyrus molecular layer, globus pallidus and substantia nigra pars reticulata, moderate densities in the hippocampus, neocortex, amygdala and striatum, and low densities in the white matter and brainstem. In situ hybridization histochemistry of human cannabinoid receptor, a ribonucleotide probe for the human cannabinoid receptor messenger RNA, showed a pattern of extremely dense transcript levels in subpopulations of cells in the hippocampus and cortex, moderate levels in hippocampal pyramidal neurons and neurons of the striatum, amygdala and hypothalamus, and no signal over dentate gyrus granule cells and most of the cells of the thalamus and upper brainstem, including the substantia nigra. In Alzheimer's brains, compared to normal brains, [3H]CP-55,940 binding was reduced by 37-45% in all of the subfields of the hippocampal formation and by 49% in the caudate. Lesser reductions (20-24%) occurred in the substantia nigra and globus pallidus, internal segment. Other neocortical and basal ganglia structures were not different from control levels. Levels of messenger RNA expression did not differ between Alzheimer's and control brains, but there were regionally discrete statistically significant losses of the intensely expressing cells in the hippocampus. The reductions in binding did not correlate with or localize to areas showing

  17. Benzyl derivatives with in vitro binding affinity for human opioid and cannabinoid receptors from the fungus Eurotium repens.

    Science.gov (United States)

    Gao, Jiangtao; León, Francisco; Radwan, Mohamed M; Dale, Olivia R; Husni, Afeef S; Manly, Susan P; Lupien, Shari; Wang, Xiaoning; Hill, Robert A; Dugan, Frank M; Cutler, Horace G; Cutler, Stephen J

    2011-07-22

    Bioassay-guided fractionation of the fungus Eurotium repens resulted in the isolation of two new benzyl derivatives, (E)-2-(hept-1-enyl)-3-(hydroxymethyl)-5-(3-methylbut-2-enyl)benzene-1,4-diol (1) and (E)-4-(hept-1-enyl)-7-(3-methylbut-2-enyl)-2,3-dihydrobenzofuran-2,5-diol (2), along with seven known compounds (3-9) including five benzaldehyde compounds, flavoglaucin (3), tetrahydroauroglaucin (4), dihydroauroglaucin (5), auroglaucin (6), and 2-(2',3-epoxy-1',3'- heptadienyl)-6-hydroxy-5-(3-methyl-2-butenyl)benzaldehyde (7), one diketopiperazine alkaloid, echinulin (8), and 5,7-dihydroxy-4-methylphthalide (9). The chemical structures of these compounds were established on the basis of extensive 1D and 2D NMR and HRMS data. Compounds 1-4 and 6 showed good binding affinity for human opioid or cannabinoid receptors. These findings have important implications for psychoactive studies with this class of compounds.

  18. Pharmacokinetics and oral bioavailability of pidotimod in humans.

    Science.gov (United States)

    Mailland, F; Coppi, G; Silingardi, S

    1994-12-01

    Pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6), a new biological response modifier, was investigated in 3 different pharmacokinetic experiments in healthy volunteers. A first trial was carried out with a cross-over design in 12 subjects, given the drug in single administration by intravenous route (200 mg in bolus) and by oral route at 3 dose levels: 200, 400 and 800 mg (tablets). The second experiment was performed in 36 subjects, by intramuscular route at 50, 100 and 200 mg (12 volunteers/group) twice a day for 15 days. Blood samples were drawn and urine collected at different times after the first and the last administration (29th) of the compound. The third experiment was done in 12 subjects given the product at the same single oral dose (800 mg) in different galenic formulations: sachets, vials and tablets, to assess the relative bioavailability, with a cross-over design. Pidotimod plasma and urinary levels were measured by HPLC. The plasma levels after parenteral administration followed a second-order pharmacokinetic, while after oral administration they were processed by a first order input-output model.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. 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 (marijuana research and clinical practice.

  20. Physiologically based pharmacokinetic modeling of ethyl acetate and ethanol in rodents and humans.

    Science.gov (United States)

    Crowell, S R; Smith, J N; Creim, J A; Faber, W; Teeguarden, J G

    2015-10-01

    A physiologically based pharmacokinetic (PBPK) model was developed and applied to a metabolic series approach for the ethyl series (i.e., ethyl acetate, ethanol, acetaldehyde, and acetate). This approach bases toxicity information on dosimetry analyses for metabolically linked compounds using pharmacokinetic data for each compound and toxicity data for parent or individual compounds. In vivo pharmacokinetic studies of ethyl acetate and ethanol were conducted in rats following IV and inhalation exposure. Regardless of route, ethyl acetate was rapidly converted to ethanol. Blood concentrations of ethyl acetate and ethanol following both IV bolus and infusion suggested linear kinetics across blood concentrations from 0.1 to 10 mM ethyl acetate and 0.01-0.8 mM ethanol. Metabolic parameters were optimized and evaluated based on available pharmacokinetic data. The respiratory bioavailability of ethyl acetate and ethanol were estimated from closed chamber inhalation studies and measured ventilation rates. The resulting ethyl series model successfully reproduces blood ethyl acetate and ethanol kinetics following IV administration and inhalation exposure in rats, and blood ethanol kinetics following inhalation exposure to ethanol in humans. The extrapolated human model was used to derive human equivalent concentrations for the occupational setting of 257-2120 ppm ethyl acetate and 72-517 ppm ethyl acetate for continuous exposure, corresponding to rat LOAELs of 350 and 1500 ppm. Copyright © 2015 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    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 (d6-BPA) delivered in cookies to adult humans after overnight fasting. The availability of the serum concentration time course of unconjugated d6-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 d6-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. Published by Elsevier Inc.

  2. Cannabinoids in late-onset Alzheimer's disease.

    Science.gov (United States)

    Ahmed, Aia; van der Marck, M A; van den Elsen, Gah; Olde Rikkert, Mgm

    2015-06-01

    Given the lack of effective treatments for late-onset Alzheimer's disease (LOAD) and the substantial burden on patients, families, health care systems, and economies, finding an effective therapy is one of the highest medical priorities. The past few years have seen a growing interest in the medicinal uses of cannabinoids, the bioactive components of the cannabis plant, including the treatment of LOAD and other physical conditions that are common in older people. Several in vitro and in vivo studies have demonstrated that cannabinoids can reduce oxidative stress, neuroinflammation, and the formation of amyloid plaques and neurofibrillary tangles, the key hallmarks of LOAD. In addition, in population-based studies, cannabinoids reduced dementia-related symptoms (e.g., behavioral disturbances). The current article provides an overview of the potential of cannabinoids in the treatment of LOAD and related neuropsychiatric symptoms in older people. We also discuss the efficacy, safety, and pharmacokinetics of cannabinoid-based drugs in older people with dementia. © 2015 American Society for Clinical Pharmacology and Therapeutics.

  3. Increased expression of cannabinoid CB₁ receptors in Achilles tendinosis.

    Directory of Open Access Journals (Sweden)

    Emmelie Björklund

    Full Text Available BACKGROUND: The endogenous cannabinoid system is involved in the control of pain. However, little is known as to the integrity of the cannabinoid system in human pain syndromes. Here we investigate the expression of the cannabinoid receptor 1 (CB₁ in human Achilles tendons from healthy volunteers and from patients with Achilles tendinosis. METHODOLOGY: Cannabinoid CB₁ receptor immunoreactivity (CB₁IR was evaluated in formalin-fixed biopsies from individuals suffering from painful Achilles tendinosis in comparison with healthy human Achilles tendons. PRINCIPAL FINDINGS: CB₁IR was seen as a granular pattern in the tenocytes. CB₁IR was also observed in the blood vessel wall and in the perineurium of the nerve. Quantification of the immunoreactivity in tenocytes showed an increase of CB₁ receptor expression in tendinosis tissue compared to control tissue. CONCLUSION: Expression of cannabinoid receptor 1 is increased in human Achilles tendinosis suggesting that the cannabinoid system may be dysregulated in this disorder.

  4. Increased Expression of Cannabinoid CB1 Receptors in Achilles Tendinosis

    Science.gov (United States)

    Björklund, Emmelie; Forsgren, Sture; Alfredson, Håkan; Fowler, Christopher J.

    2011-01-01

    Background The endogenous cannabinoid system is involved in the control of pain. However, little is known as to the integrity of the cannabinoid system in human pain syndromes. Here we investigate the expression of the cannabinoid receptor 1 (CB1) in human Achilles tendons from healthy volunteers and from patients with Achilles tendinosis. Methodology Cannabinoid CB1 receptor immunoreactivity (CB1IR) was evaluated in formalin-fixed biopsies from individuals suffering from painful Achilles tendinosis in comparison with healthy human Achilles tendons. Principal Findings CB1IR was seen as a granular pattern in the tenocytes. CB1IR was also observed in the blood vessel wall and in the perineurium of the nerve. Quantification of the immunoreactivity in tenocytes showed an increase of CB1 receptor expression in tendinosis tissue compared to control tissue. Conclusion Expression of cannabinoid receptor 1 is increased in human Achilles tendinosis suggesting that the cannabinoid system may be dysregulated in this disorder. PMID:21931835

  5. Current Knowledge on Cannabinoids in Oral Fluid

    Science.gov (United States)

    Lee, Dayong; Huestis, Marilyn A.

    2015-01-01

    Oral fluid (OF) is a new biological matrix for clinical and forensic drug testing, offering non-invasive and directly observable sample collection reducing adulteration potential, ease of multiple sample collections, lower biohazard risk during collection, recent exposure identification, and stronger correlation with blood than urine concentrations. Because cannabinoids are usually the most prevalent analytes in illicit drug testing, application of OF drug testing requires sufficient scientific data to support sensitive and specific OF cannabinoid detection. This review presents current knowledge on OF cannabinoids, evaluating pharmacokinetic properties, detection windows, and correlation with other biological matrices and impairment from field applications and controlled drug administration studies. In addition, on-site screening technologies, confirmatory analytical methods, drug stability, and effects of sample collection procedure, adulterants, and passive environmental exposure are reviewed. Delta-9-tetrahydrocannabinol OF concentrations could be > 1000 μg/L shortly after smoking, whereas minor cannabinoids are detected at 10-fold and metabolites at 1000-fold lower concentrations. OF research over the past decade demonstrated that appropriate interpretation of test results requires a comprehensive understanding of distinct elimination profiles and detection windows for different cannabinoids, which are influenced by administration route, dose, and drug use history. Thus, each drug testing program should establish cutoff criteria, collection/analysis procedures, and storage conditions tailored to its purposes. Building a scientific basis for OF testing is on-going, with continuing OF cannabinoids research on passive environmental exposure, drug use history, donor physiological conditions, and oral cavity metabolism needed to better understand mechanisms of cannabinoid OF disposition and expand OF drug testing applicability. PMID:23983217

  6. 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.

  7. 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

  8. Focus on cannabinoids and synthetic cannabinoids.

    Science.gov (United States)

    Le Boisselier, R; Alexandre, J; Lelong-Boulouard, V; Debruyne, D

    2017-02-01

    The recent emergence of a multitude of synthetic cannabinoids (SCs) has generated a wealth of new information, suggesting the usefulness of state-of-the-art on lato sensu cannabinoids. By modulating a plurality of neurotransmission pathways, the endocannabinoid system is involved in many physiological processes that are increasingly explored. SCs desired and adverse effects are considered to be more intense than those observed with cannabis smoking, which is partly explained by the full agonist activity and higher affinity for cannabinoid receptors. Neurological and cardiovascular side effects observed after cannabinoid poisoning generally respond to conventional supportive care, but severe outcomes may occur in a minority of cases, mainly observed with SCs. The likelihood of severe abuse and addiction produced by SCs are of concern for the scientific community also interested in the potential therapeutic value of cannabinoids. © 2016 American Society for Clinical Pharmacology and Therapeutics.

  9. 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.

  10. 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.

  11. Cannabinoids on the brain.

    Science.gov (United States)

    Irving, Andrew J; Rae, Mark G; Coutts, Angela A

    2002-03-09

    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.

  12. 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

  13. Blood concentrations of acrylonitrile in humans after oral administration extrapolated from in vivo rat pharmacokinetics, in vitro human metabolism, and physiologically based pharmacokinetic modeling.

    Science.gov (United States)

    Takano, Ryohji; Murayama, Norie; Horiuchi, Kana; Kitajima, Masato; Kumamoto, Masatoshi; Shono, Fumiaki; Yamazaki, Hiroshi

    2010-11-01

    The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for acrylonitrile in humans based on in vitro metabolic parameters determined using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and a prior previously developed PBPK model in rats. The model basically consists of a chemical absorption compartment, a metabolizing compartment, and a central compartment for acrylonitrile. Evaluation of a previous rat model was performed by comparisons with experimental pharmacokinetic values from blood and urine obtained from rats in vivo after oral treatment with acrylonitrile (30 mg/kg, a no-observed-adverse-effect level) for 14 days. Elimination rates of acrylonitrile in vitro were established using data from rat liver microsomes and from pooled human liver microsomes. Acrylonitrile was expected to be absorbed and cleared rapidly from the body in silico, as was the case for rats confirmed experimentally in vivo with repeated low-dose treatments. These results indicate that the simplified PBPK model for acrylonitrile is useful for a forward dosimetry approach in humans. This model may also be useful for simulating blood concentrations of other related compounds resulting from exposure to low chemical doses. Copyright © 2010 Elsevier Inc. All rights reserved.

  14. 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.

  15. Therapeutic potential of cannabinoid-based drugs.

    Science.gov (United States)

    Klein, Thomas W; Newton, Catherine A

    2007-01-01

    Cannabinoid-based drugs modeled on cannabinoids originally isolated from marijuana are now known to significantly impact the functioning of the endocannabinoid system of mammals. This system operates not only in the brain but also in organs and tissues in the periphery including the immune system. Natural and synthetic cannabinoids are tricyclic terpenes, whereas the endogenous physiological ligands are eicosanoids. Several receptors for these compounds have been extensively described, CB1 and CB2, and are G protein-coupled receptors; however, cannabinoid-based drugs are also demonstrated to function independently of these receptors. Cannabinoids regulate many physiological functions and their impact on immunity is generally antiinflammatory as powerful modulators of the cytokine cascade. This anti-inflammatory potency has led to the testing of these drugs in chronic inflammatory laboratory paradigms and even in some human diseases. Psychoactive and nonpsychoactive cannabinoid-based drugs such as Delta9-tetrahydrocannabinol, cannabidiol, HU-211, and ajulemic acid have been tested and found moderately effective in clinical trials of multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain. Furthermore, although clinical trials are not yet reported, preclinical data with cannabinoid-based drugs suggest efficacy in other inflammatory diseases such as inflammatory bowel disease, Alzheimer's disease, atherosclerosis, and osteoporosis.

  16. Designing microorganisms for heterologous biosynthesis of cannabinoids.

    Science.gov (United States)

    Carvalho, Ângela; Hansen, Esben Halkjær; Kayser, Oliver; Carlsen, Simon; Stehle, Felix

    2017-06-01

    During the last decade, the use of medical Cannabis has expanded globally and legislation is getting more liberal in many countries, facilitating the research on cannabinoids. The unique interaction of cannabinoids with the human endocannabinoid system makes these compounds an interesting target to be studied as therapeutic agents for the treatment of several medical conditions. However, currently there are important limitations in the study, production and use of cannabinoids as pharmaceutical drugs. Besides the main constituent tetrahydrocannabinolic acid, the structurally related compound cannabidiol is of high interest as drug candidate. From the more than 100 known cannabinoids reported, most can only be extracted in very low amounts and their pharmacological profile has not been determined. Today, cannabinoids are isolated from the strictly regulated Cannabis plant, and the supply of compounds with sufficient quality is a major problem. Biotechnological production could be an attractive alternative mode of production. Herein, we explore the potential use of synthetic biology as an alternative strategy for synthesis of cannabinoids in heterologous hosts. We summarize the current knowledge surrounding cannabinoids biosynthesis and present a comprehensive description of the key steps of the genuine and artificial pathway, systems biotechnology needs and platform optimization. © FEMS 2017.

  17. Designing first-in-human dose of coagulation factors: application of pharmacokinetic allometric scaling.

    Science.gov (United States)

    Mahmood, I

    2014-01-01

    The objectives of this study were to (i) evaluate the predictive performance of pharmacokinetic interspecies scaling of coagulation factors to predict clearance (CL) and (ii) project first-in-human dose based on the predicted human CL. Human CL of nine coagulation factors was predicted using two or three animal species using two methods: (i) CL vs. body weight (simple allometry) and where applicable (ii) the product of CL and brain weight vs. body weight. Based on the predicted human CL, four methods were used to project the first-in-human dose. The predicted pharmacokinetic parameters and the estimated first-in-human dose of coagulation factors were compared with the observed human values obtained from clinical trials. The results of the study indicated that the CL of coagulation factors can be predicted with reasonable accuracy in humans and a good estimate of first-in-human dose can be obtained from the predicted human CL. The suggested methods in this study are not only time and cost-effective but also provide rational alternatives to the somewhat arbitrary dose selection process for coagulation factors often used. © 2013 John Wiley & Sons Ltd.

  18. Cannabinoids and cancer: causation, remediation, and palliation.

    Science.gov (United States)

    Hall, Wayne; Christie, MacDonald; Currow, David

    2005-01-01

    This review discusses three different associations between cannabinoids and cancer. First, it assesses evidence that smoking of cannabis preparations may cause cancers of the aerodigestive and respiratory system. There have been case reports of upper-respiratory-tract cancers in young adults who smoke cannabis, but evidence from a few epidemiological cohort studies and case-control studies is inconsistent. Second, there is mixed evidence on the effects of THC and other cannabinoids on cancers: in some in vitro and in vivo studies THC and some synthetic cannabinoids have had antineoplastic effects, but in other studies THC seems to impair the immune response to cancer. As yet there is no evidence that THC or other cannabinoids have anticancer effects in humans. Third, Delta(9)-tetrahydrocannabinol (THC) may treat the symptoms and side-effects of cancer, and there is evidence that it and other cannabinoids may be useful adjuvant treatments that improve appetite, reduce nausea and vomiting, and alleviate moderate neuropathic pain in patients with cancer. The main challenge for the medical use of cannabinoids is the development of safe and effective methods of use that lead to therapeutic effects but that avoid adverse psychoactive effects. Furthermore, medical, legal, and regulatory obstacles hinder the smoking of cannabis for medical purposes. These very different uses of cannabinoids are in danger of being confused in public debate, especially in the USA where some advocates for the medical use of cannabinoids have argued for smoked cannabis rather than pharmaceutical cannabinoids. We review the available evidence on these three issues and consider their implications for policy.

  19. Human Pharmacokinetics of BL-P1654 Compared with Ampicillin

    Science.gov (United States)

    Clarke, John T.; Libke, Robert D.; Ralph, Edward D.; Luthy, Ruedi P.; Kirby, William M. M.

    1974-01-01

    BL-P1654 is a new ureido-penicillin which has significant activity against both pseudomonas and klebsiella. Its pharmacokinetics were evaluated in five studies in four healthy adult male volunteers after 1-g doses given as: 5- and 30-min intravenous infusions, a 30-min infusion 1 h after the oral administration of 1 g of probenecid, and an intramuscular injection. For comparison, volunteers also received a 30-min infusion of 1 g of ampicillin. Serum levels of the antibiotic were found to fit a two-compartment open model using a Burroughs-5500 computer. After a 30-min infusion, peak serum levels of BL-P1654 (72.8 μg/ml [standard deviation] ± 5.9) were 50% greater than those of ampicillin (53.6 ± 8.9). Six hours later, the relative difference was even greater (4.58 ± 0.25 versus 0.35 ± 0.09). At 75 min after the 1-g intramuscular injection of BL-P1654, peak serum levels averaged 28.4 ± 10.3 μg/ml. The half-life of BL-P1654 (2.04 h) was significantly longer than for ampicillin (1.15 h), and the renal clearances of BL-P1654 and ampicillin were 79 versus 244 ml/min per 1.73 m2, respectively. Probenecid produced no significant change in blood levels, volume of distribution, half-life, or renal clearance, indicating that there is no net tubular secretion of this antibiotic. PMID:4455125

  20. Pharmacology of cannabinoids.

    Science.gov (United States)

    Grotenhermen, Franjo

    2004-01-01

    Dronabinol (Delta 9-tetrahydocannabinol, THC), the main source of the pharmacological effects caused by the use of cannabis, is an agonist to both the CB1 and the CB2 subtype of cannabinoid receptors. It is available on prescription in several countries. The non-psychotropic cannabidiol (CBD), some analogues of natural cannabinoids and their metabolites, antagonists at the cannabinoid receptors and modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoid receptors are distributed in the central nervous system and many peripheral tissues including spleen, leukocytes; reproductive, urinary and gastrointestinal tracts; endocrine glands, arteries and heart. Five endogenous cannabinoids have been detected so far, of whom anandamide and 2-arachidonylglycerol are best characterized. There is evidence that besides the two cannabinoid receptor subtypes cloned so far additional cannabinoid receptor subtypes and vanilloid receptors are involved in the complex physiological functions of the cannabinoid system that include motor coordination, memory procession, control of appetite, pain modulation and neuroprotection. Strategies to modulate their activity include inhibition of re-uptake into cells and inhibition of their degradation to increase concentration and duration of action. Properties of cannabinoids that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, anti-inflammation, anti-allergic effects, sedation, improvement of mood, stimulation of appetite, anti-emesis, lowering of intraocular pressure, bronchodilation, neuroprotection and antineoplastic effects.

  1. Pharmacokinetic studies of the fragrance compound 1,8-cineol in humans during inhalation.

    Science.gov (United States)

    Jäger, W; Nasel, B; Nasel, C; Binder, R; Stimpfl, T; Vycudilik, W; Buchbauer, G

    1996-08-01

    The present study was undertaken to investigate the pharmacokinetics of 1,8-cineol in human subjects during prolonged inhalation. The results showed that 1,8-cineol is well absorbed from breathing air, with a peak plasma concentration after approximately 18 min. The elimination of this fragrance compound from the blood is biphasic, with a mean distribution half-life of 6.7 min and an elimination half-life of 104.6 min.

  2. Pharmacokinetic Evaluation of Oral Levofloxacin in Human Immunodeficiency Virus-Infected Subjects Receiving Concomitant Antiretroviral Therapy

    OpenAIRE

    Villani, P.; Viale, P.; Signorini, L.; Cadeo, B.; Marchetti, F.; Villani, A.; Fiocchi, C; Regazzi, M B; Carosi, G

    2001-01-01

    The purpose of this study was to evaluate the pharmacokinetics (PK) profile of oral levofloxacin in human immunodeficiency virus-positive patients in steady-state treatment with nelfinavir (NFV) or with efavirenz (EFV) and to determine the effects of levofloxacin on the PK parameters of these two antiretroviral agents. For levofloxacin, plasma samples were obtained at steady state during a 24-h dosing interval. Plasma NFV and EFV concentrations were evaluated before and after 4 days of levofl...

  3. Detection of the recently emerged synthetic cannabinoid 5F-MDMB-PICA in 'legal high' products and human urine samples.

    Science.gov (United States)

    Mogler, Lukas; Franz, Florian; Rentsch, Daniel; Angerer, Verena; Weinfurtner, Georg; Longworth, Mitchell; Banister, Samuel D; Kassiou, Michael; Moosmann, Bjoern; Auwärter, Volker

    2017-03-31

    Indole or indazole-based synthetic cannabinoids (SCs) bearing substituents derived from valine or tert-leucine are frequently abused new psychoactive substances (NPS). The emergence of 5F-MDMB-PICA (methyl N-{[1-(5-fluoropentyl)-1H-indol-3-yl]carbonyl}-3-methylvalinate) on the German drug market is a further example of a substance synthesized in the context of scientific research being misused by clandestine laboratories by adding it to 'legal high' products. In this work, we present the detection of 5F-MDMB-PICA in several legal high products by gas chromatography-mass spectrometry (GC-MS) analysis. To detect characteristic metabolites suitable for a proof of 5F-MDMB-PICA consumption by urine analysis, pooled human liver microsome (pHLM) assays were performed and evaluated using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QToF-MS) techniques to generate reference spectra of the in vitro phase I metabolites. The in vivo phase I metabolism was investigated by the analysis of more than 20 authentic human urine specimens and compared to the data received from the pHLM assay. Biotransformation of the 5-fluoropentyl side chain and hydrolysis of the terminal methyl ester bond are main phase I biotransformation steps. Two of the identified main metabolites formed by methyl ester hydrolysis or mono-hydroxylation at the indole ring system were evaluated as suitable urinary biomarkers and discussed regarding the interpretation of analytical findings. Exemplary analysis of one urine sample for 5F-MDMB-PICA phase II metabolites showed that two of the main phase I metabolites are subject to extensive glucuronidation prior to renal excretion. Therefore, conjugate cleavage is reasonable for enhancing sensitivity. Commercially available immunochemical pre-tests for urine proved to be unsuitable for the detection of 5F-MDMB-PICA consumption. Copyright © 2017 John Wiley & Sons, Ltd. Copyright

  4. Human solvent exposure. Factors influencing the pharmacokinetics and acute toxicity

    DEFF Research Database (Denmark)

    Bælum, Jesper

    1991-01-01

    The purpose of this review has been to discuss human and environmental factors which may influence the acute irritative and neurotoxic effects of organic solvents. The review is based on a field study and on four human experimental studies. Several studies have shown that printers and other workers...... exposed to mixtures of solvents experience an increased frequency of work related irritative and neurological symptoms although the exposure has been far below the occupational exposure limits. A series of controlled human exposure studies was carried out. Different groups of persons were exposed...

  5. 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.)

  6. Cannabinoid modulations of resting state EEG θ power and working memory are correlated in humans.

    Science.gov (United States)

    Böcker, Koen B E; Hunault, Claudine C; Gerritsen, Jeroen; Kruidenier, Maaike; Mensinga, Tjeert T; Kenemans, J Leon

    2010-09-01

    Object representations in working memory depend on neural firing that is phase-locked to oscillations in the theta band (4-8 Hz). Cannabis intake disrupts synchronicity of theta oscillations and interferes with memory performance. Sixteen participants smoked cigarettes containing 0.0, 29.3, 49.1, or 69.4 mg Delta(9)-tetrahydrocannabinol (THC) in a randomized crossover design and performed working memory and general attention tasks. Dose-dependent effects of THC were observed for resting state EEG theta and beta power, working memory (per-item search time), and attentional performance (percent errors and RT). The THC effects on EEG theta power and memory performance were correlated, whereas other EEG and behavioral effects were not. These findings confirm and extend previous results in rodents and humans, and corroborate a neurocomputational model that postulates that temporal aspects of information processing in working memory depend causally on nested oscillations in the theta and gamma (>30 Hz) bands.

  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

    Mannan-binding lectin (MBL), a human plasma protein, plays an important role in the innate immune defence. MBL recognizes microorganisms through surface carbohydrate structures. Due to genetic polymorphisms, MBL plasma concentrations range from 5 to 10,000 ng/mL. Approximately 30% of the human...... (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...

  8. 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.

  9. Dendritic Cell Regulation by Cannabinoid-Based Drugs

    Directory of Open Access Journals (Sweden)

    Mattias Svensson

    2010-08-01

    Full Text Available Cannabinoid pharmacology has made important advances in recent years after the cannabinoid system was discovered. Studies in experimental models and in humans have produced promising results using cannabinoid-based drugs for the treatment of obesity and cancer, as well as neuroinflammatory and chronic inflammatory diseases. Moreover, as we discuss here, additional studies also indicates that these drugs have immunosuppressive and anti-inflammatory properties including modulation of immune cell function. Thus, manipulation of the endocannabinoid system in vivo may provide novel therapeutic strategies against inflammatory disorders. At least two types of cannabinoid receptors, cannabinoid 1 and cannabinoid 2 receptors are expressed on immune cells such as dendritic cells (DC. Dendritic cells are recognized for their critical role in initiating and maintaining immune responses. Therefore, DC are potential targets for cannabinoid-mediated modulation. Here, we review the effects of cannabinoids on DC and provide some perspective concerning the therapeutic potential of cannabinoids for the treatment of human diseases involving aberrant inflammatory processes.

  10. Pharmacokinetic Study of Nifedipine in Healthy Adult Male Human ...

    African Journals Online (AJOL)

    Conclusion: This study confirms the rapid absorption of nifedipine in humans. AUC was similar to that previously reported for Nigerians but slightly lower than that stated in the literature for other south Asian races. Further studies on large segments of the local population using the non-compartmental model for

  11. Pharmacokinetic Study of Nifedipine in Healthy Adult Male Human ...

    African Journals Online (AJOL)

    Erah

    Conclusion: This study confirms the rapid absorption of nifedipine in humans. AUC was similar to that previously reported for Nigerians but slightly lower than that stated in the literature for other south Asian races. Further studies on large segments of the local population using the non-compartmental model for.

  12. A pharmacokinetic drug-drug interaction model of simvastatin and clarithromycin in humans.

    Science.gov (United States)

    Methaneethorn, Janthima; Chaiwong, Krissanapong; Pongpanich, Komwut; Sonsingh, Phakawat; Lohitnavy, Manupat

    2014-01-01

    Simvastatin is a HMG-CoA reductase Inhibitor and a substrate of CYP3A4. Clarithromycin is a commonly used macrolide antibiotics and a potent inhibitor of CYP3A4. When co-administered with simvastatin, clarithromycin can significantly increase simvastatin plasma concentration levels, thereby, increase the risk of rhabdomyolysis. At present, pharmacokinetic data of the interaction between both drugs are available. However, they are being used for semi-quantitative application only, not for quantitative prediction. We aimed to develop a mathematical model describing a drug-drug interaction between simvastatin and clarithromycin in humans. Selected pharmacokinetic interaction study was obtained from PubMed search. Concentration-time course data were subsequently extracted and used for model development. Compartmental pharmacokinetic interaction model was developed using Advanced Continuous Simulating Language Extreme (ACSLX), a FORTRAN language-based computer program. The drug-drug interaction between simvastatin and clarithromycin was modeled simultaneously with a parent-metabolite model for clarithromycin and a one-compartment model for simvastatin linked to its active form, simvastatin hydroxy acid. The simulated simvastatin concentrations obtained from the final model displayed satisfactory goodness of fit to the data from the literature. Our model could successfully describe concentration-time course of simvastatin-clarithromycin interaction. The resulting interaction model can be able to use for further development of a quantitative model predicting rhabdomyolysis occurrence in patients concurrently receiving simvastatin and clarithromycin.

  13. Cannabinoids and zebrafish

    NARCIS (Netherlands)

    Akhtar, Muhammad Tayyab

    2013-01-01

    Cannabinoids are a group of terpenophenolic compounds and are naturally found in the cannabis plant (Cannabis sativa L). Δ9-Tetrahydrocannabinol (Δ9-THC) is the psychoactive cannabinoid. The high lipophilicity of Δ9-THC is a hindering factor in the further development of this compound into a large

  14. Cannabinoids as Anticancer Drugs.

    Science.gov (United States)

    Ramer, Robert; Hinz, Burkhard

    2017-01-01

    The endocannabinoid system encompassing cannabinoid receptors, endogenous receptor ligands (endocannabinoids), as well as enzymes conferring the synthesis and degradation of endocannabinoids has emerged as a considerable target for pharmacotherapeutical approaches of numerous diseases. Besides palliative effects of cannabinoids used in cancer treatment, phytocannabinoids, synthetic agonists, as well as substances that increase endogenous endocannabinoid levels have gained interest as potential agents for systemic cancer treatment. Accordingly, cannabinoid compounds have been reported to inhibit tumor growth and spreading in numerous rodent models. The underlying mechanisms include induction of apoptosis, autophagy, and cell cycle arrest in tumor cells as well as inhibition of tumor cell invasion and angiogenic features of endothelial cells. In addition, cannabinoids have been shown to suppress epithelial-to-mesenchymal transition, to enhance tumor immune surveillance, and to support chemotherapeutics' effects on drug-resistant cancer cells. However, unwanted side effects include psychoactivity and possibly pathogenic effects on liver health. Other cannabinoids such as the nonpsychoactive cannabidiol exert a comparatively good safety profile while exhibiting considerable anticancer properties. So far experience with anticarcinogenic effects of cannabinoids is confined to in vitro studies and animal models. Although a bench-to-bedside conversion remains to be established, the current knowledge suggests cannabinoid compounds to serve as a group of drugs that may offer significant advantages for patients suffering from cancer diseases. The present review summarizes the role of the endocannabinoid system and cannabinoid compounds in tumor progression. © 2017 Elsevier Inc. All rights reserved.

  15. 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

  16. Cannabinoids: mechanisms and therapeutic applications in the CNS.

    Science.gov (United States)

    Drysdale, Alison J; Platt, Bettina

    2003-12-01

    Cannabinoids comprise three classes of compounds, the active components of marijuana (Cannabis sativa), as well as endogenous and synthetic derivatives. To date, two distinct cannabinoid receptors (CB1 and CB2) have been discovered, but evidence for further receptor types has been brought forward. The potential use of cannabinoids for medicinal purposes has long been known, but the mechanisms of action of both exogenously applied and endogenous cannabinoids are only partly established. For nervous system disorders, cannabinoids may be useful by modulating neurotransmission and calcium homeostasis as well as by anti-inflammatory and anti-oxidant actions. Some cannabinoids can also trigger cell death, which may be of therapeutic benefit in the treatment of malignant tumours. A number of both in vitro and in vivo models have provided promising but diverse evidence for cannabinoid protection in glutamate-mediated excitotoxicity, hypoxia and glucose deprivation, brain trauma, epilepsy and MS. Subsequent to many preclinical investigations, clinical trials are now underway in a variety of the above applications. Overall, the understanding of the therapeutic relevance of cannabinoids will rely on further investigations into the neuroprotective and neurotoxic potency of cannabinoids in animal models and humans, as much as on a further advancement of our general understanding of the endocannabinoid system and the development of specific compounds devoid of unwanted psychoactive side effects.

  17. Comparative pharmacokinetic evaluation of compressed suppositories of diclofenac sodium in humans.

    Science.gov (United States)

    Ramakrishna, S; Fadnavis, N W; Diwan, P V

    1996-02-01

    Diclofenac sodium (CAS 15307-79-6) suppositories were formulated using polyethylene glycol 4000 as the base by dispersing the drug in the molten base, congealing the mass, followed by pulverization, sieving and subsequent compression of the resultant granules. These suppositories were evaluated with respect to their pharmacokinetic behaviour in 12 healthy, male human volunteers. The results were compared with those obtained after oral administration of a commercial enteric coated tablet. Bioequivalence between rectal suppositories and commercial tablets was observed with respect to AUC0-infinity and Cmax. However, tmax differed significantly (p tablet (1.58 +/- 0.06 h). The relative rectal bioavailability was 107.19 +/- 3.2.

  18. 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

    Objective: The purpose of this analysis was to develop a population pharmacokinetic model for a novel recombinant human follicle-stimulating hormone (FSH) (FE 999049) expressed from a human cell line of foetal retinal origin (PER.C6) developed for controlled ovarian stimulation prior to assisted...

  19. Pharmacokinetics and safety of the anti-human cytomegalovirus drug letermovir in subjects with hepatic impairment.

    Science.gov (United States)

    Kropeit, Dirk; McCormick, David; Erb-Zohar, Katharina; Moiseev, Valentin S; Kobalava, Zhanna D; Stobernack, Hans-Peter; Zimmermann, Holger; Rübsamen-Schaeff, Helga

    2017-07-18

    Human cytomegalovirus constitutes a prevalent and serious threat to immunocompromised individuals and requires new treatments. Letermovir is a novel viral-terminase inhibitor that has demonstrated prophylactic/pre-emptive activity against human cytomegalovirus in Phase 2 and 3 transplant trials. As unchanged letermovir is primarily excreted via the liver by bile, this trial aimed to assess the effect of hepatic impairment on letermovir pharmacokinetics. Phase 1, open-label, parallel-group pharmacokinetic and safety comparison of multiple once-daily oral letermovir in female subjects with hepatic impairment and healthy matched controls. For 8 days, subjects with moderate hepatic impairment (n = 8) and their matched healthy controls (n = 9) received 60 mg letermovir/day and those with severe hepatic impairment (n = 8) and their matched healthy controls (n = 8) received 30 mg letermovir/day. Pharmacokinetic parameters were determined from blood samples. For subjects with moderate hepatic impairment, maximal observed concentration at steady state (Css,max ) and the area under the concentration vs. time curve over a dosing interval at steady state (AUCτ,ss ) for total letermovir were 1.37-fold (90% confidence interval: 0.87, 2.17) and 1.59-fold (0.98, 2.57) higher, respectively, than in healthy subjects. For subjects with severe hepatic impairment, Css,max and AUCτ,ss values of total letermovir were 2.34-fold (1.91, 2.88) and 3.82-fold (2.94, 4.97) higher, respectively, compared with healthy subjects. Moderate hepatic impairment increased exposure to letermovir letermovir exposure approximately 4-fold as compared with healthy subjects. Letermovir 60/30 mg/day was generally well-tolerated in subjects with hepatic impairment. © 2017 The British Pharmacological Society.

  20. Cannabinoids and Psychosis.

    Science.gov (United States)

    D'Souza, Deepak Cyril; Radhakrishnan, Rajiv; Sherif, Mohamed; Cortes-Briones, Jose; Cahill, John; Gupta, Swapnil; Skosnik, Patrick D; Ranganathan, Mohini

    2016-01-01

    There is growing interest in the relationship between cannabis and psychosis. The link between cannabis use and psychosis comprises three distinct relationships: acute psychosis associated with cannabis intoxication, acute psychosis that lasts beyond the period of acute intoxication, and persistent psychosis not time-locked to exposure. Experimental studies reveal that cannabis, tetrahydrocannabinol (THC) and synthetic cannabinoids reliably produce transient positive, negative, and cognitive symptoms in healthy volunteers. Case-studies indicate that cannabinoids can induce acute psychosis which lasts beyond the period of acute intoxication and persisting as long as a month. Exposure to cannabis in adolescence is associated with an increased risk for later psychotic disorder in adulthood; this association is consistent, somewhat specific, shows a dose-response, and is biologically plausible. The link between cannabinoids and psychosis is greater with earlier age of exposure to cannabinoids, childhood abuse and genetic vulnerability. However, cannabinoids are neither necessary nor sufficient to cause a persistent psychotic disorder. More likely cannabinoids are a 'component cause' interacting with other known (family history) and unknown factors to result in psychosis outcomes. While more research is needed to better understand the relationship between cannabinoid use and psychosis, and the neural underpinnings of this link, clinicians should be mindful of the potential risk of psychosis especially in vulnerable populations, including adolescents and those with a psychosis diathesis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. 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

    2017-11-09

    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.

  2. Pharmacokinetic and -dynamic modelling of G-CSF derivatives in humans

    Directory of Open Access Journals (Sweden)

    Scholz Markus

    2012-07-01

    Full Text Available Abstract Background The human granulocyte colony-stimulating factor (G-CSF is routinely applied to support recovery of granulopoiesis during the course of cytotoxic chemotherapies. However, optimal use of the drug is largely unknown. We showed in the past that a biomathematical compartment model of human granulopoiesis can be used to make clinically relevant predictions regarding new, yet untested chemotherapy regimen. In the present paper, we aim to extend this model by a detailed pharmacokinetic and -dynamic modelling of two commonly used G-CSF derivatives Filgrastim and Pegfilgrastim. Results Model equations are based on our physiological understanding of the drugs which are delayed absorption of G-CSF when applied to the subcutaneous tissue, dose-dependent bioavailability, unspecific first order elimination, specific elimination in dependence on granulocyte counts and reversible protein binding. Pharmacokinetic differences between Filgrastim and Pegfilgrastim were modelled as different parameter sets. Our former cell-kinetic model of granulopoiesis was essentially preserved, except for a few additional assumptions and simplifications. We assumed a delayed action of G-CSF on the bone marrow, a delayed action of chemotherapy and differences between Filgrastim and Pegfilgrastim with respect to stimulation potency of the bone marrow. Additionally, we incorporated a model of combined action of Pegfilgrastim and Filgrastim or endogenous G-CSF which interact via concurrent receptor binding. Unknown pharmacokinetic or cell-kinetic parameters were determined by fitting the predictions of the model to available datasets of G-CSF applications, chemotherapy applications or combinations of it. Data were either extracted from the literature or were received from cooperating clinical study groups. Model predictions fitted well to both, datasets used for parameter estimation and validation scenarios as well. A unique set of parameters was identified which

  3. The dietary polyphenols trans-resveratrol and curcumin selectively bind human CB1 cannabinoid receptors with nanomolar affinities and function as antagonists/inverse agonists.

    Science.gov (United States)

    Seely, Kathryn A; Levi, Mark S; Prather, Paul L

    2009-07-01

    The dietary polyphenols trans-resveratrol [5-[(1E)-2-(4-hydroxyphenyl)ethenyl]-1,3-benzenediol; found in red wine] and curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1E,6E-heptadiene-3,5-dione] (found in curry powders) exert anti-inflammatory and antioxidant effects via poorly defined mechanisms. It is interesting that cannabinoids, derived from the marijuana plant (Cannabis sativa), produce similar protective effects via CB1 and CB2 receptors. We examined whether trans-resveratrol, curcumin, and ASC-J9 [1,7-bis(3,4-dimethoxyphenyl)-5-hydroxy-1E,4E,6E-heptatriene-3-one] (a curcumin analog) act as ligands at cannabinoid receptors. All three bind to human (h) CB1 and mouse CB1 receptors with nanomolar affinities, displaying only micromolar affinities for hCB2 receptors. Characteristic of inverse agonists, the polyphenols inhibit basal G-protein activity in membranes prepared from Chinese hamster ovary (CHO)-hCB1 cells or mouse brain that is reversed by a neutral CB1 antagonist. Furthermore, they competitively antagonize G-protein activation produced by a CB1 agonist. In intact CHO-hCB1 cells, the polyphenols act as neutral antagonists, producing no effect when tested alone, whereas competitively antagonizing CB1 agonist mediated inhibition of adenylyl cyclase activity. Confirming their neutral antagonist profile in cells, the polyphenols similarly attenuate stimulation of adenylyl cyclase activity produced by a CB1 inverse agonist. In mice, the polyphenols dose-dependently reverse acute hypothermia produced by a CB1 agonist. Upon repeated administration, the polyphenols also reduce body weight in mice similar to that produced by a CB1 antagonist/inverse agonist. Finally, trans-resveratrol and curcumin share common structural motifs with other known cannabinoid receptor ligands. Collectively, we suggest that trans-resveratrol and curcumin act as antagonists/inverse agonists at CB1 receptors at dietary relevant concentrations. Therefore, these polyphenols and their

  4. Cannabis and Cannabinoids (PDQ)

    Science.gov (United States)

    ... inflammatory effects that may play a role in pain relief. Animal studies have shown that cannabinoids may prevent nerve problems (pain, numbness, tingling, swelling, and muscle weakness) caused by ...

  5. Laboratory detection of cannabinoids.

    Science.gov (United States)

    King, D L; Martel, P A; O'Donnell, C M

    1987-09-01

    Cannabis, or marijuana, has been known and used as a drug for many thousands of years. Recent interest in drug abuse and detection has spurred the development of several methodologies for cannabinoid detection. These methods include immunoassays and chromatography. Laboratories routinely performing cannabinoid testing use two or more methodologies; the accepted method is to screen with one methodology and confirm by a second. These methodologies vary widely in sensitivity, specificity, and time required for analysis. Although therapeutic applications of cannabis constituents often produce undesirable side effects, two cannabinoids, delta 9-THC and nabilone, have been approved for use as antiemetics in chemotherapy. Further investigations of cannabinoid pharmacology and structure-activity relationships may result in the development of promising new therapeutic agents.

  6. Cannabinoids and Dementia: A Review of Clinical and Preclinical Data

    Directory of Open Access Journals (Sweden)

    Michael Halpern

    2010-08-01

    Full Text Available The endocannabinoid system has been shown to be associated with neurodegenerative diseases and dementia. We review the preclinical and clinical data on cannabinoids and four neurodegenerative diseases: Alzheimer’s disease (AD, Huntington’s disease (HD, Parkinson’s disease (PD and vascular dementia (VD. Numerous studies have demonstrated an involvement of the cannabinoid system in neurotransmission, neuropathology and neurobiology of dementias. In addition, several candidate compounds have demonstrated efficacy in vitro. However, some of the substances produced inconclusive results in vivo. Therefore, only few trials have aimed to replicate the effects seen in animal studies in patients. Indeed, the literature on cannabinoid administration in patients is scarce. While preclinical findings suggest causal treatment strategies involving cannabinoids, clinical trials have only assessed the suitability of cannabinoid receptor agonists, antagonists and cannabidiol for the symptomatic treatment of dementia. Further research is needed, including in vivo models of dementia and human studies.

  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

    National Research Council Canada - National Science Library

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

    2012-01-01

    ... 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...

  8. 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., Δ9 -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 32 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.

  9. Pharmacokinetics, metabolism, and excretion of torcetrapib, a cholesteryl ester transfer protein inhibitor, in humans.

    Science.gov (United States)

    Dalvie, Deepak; Chen, Weichao; Zhang, Chenghong; Vaz, Alfin D; Smolarek, Teresa A; Cox, Loretta M; Lin, Jian; Obach, R Scott

    2008-11-01

    The pharmacokinetics, metabolism, and excretion of torcetrapib, a selective inhibitor of human cholesteryl ester transfer protein, were investigated in healthy human male volunteers after oral administration of [(14)C]torcetrapib (120-mg dose). The total mean recovery of radiolabeled dose after 21 days was 75.7%, and most of the dose (63%) was excreted in the urine. The total circulating radioactivity and unchanged torcetrapib plasma concentrations increased over the first 6 h and then declined slowly with mean terminal elimination half-lives of 373 and 211 h. Metabolism of torcetrapib was extensive in humans. Only 5.2% of the total dose constituted unchanged torcetrapib in the feces, whereas no parent was excreted unchanged in the urine. Similarly, pharmacokinetic analysis of total radioactivity and unchanged torcetrapib revealed that the area under the concentration versus time curve from zero to infinity of torcetrapib accounted for approximately 7.0% of the circulating radioactivity. Torcetrapib was metabolized to numerous metabolites via oxidation. The primary metabolic pathway involved initial oxidative decarbamoylation followed by extensive further oxidation, resulting in the formation of bistrifluoromethylbenzoic acid (M1) and quinaldic acid (M4) metabolites. A mean 40% of the total dose was excreted in the urine as M4 (and its glucuronide and urea conjugates), whereas 7.0% of the total dose was excreted as M1. In vitro studies using human subcellular fractions suggested that the initial metabolism of torcetrapib proceeds via CYP3A-mediated decarbamoylation. Subsequent oxidations lead to the major circulating and excretory metabolites M1 and M4.

  10. Pharmacokinetics, pharmacodynamics, metabolism, toxicology and residues of phenylbutazone in humans and horses.

    Science.gov (United States)

    Lees, Peter; Toutain, Pierre-Louis

    2013-06-01

    The presence of horse meat in food products destined for human consumption and labelled as beef has raised several concerns of public interest. This review deals solely with one aspect of these concerns; samples of equine tissue from horses destined for the human food chain have tested positive for the non-steroidal anti-inflammatory drug, phenylbutazone. The safety of some or all such foods for human consumers is a major concern, because it was shown many years ago that phenylbutazone therapy in humans can be associated with life threatening blood dyscrasias. As an initial basis for assessing the potential toxicity of foods containing phenylbutazone and its metabolites, this article reviews (1) the pharmacokinetic, pharmacodynamic, metabolic and toxicological profiles of phenylbutazone, with particular reference to horses and humans; (2) toxicity data in laboratory animals; (3) phenylbutazone residues in food producing species, and (4) as a preliminary assessment, the potential hazard associated with the consumption of horse meat containing phenylbutazone and its metabolites. Since phenylbutazone cannot be classified as a carcinogenic substance in humans, and noting that blood dyscrasias in humans are likely to be dose and treatment duration-dependent, the illegal and erratic presence of trace amount residues of phenylbutazone in horse meat is not a public health issue. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. A cannabinoid link between mitochondria and memory.

    Science.gov (United States)

    Hebert-Chatelain, Etienne; Desprez, Tifany; Serrat, Román; Bellocchio, Luigi; Soria-Gomez, Edgar; Busquets-Garcia, Arnau; Pagano Zottola, Antonio Christian; Delamarre, Anna; Cannich, Astrid; Vincent, Peggy; Varilh, Marjorie; Robin, Laurie M; Terral, Geoffrey; García-Fernández, M Dolores; Colavita, Michelangelo; Mazier, Wilfrid; Drago, Filippo; Puente, Nagore; Reguero, Leire; Elezgarai, Izaskun; Dupuy, Jean-William; Cota, Daniela; Lopez-Rodriguez, Maria-Luz; Barreda-Gómez, Gabriel; Massa, Federico; Grandes, Pedro; Bénard, Giovanni; Marsicano, Giovanni

    2016-11-24

    Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP. Acute cannabinoid intoxication induces amnesia in humans and animals, and the activation of type-1 cannabinoid receptors present at brain mitochondria membranes (mtCB 1 ) can directly alter mitochondrial energetic activity. Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established, the involvement of acute modulation of mitochondrial activity in high brain functions, including learning and memory, is unknown. Here, we show that acute cannabinoid-induced memory impairment in mice requires activation of hippocampal mtCB 1 receptors. Genetic exclusion of CB 1 receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB 1 receptors signal through intra-mitochondrial Gα i protein activation and consequent inhibition of soluble-adenylyl cyclase (sAC). The resulting inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system eventually leads to decreased cellular respiration. Hippocampal inhibition of sAC activity or manipulation of intra-mitochondrial PKA signalling or phosphorylation of the Complex I subunit NDUFS2 inhibit bioenergetic and amnesic effects of cannabinoids. Thus, the G protein-coupled mtCB 1 receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to memory formation, these data reveal that bioenergetic processes are primary acute regulators of cognitive functions.

  12. Cannabinoids and haemostasis

    Directory of Open Access Journals (Sweden)

    Agnieszka Zakrzeska

    2016-07-01

    Full Text Available Elements of the endocannabinoid system (cannabinoid receptors CB1, CB2, CBPT and CBED, endocannabinoids, enzymes involved in the synthesis and metabolism of endocannabinoids are located on the structures involved in the process of hemostasis. An increasing level of endocannabinoids was also observed in some pathological conditions, which may occur in disorders of hemostasis. At the same time, disconcertingly, there is an increased number of reports about incidents of cardiovascular events in smokers of marijuana. Experimental and clinical studies demonstrated multidirectional, often contradictory, effects of cannabinoids on hemostasis, including effects of the compounds on platelets, vascular endothelium, fibrinolysis and plasma coagulation systems. The mechanisms of action of cannabinoids on homeostasis depend on the cannabinoid receptors CB1, CB2, CBPT and CBED, receptors of other systems stimulated by endocannabinoids, as well as metabolites of endocannabinoids and nitrogen oxide. The range of biological functions of endo- and plant cannabinoids, expanded to include the process of hemostasis, may constitute a condition for their recognition as a new factor responsible for thromboembolism in smokers of marijuana, in pathological disorders with increased levels of endocannabinoids and in individuals with polymorphisms of FAAH C385A and A385A. On the other hand, there are compelling reasons for anti‑hemostatic action of cannabinoids.

  13. Cannabinoids, inflammation, and fibrosis.

    Science.gov (United States)

    Zurier, Robert B; Burstein, Sumner H

    2016-11-01

    Cannabinoids apparently act on inflammation through mechanisms different from those of agents such as nonsteroidal anti-inflammatory drugs (NSAIDs). As a class, the cannabinoids are generally free from the adverse effects associated with NSAIDs. Their clinical development thus provides a new approach to treatment of diseases characterized by acute and chronic inflammation and fibrosis. A concise survey of the anti-inflammatory actions of the phytocannabinoids Δ9-tetrahydrocannabinol (THC), cannabidiol, cannabichromene, and cannabinol is presented. Mention is also made of the noncannabinoid plant components and pyrolysis products, followed by a discussion of 3 synthetic preparations-Cesamet (nabilone; Meda Pharmaceuticals, Somerset, NJ, USA), Marinol (dronabinol; THC; AbbVie, Inc., North Chicago, IL, USA), and Sativex (Cannabis extract; GW Pharmaceuticals, Cambridge United Kingdom)-that have anti-inflammatory effects. A fourth synthetic cannabinoid, ajulemic acid (AJA; CT-3; Resunab; Corbus Pharmaceuticals, Norwood, MA, USA), is discussed in greater detail because it represents the most recent advance in this area and is currently undergoing 3 phase 2 clinical trials by Corbus Pharmaceuticals. The endogenous cannabinoids, including the closely related lipoamino acids, are then discussed. The review concludes with a presentation of a possible mechanism for the anti-inflammatory and antifibrotic actions of these substances. Thus, several cannabinoids may be considered candidates for development as anti-inflammatory and antifibrotic agents. Of special interest is their possible use for treatment of chronic inflammation, a major unmet medical need.-Zurier, R. B., Burstein, S. H. Cannabinoids, inflammation, and fibrosis. © FASEB.

  14. Endogenous cannabinoid system as a modulator of food intake.

    Science.gov (United States)

    Cota, D; Marsicano, G; Lutz, B; Vicennati, V; Stalla, G K; Pasquali, R; Pagotto, U

    2003-03-01

    The ability of Cannabis sativa (marijuana) to increase hunger has been noticed for centuries, although intensive research on its molecular mode of action started only after the characterization of its main psychoactive component Delta(9)-tetrahydrocannabinol in the late 1960s. Despite the public concern related to the abuse of marijuana and its derivatives, scientific studies have pointed to the therapeutic potentials of cannabinoid compounds and have highlighted their ability to stimulate appetite, especially for sweet and palatable food. Later, the discovery of specific receptors and their endogenous ligands (endocannabinoids) suggested the existence of an endogenous cannabinoid system, providing a physiological basis for biological effects induced by marijuana and other cannabinoids. Epidemiological reports describing the appetite-stimulating properties of cannabinoids and the recent insights into the molecular mechanisms underlying cannabinoid action have proposed a central role of the cannabinoid system in obesity. The aim of this review is to provide an extensive overview on the role of this neuromodulatory system in feeding behavior by summarizing the most relevant data obtained from human and animal studies and by elucidating the interactions of the cannabinoid system with the most important neuronal networks and metabolic pathways involved in the control of food intake. Finally, a critical evaluation of future potential therapeutical applications of cannabinoid antagonists in the therapy of obesity and eating disorders will be discussed.

  15. Statistical comparison of dynamic contrast-enhanced MRI pharmacokinetic models in human breast cancer.

    Science.gov (United States)

    Li, Xia; Welch, E Brian; Chakravarthy, A Bapsi; Xu, Lei; Arlinghaus, Lori R; Farley, Jaime; Mayer, Ingrid A; Kelley, Mark C; Meszoely, Ingrid M; Means-Powell, Julie; Abramson, Vandana G; Grau, Ana M; Gore, John C; Yankeelov, Thomas E

    2012-07-01

    By fitting dynamic contrast-enhanced MRI data to an appropriate pharmacokinetic model, quantitative physiological parameters can be estimated. In this study, we compare four different models by applying four statistical measures to assess their ability to describe dynamic contrast-enhanced MRI data obtained in 28 human breast cancer patient sets: the chi-square test (χ(2)), Durbin-Watson statistic, Akaike information criterion, and Bayesian information criterion. The pharmacokinetic models include the fast exchange limit model with (FXL_v(p)) and without (FXL) a plasma component, and the fast and slow exchange regime models (FXR and SXR, respectively). The results show that the FXL_v(p) and FXR models yielded the smallest χ(2) in 45.64 and 47.53% of the voxels, respectively; they also had the smallest number of voxels showing serial correlation with 0.71 and 2.33%, respectively. The Akaike information criterion indicated that the FXL_v(p) and FXR models were preferred in 42.84 and 46.59% of the voxels, respectively. The Bayesian information criterion also indicated the FXL_v(p) and FXR models were preferred in 39.39 and 45.25% of the voxels, respectively. Thus, these four metrics indicate that the FXL_v(p) and the FXR models provide the most complete statistical description of dynamic contrast-enhanced MRI time courses for the patients selected in this study. Copyright © 2011 Wiley Periodicals, Inc.

  16. Statistical Comparison of DCE-MRI Pharmacokinetic Models in Human Breast Cancer

    Science.gov (United States)

    Li, Xia; Welch, E. Brian; Chakravarthy, A. Bapsi; Xu, Lei; Arlinghaus, Lori R.; Farley, Jaime; Mayer, Ingrid A.; Kelley, Mark C.; Meszoely, Ingrid M.; Means-Powell, Julie; Abramson, Vandana G.; Grau, Ana M.; Gore, John C.; Yankeelov, Thomas E.

    2011-01-01

    By fitting dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) data to an appropriate pharmacokinetic model, quantitative physiological parameters can be estimated. In this study, we compare four different models by applying four statistical measures to assess their ability to describe DCE-MRI data obtained in 28 human breast cancer patient sets: the chi-square test (χ2), Durbin-Watson statistic (DW), Akaike Information Criteria (AIC), and Bayesian Information Criterion (BIC). The pharmacokinetic models include: the fast exchange limit model with (FXL_vp) and without (FXL) a plasma component, and the fast and slow exchange regime models (FXR and SXR, respectively). The results show that the FXL_vp and FXR models yielded the smallest χ2 in 45.64% and 47.53% of the voxels, respectively; they also had the smallest number of voxels showing serial correlation with 0.71% and 2.33%, respectively. The AIC indicated that the FXL_vp and FXR models were preferred in 42.84% and 46.59% of the voxels, respectively. The BIC also indicated the FXL_vp and FXR models were preferred in 39.39% and 45.25% of the voxels, respectively. Thus, these four metrics indicate that the FXL_vp and the FXR models provide the most complete statistical description of DCE-MRI time courses for the patients selected in this study. PMID:22127821

  17. Cannabinoids and autoimmune diseases: A systematic review.

    Science.gov (United States)

    Katchan, Valeria; David, Paula; Shoenfeld, Yehuda

    2016-06-01

    Cannabinoids have shown to have a variety effects on body systems. Through CB1 and CB2 receptors, amongst other, they exert an effect by modulating neurotransmitter and cytokine release. Current research in the role of cannabinoids in the immune system shows that they possess immunosuppressive properties. They can inhibit proliferation of leucocytes, induce apoptosis of T cells and macrophages and reduce secretion of pro-inflammatory cytokines. In mice models, they are effective in reducing inflammation in arthritis, multiple sclerosis, have a positive effect on neuropathic pain and in type 1 diabetes mellitus. They are effective as treatment for fibromyalgia and have shown to have anti-fibrotic effect in scleroderma. Studies in human models are scarce and not conclusive and more research is required in this field. Cannabinoids can be therefore promising immunosuppressive and anti-fibrotic agents in the therapy of autoimmune disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. 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.

  19. The neurobiology and evolution of cannabinoid signalling.

    Science.gov (United States)

    Elphick, M R; Egertová, M

    2001-03-29

    The plant Cannabis sativa has been used by humans for thousands of years because of its psychoactivity. The major psychoactive ingredient of cannabis is Delta(9)-tetrahydrocannabinol, which exerts effects in the brain by binding to a G-protein-coupled receptor known as the CB1 cannabinoid receptor. The discovery of this receptor indicated that endogenous cannabinoids may occur in the brain, which act as physiological ligands for CB1. Two putative endocannabinoid ligands, arachidonylethanolamide ('anandamide') and 2-arachidonylglycerol, have been identified, giving rise to the concept of a cannabinoid signalling system. Little is known about how or where these compounds are synthesized in the brain and how this relates to CB1 expression. However, detailed neuroanatomical and electrophysiological analysis of mammalian nervous systems has revealed that the CB1 receptor is targeted to the presynaptic terminals of neurons where it acts to inhibit release of 'classical' neurotransmitters. Moreover, an enzyme that inactivates endocannabinoids, fatty acid amide hydrolase, appears to be preferentially targeted to the somatodendritic compartment of neurons that are postsynaptic to CB1-expressing axon terminals. Based on these findings, we present here a model of cannabinoid signalling in which anandamide is synthesized by postsynaptic cells and acts as a retrograde messenger molecule to modulate neurotransmitter release from presynaptic terminals. Using this model as a framework, we discuss the role of cannabinoid signalling in different regions of the nervous system in relation to the characteristic physiological actions of cannabinoids in mammals, which include effects on movement, memory, pain and smooth muscle contractility. The discovery of the cannabinoid signalling system in mammals has prompted investigation of the occurrence of this pathway in non-mammalian animals. Here we review the evidence for the existence of cannabinoid receptors in non-mammalian vertebrates

  20. Cannabinoids in cancer pain management.

    Science.gov (United States)

    Huskey, Angela

    2006-01-01

    The clinical use of cannabinoids in cancer pain management is reviewed. The endocannabionoid system, cannabinoid receptors, evidence for analgesic effects, other uses in cancer and related issues are discussed.

  1. Cannabinoid receptors in invertebrates.

    Science.gov (United States)

    McPartland, J M; Agraval, J; Gleeson, D; Heasman, K; Glass, M

    2006-03-01

    Two cannabinoid receptors, CB1 and CB2, are expressed in mammals, birds, reptiles, and fish. The presence of cannabinoid receptors in invertebrates has been controversial, due to conflicting evidence. We conducted a systematic review of the literature, using expanded search parameters. Evidence presented in the literature varied in validity, ranging from crude in vivo behavioural assays to robust in silico ortholog discovery. No research existed for several clades of invertebrates; we therefore tested for cannabinoid receptors in seven representative species, using tritiated ligand binding assays with [3H]CP55,940 displaced by the CB1-selective antagonist SR141716A. Specific binding of [3H]CP55,940 was found in neural membranes of Ciona intestinalis (Deuterstoma, a positive control), Lumbricusterrestris (Lophotrochozoa), and three ecdysozoans: Peripatoides novae-zealandiae (Onychophora), Jasus edwardi (Crustacea) and Panagrellus redivivus (Nematoda); the potency of displacement by SR141716A was comparable to measurements on rat cerebellum. No specific binding was observed in Actinothoe albocincta (Cnidaria) or Tethya aurantium (Porifera). The phylogenetic distribution of cannabinoid receptors may address taxonomic questions; previous studies suggested that the loss of CB1 was a synapomorphy shared by ecdysozoans. Our discovery of cannabinoid receptors in some nematodes, onychophorans, and crustaceans does not contradict the Ecdysozoa hypothesis, but gives it no support. We hypothesize that cannabinoid receptors evolved in the last common ancestor of bilaterians, with secondary loss occurring in insects and other clades. Conflicting data regarding Cnidarians precludes hypotheses regarding the last common ancestor of eumetazoans. No cannabinoid receptors are expressed in sponges, which probably diverged before the origin of the eumetazoan ancestor.

  2. 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."

  3. 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.

  4. Quantitative determination of dithiocarbamates in human plasma, serum, erythrocytes and urine: pharmacokinetics of broccoli sprout isothiocyanates in humans.

    Science.gov (United States)

    Ye, Lingxiang; Dinkova-Kostova, Albena T; Wade, Kristina L; Zhang, Yuesheng; Shapiro, Theresa A; Talalay, Paul

    2002-02-01

    Humans are exposed to substantial quantities of isothiocyanates and glucosinolates from vegetables. Since dietary isothiocyanates are widely regarded as potentially important chemoprotectors against cancer, reliable methods for measuring the plasma and tissue pharmacokinetics of isothiocyanates and their dithiocarbamate metabolites are essential for defining dosing regimens. Isothiocyanates (ITC) and dithiocarbamates (DTC) react quantitatively with 1,2-benzenedithiol to produce 1,3-benzodithiole-2-thione that can be quantified spectroscopically. Although this cyclocondensation reaction has been highly useful for analyzing plant material and urine samples, the determination of DTC/ITC (the total quantity of DTC and ITC components in a sample that react in the cyclocondensation reaction) in blood and tissues has been hampered by their low levels and the high concentrations of proteins that interfere with the cyclocondensation reaction. The protein content of blood and tissues was reduced by the precipitation with polyethylene glycol (PEG) or ultrafiltration, and the sensitivity of the method was increased substantially by the solid phase extraction of the cyclocondensation product. Pharmacokinetic measurements were made in four human volunteers who received single doses of about 200 micromol of broccoli sprout isothiocyanates (largely sulforaphane, with lesser amounts of iberin and erucin). Isothiocyanates were absorbed rapidly, reached peak concentrations of 0.943-2.27 micromol/l in plasma, serum and erythrocytes at 1 h after feeding and declined with first-order kinetics (half-life of 1.77+/-0.13 h). The cumulative excretion at 8 h was 58.3+/-2.8% of the dose. Clearance was 369+/-53 ml/min, indicating active renal tubular secretion. A sensitive and specific method for quantifying DTC levels in human plasma, serum, and erythrocytes has been devised. Determinations of ITC/DTC levels are important because: (i) dietary isothiocyanates are of potential value in reducing

  5. Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects.

    Science.gov (United States)

    Kanaze, F I; Bounartzi, M I; Georgarakis, M; Niopas, I

    2007-04-01

    Hesperetin and naringenin, the aglycones of the flavanone glycosides hesperidin and naringin, occur naturally in citrus fruits. They exert interesting pharmacological properties such as antioxidant, anti-inflammatory, blood lipid and cholesterol lowering and are considered to contribute to health benefits in humans. However, no information is available on the pharmacokinetics of the citrus flavanones hesperetin and naringenin after their oral administration to humans as pure aglycones. Therefore, the objective of the present investigation was the evaluation of the pharmacokinetic parameters of hesperetin and naringenin in plasma and urine, after their single oral administration in humans in the form of solid dispersion capsules, and also to improve the absorption rate of flavanones by using aglycones rather than the naturally occurring glycosides. Six healthy volunteers received orally 135 mg of each compound, hesperetin and naringenin, under fasting conditions. Blood samples were collected at 14 different time points over a 12 h period. Urine was collected over 24 h, in five sequential timed intervals. Plasma and urine hesperetin and naringenin concentrations, after enzymatic hydrolysis of their conjugated forms, were measured using validated high-pressure liquid chromatography methods. Pharmacokinetic parameters for hesperetin and naringenin, such as C(max), T(max), AUC(0-t), AUC(0-infinity), CL/F, V/F, t(1/2), MRT, A(e), A(e)((0-24)), and R(max) were calculated from their plasma or urine concentrations. Pharmacokinetic analysis showed that both hesperetin and naringenin were rapidly absorbed and their concentrations in plasma observed 20 min after dosing and reached a peak in 4.0 and 3.5 h, respectively. The mean peak plasma concentration (C(max)) for hesperetin and naringenin were 825.78+/-410.63 ng/ml (2731.8+/-1358.4 nmol/l) and 2009.51+/-770.82 ng/ml (7386.6+/-2833.4 nmol/l), respectively and the mean AUC(0-infinity) values were 4846.20+/-1675.99 ng h/ml and

  6. Cannabinoids and gliomas.

    Science.gov (United States)

    Velasco, Guillermo; Carracedo, Arkaitz; Blázquez, Cristina; Lorente, Mar; Aguado, Tania; Haro, Amador; Sánchez, Cristina; Galve-Roperh, Ismael; Guzmán, Manuel

    2007-08-01

    Cannabinoids, the active components of Cannabis sativa L., act in the body by mimicking endogenous substances--the endocannabinoids--that activate specific cell surface receptors. Cannabinoids exert various palliative effects in cancer patients. In addition, cannabinoids inhibit the growth of different types of tumor cells, including glioma cells, in laboratory animals. They do so by modulating key cell signaling pathways, mostly the endoplasmic reticulum stress response, thereby inducing antitumoral actions such as the apoptotic death of tumor cells and the inhibition of tumor angiogenesis. Of interest, cannabinoids seem to be selective antitumoral compounds, as they kill glioma cells, but not their non-transformed astroglial counterparts. On the basis of these preclinical findings, a pilot clinical study of Delta(9)-tetrahydrocannabinol (THC) in patients with recurrent glioblastoma multiforme has been recently run. The good safety profile of THC, together with its possible growth-inhibiting action on tumor cells, justifies the setting up of future trials aimed at evaluating the potential antitumoral activity of cannabinoids.

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

    OpenAIRE

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

    2015-01-01

    BACKGROUND: 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. METHODS: 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. ...

  8. Qualitative confirmation of 9 synthetic cannabinoids and 20 metabolites in human urine using LC-MS/MS and library search.

    Science.gov (United States)

    Wohlfarth, Ariane; Scheidweiler, Karl B; Chen, Xiaohong; Liu, Hua-fen; Huestis, Marilyn A

    2013-04-02

    Synthetic cannabinoids are an emerging illicit drug class. The variety of available substances is large and ever-changing, making it difficult for laboratories to remain current. We present a qualitative LC-MS/MS method identifying urinary metabolites of JWH-018, JWH-073, JWH-081, JWH-122, JWH-200, JWH-210, JWH-250, RCS-4, and AM2201 and the parent compounds JWH-018, JWH-073, JWH-081, JWH-122, JWH-210, JWH-250, RCS-4, AM2201, and MAM2201. After enzymatic hydrolysis, urinary proteins were precipitated with acetonitrile. Chromatography utilized a 10 min gradient on a Kinetex XB-C18 column with 0.1% formic acid in water and acetonitrile. Scheduled multiple reaction monitoring "survey scans" were followed by information-dependent acquisition-enhanced product ion scan experiments on an ABSciex 5500 QTRAP mass spectrometer. Analytes were identified by software-assisted library searching against reference spectra. The method was fully validated, including proof of selectivity (no exogenous or endogenous interferences were observed), assessment of matrix effects (95-122%) and recovery (53-95%), determination of limits of detection (0.5-10 ng/mL), carry-over studies (thresholds between 100 and 1000 ng/mL), and determination of autosampler stability (samples were stable for at least 3 days). Hydrolysis efficiency was thoroughly investigated for a wide range of glucuronides and for the reference standard, JWH-018 5-hydroxypentyl glucuronide.

  9. Qualitative Confirmation of 9 Synthetic Cannabinoids and 20 Metabolites in Human Urine Using LC–MS/MS and Library Search

    Science.gov (United States)

    Wohlfarth, Ariane; Scheidweiler, Karl B.; Chen, Xiaohong; Liu, Hua-fen; Huestis, Marilyn A.

    2013-01-01

    Introduction Synthetic cannabinoids are an emerging illicit drug class. The variety of available substances is large and ever-changing, making it difficult for laboratories to remain current. We present a qualitative LC–MS/MS method identifying urinary metabolites of JWH-018, JWH-073, JWH-081, JWH-122, JWH-200, JWH-210, JWH-250, RCS-4, and AM2201 and the parent compounds JWH-018, JWH-073, JWH-081, JWH-122, JWH-210, JWH-250, RCS-4, AM2201, and MAM2201. Methods After enzymatic hydrolysis, urinary proteins were precipitated with acetonitrile. Chromatography utilized a 10 min gradient on a Kinetex XB-C18 column with 0.1% formic acid in water and acetonitrile. Scheduled multiple reaction monitoring “survey scans” were followed by information-dependent acquisition-enhanced product ion scan experiments on an ABSciex 5500 QTRAP mass spectrometer. Analytes were identified by software-assisted library searching against reference spectra. Results The method was fully validated, including proof of selectivity (no exogenous or endogenous interferences were observed), assessment of matrix effects (95–122%) and recovery (53–95%), determination of limits of detection (0.5–10 ng/mL), carry-over studies (thresholds between 100 and 1000 ng/mL), and determination of autosampler stability (samples were stable for at least 3 days). Hydrolysis efficiency was thoroughly investigated for a wide range of glucuronides and for the reference standard, JWH-018 5-hydroxypentyl glucuronide PMID:23458260

  10. Acute induction of anxiety in humans by delta-9-tetrahydrocannabinol related to amygdalar cannabinoid-1 (CB1) receptors.

    Science.gov (United States)

    Bhattacharyya, Sagnik; Egerton, Alice; Kim, Euitae; Rosso, Lula; Riano Barros, Daniela; Hammers, Alexander; Brammer, Michael; Turkheimer, Federico E; Howes, Oliver D; McGuire, Philip

    2017-11-03

    Use of Cannabis, the most widely used illicit drug worldwide, is associated with acute anxiety, and anxiety disorders following regular use. The precise neural and receptor basis of these effects have not been tested in man. Employing a combination of functional MRI (fMRI) and positron emission tomography (PET), we investigated whether the effects of delta-9-tetrahydrocannabinol (delta-9-THC), the main psychoactive ingredient of cannabis, on anxiety and on amygdala response while processing fearful stimuli were related to local availability of its main central molecular target, cannabinoid-1 (CB1) receptors in man. Fourteen healthy males were studied with fMRI twice, one month apart, following an oral dose of either delta-9-THC (10 mg) or placebo, while they performed a fear-processing task. Baseline availability of the CB1 receptor was studied using PET with [(11)C]MePPEP, a CB1 inverse agonist radioligand. Relative to the placebo condition, delta-9-THC induced anxiety and modulated right amygdala activation while processing fear. Both these effects were positively correlated with CB1 receptor availability in the right amygdala. These results suggest that the acute effects of cannabis on anxiety in males are mediated by the modulation of amygdalar function by delta-9-THC and the extent of these effects are related to local availability of CB1 receptors.

  11. 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

  12. Characterization of transplacental transfer of paroxetine in perfused human placenta: development of a pharmacokinetic model to evaluate tapered dosing.

    Science.gov (United States)

    Nagai, Marie; Ohtani, Hisakazu; Satoh, Hiroki; Matsuoka, Sayo; Hori, Satoko; Fujii, Tomoyuki; Taketani, Yuji; Sawada, Yasufumi

    2013-12-01

    The aim of this study was to determine whether a tapered dosage regimen of paroxetine in pregnant women might be useful to avoid withdrawal syndromes in neonates after delivery. We characterized the transplacental transfer of paroxetine in perfused human placenta, fitting a pharmacokinetic model to the results and applying the model and parameters to evaluate a tapered dosage regimen. Paroxetine was perfused from the maternal or fetal side of an isolated human placental preparation with various perfusion protocols, and paroxetine concentrations in the effluent and placental tissue were determined. The transplacental pharmacokinetic parameters of paroxetine were estimated by simultaneous fitting of a five-compartment transplacental pharmacokinetic model to the set of paroxetine concentration profiles. The developed model and parameters were used to simulate the maternal and fetal concentrations of paroxetine, and the results were compared with reported data. Paroxetine showed a larger distribution volume in placental tissue and a smaller transplacental transfer as compared with antipyrine, a passive diffusion marker. A five-compartment model could well describe the transplacental transfer of paroxetine and could well simulate the maternal and umbilical venous concentrations of paroxetine at delivery. Transplacental transfer kinetic parameters of paroxetine were estimated by fitting a pharmacokinetic model to perfusion study data. The model and parameters appeared to be suitable for simulation of paroxetine kinetics in fetus. The model was also applicable to design a dosage regimen to avoid an abrupt decrease of paroxetine concentration in fetal plasma.

  13. The antitumor action of cannabinoids on glioma tumorigenesis.

    Science.gov (United States)

    Zogopoulos, Panagiotis; Korkolopoulou, Penelope; Patsouris, Efstratios; Theocharis, Stamatios

    2015-06-01

    Cannabinoids are a class of chemical compounds with a wide spectrum of pharmacological effects, mediated by two specific plasma membrane receptors (CB1 and CB2). Recently, CB1 and CB2 expression levels have been detected in human tumors, including those of brain. Cannabinoids-endocannabinoids exert anti-inflammatory, anti-proliferative, anti-invasive, anti-metastatic and pro-apoptotic effects in different cancer types, both in vitro and in vivo in animal models, after local or systemic administration. We present the available experimental and clinical data, to date, regarding the antitumor action of cannabinoids on the tumorigenesis of gliomas.

  14. Interspecies difference of luteolin and apigenin after oral administration of Chrysanthemum morifolium extract and prediction of human pharmacokinetics.

    Science.gov (United States)

    Li, L P; Wu, X D; Chen, Z J; Sun, S Y; Ye, J F; Zeng, S; Jiang, H D

    2013-03-01

    The aims of the present study were to study the interspecies difference in the pharmacokinetics of luteolin and apigenin occurring in Chrysanthemum morifolium extract (CME) among rats, beagle dogs, mini-pigs, and humans, and compared the human pharmacokinetic parameters with the data predicted from the above three animals. The plasma concentrations of luteolin and apigenin were determined with a RP-HPLC method. An interspecies difference of pharmacokinetics was found, especially between rats and other species, the plasma concentration of luteolin was much lower than that of apigenin in rats, although the content of luteolin in CME was higherthan that of apigenin, whereas the plasma concentration of luteolin was much higher than that of apigenin in dogs, mini-pigs and humans. Animal scale-up of some pharmacokinetic parameters of luteolin and apigenin were also performed after rats, beagle dogs, mini-pigs and humans were orally given CME at dosages of 400 mg/kg, 102 mg/kg, 90 mg/kg, and 20 mg/kg, respectively. Linear relationships were obtained between log mean retention time (MRT) and log species body weight (W) (kg), and log elimination half-life (t1/2) (h) and logW. The corresponding allometric equations were MRT=9.382W(0.1711) (R2 = 0.9999) and t1/2 = 4.811W(0.1093) (R2 = 0.9013) for luteolin, MRT = 12.53W(0.0356) (R2 = 0.9980) and t1/2 = 7.940W(0.0294) (R2 = 0.9258) for apigenin, respectively. The predicted human pharmacokinetic parameters (MRT and t1/2) by an allometric approach were 18.6 h and 7.46 h for luteolin, 14.3 h and 8.95 h for apigenin, respectively, which were close to the values obtained from humans (20 mg CME/kg) in the present study. The study has demonstrated the possibility to extrapolate the pharmacokinetic behavior of flavonoids from animals to humans.

  15. Stereoselective analysis of labetalol in human plasma by LC-MS/MS: application to pharmacokinetics.

    Science.gov (United States)

    Carvalho, Teresa Maria De Jesus Ponte; Cavalli, Ricardo De Carvalho; Marques, Maria Paula; Da Cunha, Sérgio Pereira; Baraldi, Claúdia De Oliveira; Lanchote, Vera Lúcia

    2009-08-01

    Labetalol is clinically available as a mixture of two racemates (four stereoisomers). The stereoisomer (R,R) has as main activity the beta1-antagonism and the stereoisomer (S,R) is highly selective for the alpha1 adrenoceptor and is responsible for most of the alpha-blocker activity. In the present investigation, a method for the analysis of labetalol stereoisomers in human plasma was developed and applied to pharmacokinetic studies. Plasma samples (0.5 ml) were extracted with methyl tert-butyl ether at pH 9.5. The four labetalol stereoisomers were analyzed by LC-MS/MS on a Chirobiotic V column using a mobile phase consisting of methanol, acetic acid, and diethylamine, with a recovery of more than 90% for all four. The quantitation limit was 0.5 ng/ml and linearity was observed at 250 ng/ml plasma for each stereoisomer. Studies of precision and accuracy presented coefficients of variation and percentage inaccuracy of less than 15%, indicating that the method is precise and accurate. The method was applied to the study of the kinetic disposition of labetalol over a period of 12 h after oral administration of a single 100 mg dose to a hypertensive pregnant woman. The clinical study revealed stereoselectivity in the pharmacokinetics of labetalol, with a lower plasma proportion for the active stereoisomers (R,R)-labetalol and (S,R)-labetalol. The stereoselectivity observed after oral administration is due to the hepatic metabolism and the first pass effect, with an AUC(R,R)/AUC(S,S) ratio of 0.5. Copyright 2008 Wiley-Liss, Inc.

  16. Synthetic cannabinoids revealing adrenoleukodystrophy.

    Science.gov (United States)

    Fellner, Avi; Benninger, Felix; Djaldetti, Ruth

    2016-02-01

    We report a 41-year-old man who presented with a first generalized tonic-clonic seizure after recent consumption of a synthetic cannabinoid. MRI showed extensive bilateral, mainly frontal, white matter lesions. Blood analysis for very long chain fatty acids was compatible with adrenoleukodystrophy, and a missense mutation in the ABCD1 gene confirmed the diagnosis. We hypothesize that cannabinoid use might have contributed to metabolic decompensation with subacute worsening of the underlying condition. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Development of a Physiologically Based Model to Describe the Pharmacokinetics of Methylphenidate in Juvenile and Adult Humans and Nonhuman Primates

    Science.gov (United States)

    Yang, Xiaoxia; Morris, Suzanne M.; Gearhart, Jeffery M.; Ruark, Christopher D.; Paule, Merle G.; Slikker, William; Mattison, Donald R.; Vitiello, Benedetto; Twaddle, Nathan C.; Doerge, Daniel R.; Young, John F.; Fisher, Jeffrey W.

    2014-01-01

    The widespread usage of methylphenidate (MPH) in the pediatric population has received considerable attention due to its potential effect on child development. For the first time a physiologically based pharmacokinetic (PBPK) model has been developed in juvenile and adult humans and nonhuman primates to quantitatively evaluate species- and age-dependent enantiomer specific pharmacokinetics of MPH and its primary metabolite ritalinic acid. The PBPK model was first calibrated in adult humans using in vitro enzyme kinetic data of MPH enantiomers, together with plasma and urine pharmacokinetic data with MPH in adult humans. Metabolism of MPH in the small intestine was assumed to account for the low oral bioavailability of MPH. Due to lack of information, model development for children and juvenile and adult nonhuman primates primarily relied on intra- and interspecies extrapolation using allometric scaling. The juvenile monkeys appear to metabolize MPH more rapidly than adult monkeys and humans, both adults and children. Model prediction performance is comparable between juvenile monkeys and children, with average root mean squared error values of 4.1 and 2.1, providing scientific basis for interspecies extrapolation of toxicity findings. Model estimated human equivalent doses in children that achieve similar internal dose metrics to those associated with pubertal delays in juvenile monkeys were found to be close to the therapeutic doses of MPH used in pediatric patients. This computational analysis suggests that continued pharmacovigilance assessment is prudent for the safe use of MPH. PMID:25184666

  18. A novel control of human keratin expression: cannabinoid receptor 1-mediated signaling down-regulates the expression of keratins K6 and K16 in human keratinocytes in vitro and in situ

    Directory of Open Access Journals (Sweden)

    Yuval Ramot

    2013-02-01

    Full Text Available Cannabinoid receptors (CB are expressed throughout human skin epithelium. CB1 activation inhibits human hair growth and decreases proliferation of epidermal keratinocytes. Since psoriasis is a chronic hyperproliferative, inflammatory skin disease, it is conceivable that the therapeutic modulation of CB signaling, which can inhibit both proliferation and inflammation, could win a place in future psoriasis management. Given that psoriasis is characterized by up-regulation of keratins K6 and K16, we have investigated whether CB1 stimulation modulates their expression in human epidermis. Treatment of organ-cultured human skin with the CB1-specific agonist, arachidonoyl-chloro-ethanolamide (ACEA, decreased K6 and K16 staining intensity in situ. At the gene and protein levels, ACEA also decreased K6 expression of cultured HaCaT keratinocytes, which show some similarities to psoriatic keratinocytes. These effects were partly antagonized by the CB1-specific antagonist, AM251. While CB1-mediated signaling also significantly inhibited human epidermal keratinocyte proliferation in situ, as shown by K6/Ki-67-double immunofluorescence, the inhibitory effect of ACEA on K6 expression in situ was independent of its anti-proliferative effect. Given recent appreciation of the role of K6 as a functionally important protein that regulates epithelial wound healing in mice, it is conceivable that the novel CB1-mediated regulation of keratin 6/16 revealed here also is relevant to wound healing. Taken together, our results suggest that cannabinoids and their receptors constitute a novel, clinically relevant control element of human K6 and K16 expression.

  19. Evaluation of Pharmacokinetics, and Bioavailability of Higher Doses of Tocotrienols in Healthy Fed Humans

    Science.gov (United States)

    Qureshi, Asaf A; Khan, Dilshad A; Silswal, Neerupma; Saleem, Shahid; Qureshi, Nilofer

    2016-01-01

    .078; volume of distribution (Vd/f, mg/h) 0.34, 0.30; and elimination rate constant (ke; h-1) 0.25, 0.17, respectively of δ- tocotrienol isomer. Similar results of these parameters were reported for γ-tocotrienol, β- tocotrienol, α-tocotrienol, δ-tocopherol, γ-tocopherol, and β-tocopherol, except for α- tocopherol. Conclusions This study has described pharmacokinetics using higher doses of 750 mg/d and 1000 mg/d of δ-tocotrienol. These results confirmed earlier findings that Tmax was 3-4 h for all isomers of tocotrienols and tocopherols except for α-tocopherol (6 h). These higher doses of tocotrienols were found safe in humans and may be useful for treatments of various types of cancer, diabetes, and Alzheimer's disease. PMID:27493840

  20. Imaging the cannabinoid CB1 receptor in humans with [11C]OMAR: assessment of kinetic analysis methods, test–retest reproducibility, and gender differences

    Science.gov (United States)

    Normandin, Marc D; Zheng, Ming-Qiang; Lin, Kuo-Shyan; Mason, N Scott; Lin, Shu-Fei; Ropchan, Jim; Labaree, David; Henry, Shannan; Williams, Wendol A; Carson, Richard E; Neumeister, Alexander; Huang, Yiyun

    2015-01-01

    The Radiotracer [11C]OMAR was developed for positron emission tomography (PET) imaging of cannabinoid type-1 receptors (CB1R). The objectives of the present study were to evaluate kinetic analysis methods, determine test–retest reliability, and assess gender differences in receptor availability. Dynamic PET data were acquired in 10 human subjects, and analyzed with one-tissue (1T) and two-tissue (2T) compartment models and by the Logan and multilinear analysis (MA1) methods to estimate regional volume of distribution (VT). The 2T model inclusive of a vascular component (2TV) and MA1 were the preferred techniques. Test–retest reliability of VT was good (mean absolute deviation ~9% intraclass correlation coefficient ~0.7). Tracer parent fraction in plasma was lower in women (PMA1 method and demonstrate the utility of this tracer for in vivo imaging of CB1R. In addition, results from the present study indicate that gender difference in receptor binding should be taken into consideration when [11C]OMAR is used to quantify CB1R availability in neuropsychiatric disorders. PMID:25833345

  1. Simultaneous quantification of major cannabinoids and metabolites in human urine and plasma by HPLC-MS/MS and enzyme-alkaline hydrolysis.

    Science.gov (United States)

    Aizpurua-Olaizola, Oier; Zarandona, Iratxe; Ortiz, Laura; Navarro, Patricia; Etxebarria, Nestor; Usobiaga, Aresatz

    2017-04-01

    A high performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) method for simultaneous quantification of Δ9-tetrahydrocannabinol (THC), its two metabolites 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH), and four additional cannabinoids (cannabidiol (CBD), cannabigerol (CBG), tetrahydrocannabivarin (THCV), and cannabinol (CBN)) in 1 mL of human urine and plasma was developed and validated. The hydrolysis process was studied to ensure complete hydrolysis of glucuronide conjugates and the extraction of a total amount of analytes. Initially, urine and plasma blank samples were spiked with THC-COOH-glucuronide and THC-glucuronide, and four different pretreatment methods were compared: hydrolysis-free method, enzymatic hydrolysis with Escherichia Coli β-glucuronidase, alkaline hydrolysis with 10 M NaOH, and enzyme-alkaline tandem hydrolysis. The last approach assured the maximum efficiencies (close to 100%) for both urine and plasma matrices. Regarding the figures of merit, the limits of detection were below 1 ng/mL for all analytes, the accuracy ranged from 84% to 115%, and both within-day and between-day precision were lower than 12%. Finally, the method was successfully applied to real urine and plasma samples from cannabis users. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  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

    Various experimental animal models are used in haemophilia research, however, little is known about how well the different species predict pharmacokinetic (PK) profiles in haemophilia patients. The aim of the current study was to describe the plasma concentration-time profile of recombinant...... 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...... for nonlinear kinetics and gender-specific difference in clearance for rFVIII. The predictive performance of the animal population PK models of rFVIIa and rFVIII revealed significant species-variation. The developed PK models of rFVIIa and rFVIII in monkeys and dogs along with allometric interspecies scaling...

  3. Human-on-a-chip design strategies and principles for physiologically based pharmacokinetics/pharmacodynamics modeling.

    Science.gov (United States)

    Abaci, Hasan Erbil; Shuler, Michael L

    2015-04-01

    Advances in maintaining multiple human tissues on microfluidic platforms has led to a growing interest in the development of microphysiological systems for drug development studies. Determination of the proper design principles and scaling rules for body-on-a-chip systems is critical for their strategic incorporation into physiologically based pharmacokinetic (PBPK)/pharmacodynamic (PD) model-aided drug development. While the need for a functional design considering organ-organ interactions has been considered, robust design criteria and steps to build such systems have not yet been defined mathematically. In this paper, we first discuss strategies for incorporating body-on-a-chip technology into the current PBPK modeling-based drug discovery to provide a conceptual model. We propose two types of platforms that can be involved in the different stages of PBPK modeling and drug development; these are μOrgans-on-a-chip and μHuman-on-a-chip. Then we establish the design principles for both types of systems and develop parametric design equations that can be used to determine dimensions and operating conditions. In addition, we discuss the availability of the critical parameters required to satisfy the design criteria, consider possible limitations for estimating such parameter values and propose strategies to address such limitations. This paper is intended to be a useful guide to the researchers focused on the design of microphysiological platforms for PBPK/PD based drug discovery.

  4. Development and Validation of Acyclovir HPLC External Standard Method in Human Plasma: Application to Pharmacokinetic Studies

    Directory of Open Access Journals (Sweden)

    Selvadurai Muralidharan

    2014-01-01

    Full Text Available A simple, rapid, and selective RP-HPLC method was developed for the estimation of acyclovir in human plasma. The method involves a simple protein precipitation technique. Chromatographic separation was carried out on a reverse phase C18 column using mixture of 5 mM ammonium acetate (pH 4.0 and acetonitrile (40 : 60, v/v at a flow rate of 1.0 mL/min with UV detection at 290 nm. The retention time of acyclovir was 4.12 minutes. The method was validated and found to be linear in the range of 25.0–150.0 ng/mL. Validation studies were achieved by using the fundamental parameters, including accuracy, precision, selectivity, sensitivity, linearity and range, stability studies, limit of detection (LOD, and limit of quantitation (LOQ. It shows recovery at 91.0% which is more precise and accurate compared to the other method. These results indicated that the bioanalytical method was linear, precise, and accurate. The new bioanalytical method was successfully applied to a pharmacokinetic linearity study in human plasma.

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

    Science.gov (United States)

    2008-02-01

    targets and mechanism based agents for its treatment has become a challenging issue. In recent years, cannabinoids, the active components of Cannabis ...human prostate cancer cells. Specific aim II of the proposal was designed to investigate the therapeutic potential of cannabinoids under in vivo...for PSA by specific immunoassay. Protocol-2 This protocol was designed to assess the therapeutic potential of WIN-55,212-2. For this purpose

  6. Cannabinoids, endocannabinoids, and cancer.

    Science.gov (United States)

    Hermanson, Daniel J; Marnett, Lawrence J

    2011-12-01

    The endocannabinoid system consists of an array of endogenously produced bioactive lipids that activate cannabinoid receptors. Although the primary focus of endocannabinoid biology has been on neurological and psychiatric effects, recent work has revealed several important interactions between the endocannabinoid system and cancer. Several different types of cancer have abnormal regulation of the endocannabinoid system that contributes to cancer progression and correlates to clinical outcomes. Modulation of the endocannabinoid system by pharmacological agents in various cancer types reveals that it can mediate antiproliferative and apoptotic effects by both cannabinoid receptor-dependent and -independent pathways. Selective agonists and antagonists of the cannabinoid receptors, inhibitors of endocannabinoid hydrolysis, and cannabinoid analogs have been utilized to probe the pathways involved in the effects of the endocannabinoid system on cancer cell apoptosis, proliferation, migration, adhesion, and invasion. The antiproliferative and apoptotic effects produced by some of these pharmacological probes reveal that the endocannabinoid system is a promising new target for the development of novel chemotherapeutics to treat cancer.

  7. Cannabinoids and cancer.

    Science.gov (United States)

    Kogan, Natalya M

    2005-10-01

    Marijuana has been used in medicine for millennia, but it was not until 1964 that delta9-tetrahydrocannabinol (delta9-THC), its major psychoactive component, was isolated in pure form and its structure was elucidated. Shortly thereafter it was synthesized and became readily available. However, it took another decade until the first report on its antineoplastic activity appeared. In 1975, Munson discovered that cannabinoids suppress Lewis lung carcinoma cell growth. The mechanism of this action was shown to be inhibition of DNA synthesis. Antiproliferative action on some other cancer cells was also found. In spite of the promising results from these early studies, further investigations in this area were not reported until a few years ago, when almost simultaneously two groups initiated research on the antiproliferative effects of cannabinoids on cancer cells: Di Marzo's group found that cannabinoids inhibit breast cancer cell proliferation, and Guzman's group found that cannabinoids inhibit the growth of C6 glioma cell. Other groups also started work in this field, and today, a wide array of cancer cell lines that are affected is known, and some mechanisms involved have been elucidated.

  8. Pharmacokinetics of 6-, 8-, 10-Gingerols and 6-Shogaol and Conjugate Metabolites in Healthy Human Subjects

    Science.gov (United States)

    Zick, Suzanna M.; Djuric, Zora; Ruffin, Mack T.; Litzinger, Amie J.; Normolle, Daniel P.; Feng, Meihua Rose; Brenner, Dean E.

    2009-01-01

    Background Ginger demonstrates promising anticancer properties. No research has examined the pharmacokinetics of the ginger constituents 6-, 8-, 10-gingerol and 6-shogaol in humans. We conducted a clinical trial with 6-, 8-, 10-gingerol and 6-shogaol examining the pharmacokinetics and tolerability of these analytes and their conjugate metabolites Methods Human volunteers were given ginger at doses from 100 mg, to 2.0 g (N=27), and blood samples were obtained at 15 minutes to 72 hours after a single oral dose. Participants were allocated in a dose-escalation manner starting with 100 mg. There was a total of three participants at each dose except for 1.0 g (N=6) and 2.0 g (N=9). Results No participant had detectable free 6-, 8-, 10-gingerol or 6-shogaol, but 6-, 8-, 10-gingerol and 6-shogaol glucuronides were detected. The 6-gingerol sulfate conjugate was detected above the 1.0 g dose but there were no detectable 10-gingerol or 6-shogaol sulfates except for one participant with detectable 8-gingerol sulfate. The Cmax and AUC values (Mean±SE) estimated for the 2.0 g dose are 0.85±0.43, 0.23±0.16, 0.53±0.40, and 0.15±0.12 μg/mL ; and 65.6.33±44.4, 18.1±20.3, 50.1±49.3, and 10.9±13.0 μg·hr/mL for 6-, 8-, 10-gingerol, and 6-shogaol. The corresponding tmax values are 65.6±44.4, 73.1±29.4, 75.0±27.8, and 65.6±22.6 minutes and the analytes had elimination half-lives gingerol and 6-shogaol conjugates were present as either glucuronide or sulfate conjugates, not as mixed conjugates, although 6-, 10-gingerol were an exception. Conclusion Six-, 8-, 10-gingerol and 6-shogaol is absorbed after oral dosing and can be detected as glucuronide and sulfate conjugates. PMID:18708382

  9. Efficacy and safety of medical cannabinoids in older subjects: A systematic review

    NARCIS (Netherlands)

    Elsen, G.A.H. van den; Ahmed, A.I.A.; Lammers, M.; Kramers, C.; Verkes, R.J.; Marck, M.A. van der; Olde Rikkert, M.G.M.

    2014-01-01

    This systematic review aims to integrate the evidence on indications, efficacy, safety and pharmacokinetics of medical cannabinoids in older subjects. The literature search was conducted using PubMed, EMBASE, CINAHL and Cochrane Library. We selected controlled trials including solely older subjects

  10. Simultaneous determination and pharmacokinetic study of roxithromycin and ambroxol hydrochloride in human plasma by LC-MS/MS.

    Science.gov (United States)

    Hang, Tai-Jun; Zhang, Meng; Song, Min; Shen, Jian-Ping; Zhang, Yin-di

    2007-07-01

    Although roxithromycin and ambroxol HCl were often administered concomitantly for the treatment of respiratory infections, the pharmacokinetic interactions between them have not been reported. We investigated the interactions between these drugs in health male Chinese volunteers by LC-MS/MS in human plasma. The pharmacokinetics were studied in 12 healthy male Chinese volunteers after an overnight fast by a single oral dose, 4-way crossover design with a period of 7-day washout. Each subjects was randomized to receive a single oral dose of 1 compound roxithromycin (150 mg) and ambroxol HCl (30 mg) dispersible tablet (test formulation, treatment A), one 150 mg roxithromycin dispersible tablet together with one 30 mg ambroxol HCl tablet (combined reference formulations, treatment B), one 150 mg roxithromycin dispersible tablet (reference formulation I, treatment C), or one 30 mg ambroxol HCl tablet (reference formulation II, treatment D) with 250 ml of water. Venous blood was collected at pre-dose (0 h) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72 h after dosing. The plasma concentrations of roxithromycin and ambroxol HCl were simultaneously determined by using a validated internal standard LC-MS/MS method. No significant differences were observed for the major pharmacokinetic parameters such as C(max), T(max), t(1/2) and AUC of both roxithromycin and ambroxol HCl between different treatments. The pharmacokinetics of both roxithromycin and ambroxol HCl are not affected by their concomitant oral administration. Therefore, there are no obvious pharmacokinetic interactions between roxithromycin and ambroxol HCl after oral administration. Roxithromycin and ambroxol HCl dispersible tablets were bioequivalent with reference to the roxithromycin dispersible tablets and ambroxol HCl tablets in combination usage.

  11. Simulation of Human Plasma Concentrations of Thalidomide and Primary 5-Hydroxylated Metabolites Explored with Pharmacokinetic Data in Humanized TK-NOG Mice.

    Science.gov (United States)

    Nishiyama, Sayako; Suemizu, Hiroshi; Shibata, Norio; Guengerich, F Peter; Yamazaki, Hiroshi

    2015-11-16

    Plasma concentrations of thalidomide and primary 5-hydroxylated metabolites including 5,6-dihydroxythalidomide and glutathione (GSH) conjugate(s) were investigated in chimeric mice with highly "humanized" liver cells harboring cytochrome P450 3A5*1. Following oral administration of thalidomide (100 mg/kg), plasma concentrations of GSH conjugate(s) of 5-hydroxythalidomide were higher in humanized mice than in controls. Simulation of human plasma concentrations of thalidomide were achieved with a simplified physiologically based pharmacokinetic model in accordance with reported thalidomide concentrations. The results indicate that the pharmacokinetics in humans of GSH conjugate and/or catechol primary 5-hydroxylated thalidomide contributing in vivo activation can be estimated for the first time.

  12. 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.

  13. 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.

  14. Time course of pharmacokinetic and hormonal effects of inhaled high-dose salvinorin A in humans.

    Science.gov (United States)

    Johnson, Matthew W; MacLean, Katherine A; Caspers, Michael J; Prisinzano, Thomas E; Griffiths, Roland R

    2016-04-01

    Salvinorin A is a kappa opioid agonist and the principal psychoactive constituent of the Salvia divinorum plant, which has been used for hallucinogenic effects. Previous research on salvinorin A pharmacokinetics likely underestimated plasma levels typically resulting from the doses administered due to inefficient vaporization and not collecting samples during peak drug effects. Six healthy adults inhaled a single high dose of vaporized salvinorin A (n = 4, 21 mcg/kg; n = 2, 18 mcg/kg). Participant- and monitor-rated effects were assessed every 2 min for 60 min post-inhalation. Blood samples were collected at 13 time points up to 90 min post-inhalation. Drug levels peaked at 2 min and then rapidly decreased. Drug levels were significantly, positively correlated with participant and monitor drug effect ratings. Significant elevations in prolactin were observed beginning 5 min post-inhalation and peaking at 15 min post-inhalation. Cortisol showed inconsistent increases across participants. Hormonal responses were not well correlated with drug levels. This is the first study to demonstrate a direct relationship between changes in plasma levels of salvinorin A and drug effects in humans. The results confirm the efficacy of an inhalation technique for salvinorin A. © The Author(s) 2016.

  15. 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.

  16. Preclinical pharmacokinetics and biodistribution of human papillomavirus DNA vaccine delivered in human endogenous retrovirus envelope-coated baculovirus vector.

    Science.gov (United States)

    Cho, Hee-Jeong; Lee, Soondong; Im, Saewon; Kim, Mi-Gyeong; Lee, Jaewoo; Lee, Hee-Jung; Lee, Keyong Ho; Kim, Sujeong; Kim, Young Bong; Oh, Yu-Kyoung

    2012-02-01

    Test pharmacokinetics and biodistribution of a human papillomavirus(HPV)16L1 DNA vaccine delivered in human endogenous retrovirus envelope protein (HERV)-expressing baculovirus (AcHERV) and those of naked plasmid vaccine. HPV16L1 gene was administrated as a naked plasmid or in AcHERV to mice via intravenous and intramuscular routes. HPV16L1 gene was extracted and assayed by quantitative real-time polymerase chain reaction, which was determined to have a detection limit of 50 copies/µg genomic DNA.. Mean residence times of HPV16L1 in AcHERV were 4.8- and 272.2-fold higher than naked HPV16L1 DNA vaccines after intramuscular and intravenous administration, respectively. Naked HPV16L1 DNA levels 1 month after injection were >3 orders of magnitude lower in each tissue tested than AcHERV-delivered HPV16L1, which was retained in most tissues without specific tissue tropism. AcHERV-delivered HPV16L1 administered intramuscularly persisted at the injection sites. However, the levels of copy numbers in muscle were low (1,800/μg genomic DNA) after 1 month, and undetectable after 6 months. HPV16L1 delivered via AcHERV resides longer in the body than HPV16L1 in naked form. The lack of tissue tropism ensures the safety of AcHERV vectors for further development.

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

    Science.gov (United States)

    Zendelovska, Dragica; Simeska, Suzana; Atanasovska, Emilija; Georgievska, Kalina; Kikerkov, Igor; Labachevski, Nikola; Jakovski, Krume; Balkanov, Trajan

    2015-03-15

    The aim of this study is estimation of pharmacokinetic parameters: Cmax, tmax, t1/2, AUC0-t and AUC0-∞ with the two-way analysis of variance, single observation (ANOVA) for two preparations containing acyclovir. In order to evaluate pharmacokinetic study of acyclovir, method for quantitative determination of acyclovir in human plasma should be simple, rapid and reproducible. Therefore, the method is developed, validated and applied for analysis of acyclovir in plasma samples obtained from healthy volunteers. High performance liquid chromatographic (HPLC) method with UV-detection for the determination of acyclovir in human plasma is presented. This method involves protein precipitation with 20 % (V/V) perchloric acid. The chromatographic separation was accomplished on a reversed phase C8 column with a mobile phase composed of 0.1 % (V/V) triethylamine in water (pH 2.5). No internal standard is required. UV detection was set at 255 nm. The method was successfully applied for the evaluation of pharmacokinetic profiles of acyclovir tablets in 24 healthy volunteers. The validation results shows that proposed method is rugged, precise (RSDs for intra- and inter-day precision ranged from 1.02 to 8.37 %) and accurate (relative errors are less than 6.66 %). The calibration curve was linear in the concentration range of 0.1-2.0 µg/ml and the limit of quantification was 0.1 µg/ml. The Cmax, tmax and AUCs for the two products were not statistically different (p>0.05), suggesting that the plasma profiles generated by Zovirax were comparable to those produced by acyclovir manufactured by Jaka 80 company. 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. 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

  19. 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...

  20. 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.

  1. Fentanyl pharmacokinetics is not dependent on hepatic uptake by organic anion-transporting polypeptide 1B1 in human beings.

    Science.gov (United States)

    Ziesenitz, Victoria C; König, Sonja K; Mahlke, Nina; Jantos, Ricarda; Skopp, Gisela; Weiss, Johanna; Haefeli, Walter E; Mikus, Gerd

    2013-07-01

    A recent study investigating the pharmacokinetics of fentanyl in Sprague-Dawley rats suggested fentanyl to be a substrate of rat organic anion-transporting polypeptide Oatp. In human beings, the most important OATP for the pharmacokinetics of many drugs is OATP1B1. Therefore, genetic variants of OATP1B1 (SLCO1B1) might modulate fentanyl pharmacokinetics and efficacy in human beings. Sixteen healthy male and female volunteers, homozygous for SLCO1B1*1a (genetic wild-type) (n = 11) or *15 (deficient haplotype carrying the single-nucleotide polymorphisms rs2306283 and rs4149056 and exhibiting altered transport activity; n = 5), were included in this randomized crossover study. The participants received fentanyl (5 μg/kg) intravenously alone or with the OATP inhibitor rifampicin (600 mg single oral dose). The pharmacokinetics of fentanyl and norfentanyl were determined by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). In addition, fentanyl uptake in vitro was evaluated in OATP1B1 overexpressing HEK293 cells and compared to a mock-transfected cell line. In the clinical trial, fentanyl clearance was 18.8 ± 8.2 mL/min. kg in SLCO1B1*1a and 19.5 ± 1.8 mL/min/kg in SLCO1B1*15 carriers and not significantly different between the genotypes. During rifampicin, fentanyl clearance was 15.0 ± 4.4 mL/min/kg in SLCO1B1*1a and 16.7 ± 5.9 mL/min/kg in SLCO1B1*15 carriers (p > 0.5). In addition, in vitro data also indicate that fentanyl is not transported by OATP1B1. In conclusion, our data indicate that OATP1B1 has no impact on fentanyl pharmacokinetics in human beings. © 2013 Nordic Pharmacological Society. Published by John Wiley & Sons Ltd.

  2. [Different views on the association between cannabinoids and cancer].

    Science.gov (United States)

    Vidinský, B; Gál, P; Mojzis, J

    2006-01-01

    Cannabinoids are the major active components of the most widely used illegal drug - marihuana. They have a long history of the medicinal use. However, they are still a controversial topic in oncological praxis. Cannabinoids play a role in different organs of human body and they are an integral part of the newly described endocannabinoid system, which regulates several body functions. The important function of endocannabinoids which is related to cancer, is the regulation of cell cycle and cell survival pathways. Presented review gives three different views on the association between cannabinoids and cancer. First, the treatment of adverse symptoms of oncological therapy - nausea and vomiting inhibition, appetite stimulation, pain relieving, mood modulation and muscle stiffness relieving. Second, in the late 1990s, three possible mechanisms of antitumour action were identified - apoptosis induction, direct cell cycle arrest and angiogenesis and metastasis inhibition. The phase I/II of clinical trials are carrying out in Spain. They study effects of local administration of tetrahydrokanabinol on the growth of glioblastoma multiforme. Third, the results of the newest study focused on the association between cannabinoids use and cancer risk showed no significant association between increased cancer incidence and cannabinoids use and it does not depend on the amount of used cannabis. It is important to establish the association between marihuana use and cancer risk regarding the consideration of advantages and risks of medicinal cannabinoids use and the impact on public health.

  3. 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...

  4. Simultaneous pharmacokinetics evaluation of human cytochrome P450 probes, caffeine, warfarin, omeprazole, metoprolol and midazolam, in common marmosets (Callithrix jacchus).

    Science.gov (United States)

    Uehara, Shotaro; Inoue, Takashi; Utoh, Masahiro; Toda, Akiko; Shimizu, Makiko; Uno, Yasuhiro; Sasaki, Erika; Yamazaki, Hiroshi

    2016-01-01

    1. Pharmacokinetics of human cytochrome P450 probes (caffeine, racemic warfarin, omeprazole, metoprolol and midazolam) composite, after single intravenous and oral administrations at doses of 0.20 and 1.0 mg kg(-1), respectively, to four male common marmosets were investigated. 2. The plasma concentrations of caffeine and warfarin decreased slowly in a monophasic manner but those of omeprazole, metoprolol and midazolam decreased extensively after intravenous and oral administrations, in a manner that approximated those as reported for pharmacokinetics in humans. 3. Bioavailabilities were ∼100% for caffeine and warfarin, but omeprazole and metoprolol. Bioavailability of midazolam was 4% in marmosets, presumably because of contribution of marmoset P450 3A4 expressed in small intestine and liver, with a high catalytic efficiency for midazolam 1'-hydroxylation as evident in the recombinant system. 4. These results suggest that common marmosets, despite their rapid clearance of some human P450 probe substrates, could be an experimental model for humans and that marmoset P450s have functional characteristics that differ from those of human and/or cynomolgus monkey P450s in some aspects, indicating their importance in modeling in P450-dependent drug metabolism studies in marmosets and of further studies.

  5. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes

    Science.gov (United States)

    De Petrocellis, Luciano; Ligresti, Alessia; Moriello, Aniello Schiano; Allarà, Marco; Bisogno, Tiziana; Petrosino, Stefania; Stott, Colin G; Di Marzo, Vincenzo

    2011-01-01

    BACKGROUND AND PURPOSE Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) interact with transient receptor potential (TRP) channels and enzymes of the endocannabinoid system. EXPERIMENTAL APPROACH The effects of 11 pure cannabinoids and botanical extracts [botanical drug substance (BDS)] from Cannabis varieties selected to contain a more abundant cannabinoid, on TRPV1, TRPV2, TRPM8, TRPA1, human recombinant diacylglycerol lipase α (DAGLα), rat brain fatty acid amide hydrolase (FAAH), COS cell monoacylglycerol lipase (MAGL), human recombinant N-acylethanolamine acid amide hydrolase (NAAA) and anandamide cellular uptake (ACU) by RBL-2H3 cells, were studied using fluorescence-based calcium assays in transfected cells and radiolabelled substrate-based enzymatic assays. Cannabinol (CBN), cannabichromene (CBC), the acids (CBDA, CBGA, THCA) and propyl homologues (CBDV, CBGV, THCV) of CBD, cannabigerol (CBG) and THC, and tetrahydrocannabivarin acid (THCVA) were also tested. KEY RESULTS CBD, CBG, CBGV and THCV stimulated and desensitized human TRPV1. CBC, CBD and CBN were potent rat TRPA1 agonists and desensitizers, but THCV-BDS was the most potent compound at this target. CBG-BDS and THCV-BDS were the most potent rat TRPM8 antagonists. All non-acid cannabinoids, except CBC and CBN, potently activated and desensitized rat TRPV2. CBDV and all the acids inhibited DAGLα. Some BDS, but not the pure compounds, inhibited MAGL. CBD was the only compound to inhibit FAAH, whereas the BDS of CBC > CBG > CBGV inhibited NAAA. CBC = CBG > CBD inhibited ACU, as did the BDS of THCVA, CBGV, CBDA and THCA, but the latter extracts were more potent inhibitors. CONCLUSIONS AND IMPLICATIONS These results are relevant to the analgesic, anti-inflammatory and anti-cancer effects of cannabinoids and Cannabis extracts. LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011

  6. Characterization and pharmacokinetic study of recombinant human N-acetylgalactosamine-6-sulfate sulfatase.

    Science.gov (United States)

    Tomatsu, Shunji; Montaño, Adriana M; Gutierrez, Monica; Grubb, Jeffrey H; Oikawa, Hirotaka; Dung, Vu Chi; Ohashi, Amiko; Nishioka, Tatsuo; Yamada, Masamichi; Yamada, Mana; Tosaka, Yasuhiro; Trandafirescu, Georgeta G; Orii, Tadao

    2007-05-01

    Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disorder caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). The aims of this study were to establish Chinese hamster ovary (CHO) cells overexpressing recombinant human GALNS (rhGALNS) and to assess pharmacokinetics and tissue distribution of purified enzymes by using MPS IVA knock-out mouse (Galns(-/-)). The CHO-cell derived rhGALNS was purified from the media by a two-step affinity chromatography procedure. The rhGALNS was administered intravenously to 3-month-old Galns(-/-) mice at a single dose of 250U/g of body weight. The treated mice were examined by assaying the GALNS activity at baseline and up to 240min to assess clearance of the enzyme from blood circulation. The mice were sacrificed 4h after infusion of the enzyme to study the enzyme distribution in tissues. The rhGALNS was purified 1317-fold with 71% yield. The enzyme was taken up by Galns(-/-) chondrocytes (150U/mg/15h). The uptake was inhibited by mannose-6-phosphate. The enzyme activity disappeared from circulation with a half-life of 2.9min. After enzyme infusion, the enzyme was taken up and detected in multiple tissues (40.7% of total infused enzymes in liver). Twenty-four hours after a single infusion of the fluorescence-labeled enzymes into MPS IVA mice, biodistribution pattern showed the amount of tagged enzyme retained in bone, bone marrow, liver, spleen, kidney, and heart. In conclusion, we have shown that the phosphorylated rhGALNS is delivered to multiple tissues, including bone, and that it functions bioactively in Galns(-/-) chondrocytes implying a potential enzyme replacement treatment.

  7. Cannabinoid receptor CB1 regulates STAT3 activity and its expression dictates the responsiveness to SR141716 treatment in human glioma patients' cells

    Science.gov (United States)

    Ciaglia, Elena; Torelli, Giovanni; Pisanti, Simona; Picardi, Paola; D'Alessandro, Alba; Laezza, Chiara; Malfitano, Anna Maria; Fiore, Donatella; Zottola, Antonio Christian Pagano; Proto, Maria Chiara; Catapano, Giuseppe; Gazzerro, Patrizia; Bifulco, Maurizio

    2015-01-01

    Herein we show that a majority of human brain tumor samples and cell lines over-expressed cannabinoid receptor CB1 as compared to normal human astrocytes (NHA), while uniformly expressed low levels of CB2. This finding prompted us to investigate the therapeutic exploitation of CB1 inactivation by SR141716 treatment, with regard to its direct and indirect cell-mediated effects against gliomas. Functional studies, using U251MG glioma cells and primary tumor cell lines derived from glioma patients expressing different levels of CB1, highlighted SR141716 efficacy in inducing apoptosis via G1 phase stasis and block of TGF-β1 secretion through a mechanism that involves STAT3 inhibition. According to the multivariate role of STAT3 in the immune escape too, interestingly SR141716 lead also to the functional and selective expression of MICA/B on the surface of responsive malignant glioma cells, but not on NHA. This makes SR141716 treated-glioma cells potent targets for allogeneic NK cell-mediated recognition through a NKG2D restricted mechanism, thus priming them for NK cell antitumor reactivity. These results indicate that CB1 and STAT3 participate in a new oncogenic network in the complex biology of glioma and their expression levels in patients dictate the efficacy of the CB1 antagonist SR141716 in multimodal glioma destruction. SIGNIFICANCE CB1 is implicated in the regulation of cellular processes linked to survival, proliferation, invasion and angiogenesis in several physio-pathological conditions. We shed light on previously unrecognized molecular mechanism of CB1-mediated modulation of human glioma progression and provide the first and original demonstration of CB1-STAT3 axis as a new target and predictor biomarkers of the benefit from specific therapies. Indeed CB1 antagonism capable of tumoral cell division' control while making the glioma immunovisible and engaging the immune system to fight it may represent a hopeful alternative to other established

  8. Transdermal delivery of ketorolac tromethamine: permeation enhancement, device design, and pharmacokinetics in healthy humans.

    Science.gov (United States)

    Roy, S D; Manoukian, E

    1995-10-01

    Transdermal delivery of ketorolac tromethamine, a potent non-narcotic analgesic, through human skin in vitro and in vivo was investigated. In order to enhance and sustain the flux of ketorolac through human skin, various compositions of isopropyl alcohol (IPA), water, and isopropyl myristate (IPM) were evaluated. The solubility of ketorolac acid in an IPA/water binary vehicle mixture increased as the volume fraction of IPA increased from 0 to 90%. The solubility of ketorolac acid in an IPA/water/IPM (saturated) ternary vehicle mixture was practically the same as in the IPA/water binary vehicle mixture. The permeation of ketorolac acid through cadaver skin was evaluated using modified Franz diffusion cells. The skin flux increased as the IPA volume fraction was increased from 0 to 50% and then leveled off beyond 80% IPA loading. When IPM was added to the IPA/water binary vehicle mixture, a significant increase in the skin flux of ketorolac was observed. The skin flux decreased exponentially as the donor solution pH was raised from 3.5 to 7.0. The permeability of ketorolac through various membranes such as a microporous membrane and pressure-sensitive adhesive was evaluated. While a microporous membrane offered practically no diffusion resistance, the in vitro flux of ketorolac through cadaver skin decreased substantially upon lamination of pressure-sensitive adhesive onto a microporous membrane. Three liquid-reservoir type transdermal devices were fabricated using 6.5% ketorolac tromethamine gel, a microporous membrane, an adhesive membrane, and polyester backing film: TD-A (microporous membrane/acrylic adhesive), TD-B (microporous membrane/silicone adhesive), and TD-C (microporous membrane). The pharmacokinetics of ketorolac in 10 healthy humans following application of a transdermal device for 24 h was evaluated. The maximum plasma concentrations (Cmax) were 0.20, 0.18, and 0.82 microgram/mL for TD-A, TD-B, and TD-C, respectively. The total AUC values for the

  9. 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.

  10. 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-linear regr......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...

  11. PHRMA CPCDC initiative on predictive models of human pharmacokinetics, part 5: prediction of plasma concentration-time profiles in human by using the physiologically-based pharmacokinetic modeling approach.

    Science.gov (United States)

    Poulin, Patrick; Jones, Rhys D O; Jones, Hannah M; Gibson, Christopher R; Rowland, Malcolm; Chien, Jenny Y; Ring, Barbara J; Adkison, Kimberly K; Ku, M Sherry; He, Handan; Vuppugalla, Ragini; Marathe, Punit; Fischer, Volker; Dutta, Sandeep; Sinha, Vikash K; Björnsson, Thorir; Lavé, Thierry; Yates, James W T

    2011-10-01

    The objective of this study is to assess the effectiveness of physiologically based pharmacokinetic (PBPK) models for simulating human plasma concentration-time profiles for the unique drug dataset of blinded data that has been assembled as part of a Pharmaceutical Research and Manufacturers of America initiative. Combinations of absorption, distribution, and clearance models were tested with a PBPK approach that has been developed from published equations. An assessment of the quality of the model predictions was made on the basis of the shape of the plasma time courses and related parameters. Up to 69% of the simulations of plasma time courses made in human demonstrated a medium to high degree of accuracy for intravenous pharmacokinetics, whereas this number decreased to 23% after oral administration based on the selected criteria. The simulations resulted in a general underestimation of drug exposure (Cmax and AUC0- t ). The explanations for this underestimation are diverse. Therefore, in general it may be due to underprediction of absorption parameters and/or overprediction of distribution or oral first-pass. The implications of compound properties are demonstrated. The PBPK approach based on in vitro-input data was as accurate as the approach based on in vivo data. Overall, the scientific benefit of this modeling study was to obtain more extensive characterization of predictions of human PK from PBPK methods. Copyright © 2011 Wiley-Liss, Inc.

  12. Cannabinoid function in learning, memory and plasticity.

    Science.gov (United States)

    Riedel, G; Davies, S N

    2005-01-01

    Marijuana and its psychoactive constituents induce a multitude of effects on brain function. These include deficits in memory formation, but care needs to be exercised since many human studies are flawed by multiple drug abuse, small sample sizes, sample selection and sensitivity of psychological tests for subtle differences. The most robust finding with respect to memory is a deficit in working and short-term memory. This requires intact hippocampus and prefrontal cortex, two brain regions richly expressing CB1 receptors. Animal studies, which enable a more controlled drug regime and more constant behavioural testing, have confirmed human results and suggest, with respect to hippocampus, that exogenous cannabinoid treatment selectively affects encoding processes. This may be different in other brain areas, for instance the amygdala, where a predominant involvement in memory consolidation and forgetting has been firmly established. While cannabinoid receptor agonists impair memory formation, antagonists reverse these deficits or act as memory enhancers. These results are in good agreement with data obtained from electrophysiological recordings, which reveal reduction in neural plasticity following cannabinoid treatment, and increased plasticity following antagonist exposure. The mixed receptor properties of the pharmacological tool, however, make it difficult to define the exact role of any CB1 receptor population in memory processes with any certainty. This makes it all the more important that behavioural studies use selective administration of drugs to specific brain areas, rather than global administration to whole animals. The emerging role of the endogenous cannabinoid system in the hippocampus may be to facilitate the induction of long-term potentiation/the encoding of information. Administration of exogenous selective CB1 agonists may therefore disrupt hippocampus-dependent learning and memory by 'increasing the noise', rather than 'decreasing the signal' at

  13. Normal aging in rats and pathological aging in human Alzheimer's disease decrease FAAH activity: modulation by cannabinoid agonists.

    Science.gov (United States)

    Pascual, A C; Martín-Moreno, A M; Giusto, N M; de Ceballos, M L; Pasquaré, S J

    2014-12-01

    Anandamide is an endocannabinoid involved in several physiological functions including neuroprotection. Anandamide is synthesized on demand and its endogenous level is regulated through its degradation, where fatty acid amide hydrolase plays a major role. The aim of this study was to characterize anandamide breakdown in physiological and pathological aging and its regulation by CB1 and CB2 receptor agonists. Fatty acid amide hydrolase activity was analyzed in an independent cohort of human cortical membrane samples from control and Alzheimer's disease patients, and in membrane and synaptosomes from adult and aged rat cerebral cortex. Our results demonstrate that fatty acid amide hydrolase activity decreases in the frontal cortex from human patients with Alzheimer's disease and this effect is mimicked by Aβ(1-40) peptide. This activity increases and decreases in aged rat cerebrocortical membranes and synaptosomes, respectively. Also, while the presence of JWH-133, a CB2 selective agonist, slightly increases anandamide hydrolysis in human controls, it decreases this activity in adults and aged rat cerebrocortical membranes and synaptosomes. In the presence of WIN55,212-2, a mixed CB1/CB2 agonist, anandamide hydrolysis increases in Alzheimer's disease patients but decreases in human controls as well as in adult and aged rat cerebrocortical membranes and synaptosomes. Although a similar profile is observed in fatty acid amide hydrolase activity between aged rat synaptic endings and human Alzheimer's disease brains, it is differently modulated by CB1/CB2 agonists. This modulation leads to a reduced availability of anandamide in Alzheimer's disease and to an increased availability of this endocannabinoid in aging. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. The effect of obesity and repeated exposure on pharmacokinetic response to grape polyphenols in humans

    Science.gov (United States)

    Obesity is associated with lower circulating nutrients, though the reason is unclear. Since obesity may affect intestinal function, differential absorption may play a role. We investigated the pharmacokinetic response of polyphenols in obese/overweight and lean individuals from a dose of grape poly...

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

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, Jeffrey W., E-mail: jeffrey.fisher@fda.hhs.gov; Twaddle, Nathan C.; Vanlandingham, Michelle; Doerge, Daniel R.

    2011-11-15

    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 {mu}g 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 (Voelkel et al., 2002). Voelkel 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 Voelkel 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: Black-Right-Pointing-Pointer A bisphenol A (BPA) PBPK model for the infant and adult monkey was constructed. Black-Right-Pointing-Pointer The hepatic metabolic rate of BPA increased with age of the monkey. Black-Right-Pointing-Pointer The systemic clearance rate of metabolites increased with age of the monkey. Black-Right-Pointing-Pointer Gut wall metabolism of orally administered BPA was substantial across all ages of monkeys. Black-Right-Pointing-Pointer Aglycone BPA plasma concentrations were predicted in humans orally given oral doses of deuterated BPA.

  16. Equivalent potency and pharmacokinetics of recombinant human growth hormones with or without an N-terminal methionine.

    Science.gov (United States)

    Moore, J A; Rudman, C G; MacLachlan, N J; Fuller, G B; Burnett, B; Frane, J W

    1988-06-01

    Two forms of human GH (hGH) have been produced by recombinant DNA technology. One form has an amino acid sequence identical to that of the natural pituitary hormone (rhGH) and the other form has an additional N-terminal methionine (Met-hGH). The biological potencies of these 2 polypeptides have been compared in hypophysectomized rats in a multidose study measuring body weights and several long bone growth parameters. The pharmacokinetic profiles after iv and sc injection were determined in cynomolgus monkeys in a 4-period cross-over study. All of the measured parameters in all the studies indicated that there was no difference in the two forms of hGH. Measurements taken after 27 daily injections of rhGH or Met-hGH (30-500 micrograms/kg.day) indicated that femur length and width of the proliferative zone in the tibial epiphysis showed dose-related effects for both forms of hGH but no difference between them. The relative potency, based on body weight gain, was calculated using a parallel line bioassay. Weight gain after 8 daily injections in the 5-dose long bone growth study indicated a rhGH potency of 0.80 (95% confidence interval, 0.5-1.23) relative to Met-hGH. It was concluded that the presence of an N-terminal methionine on hGH has no effect on potency in this model. The pharmacokinetic parameters after iv administration were estimated by fitting serum concentration-time data to a 2-compartment model. Parameters after sc injection were computed by compartment-independent methods. Met-hGH and rhGH had very similar pharmacokinetic profiles after both routes of administration. Comparison of the pharmacokinetic parameters indicated that the clearance after iv administration (rhGH, 15 ml/min; Met-hGH, 13 ml/min) and the sc bioavailability (rhGH, 0.72 +/- 0.21; Met-hGH, 0.59 +/- 0.21) were not significantly different for the 2 forms of hGH. It was concluded that rhGH and Met-hGH have equivalent bioavailability and pharmacokinetics in cynomolgus monkeys.

  17. Cannabis, cannabinoids and reproduction.

    Science.gov (United States)

    Park, Boram; McPartland, John M; Glass, Michelle

    2004-02-01

    In most countries Cannabis is the most widely used illegal drug. Its use during pregnancy in developed nations is estimated to be approximately 10%. Recent evidence suggests that the endogenous cannabinoid system, now consisting of two receptors and multiple endocannabinoid ligands, may also play an important role in the maintenance and regulation of early pregnancy and fertility. The purpose of this review is therefore twofold, to examine the impact that cannabis use may have on fertility and reproduction, and to review the potential role of the endocannabinoid system in hormonal regulation, embryo implantation and maintenance of pregnancy.

  18. A systems biology approach to dynamic modeling and inter-subject variability of statin pharmacokinetics in human hepatocytes

    Directory of Open Access Journals (Sweden)

    Thasler Wolfgang E

    2011-05-01

    Full Text Available Abstract Background The individual character of pharmacokinetics is of great importance in the risk assessment of new drug leads in pharmacological research. Amongst others, it is severely influenced by the properties and inter-individual variability of the enzymes and transporters of the drug detoxification system of the liver. Predicting individual drug biotransformation capacity requires quantitative and detailed models. Results In this contribution we present the de novo deterministic modeling of atorvastatin biotransformation based on comprehensive published knowledge on involved metabolic and transport pathways as well as physicochemical properties. The model was evaluated on primary human hepatocytes and parameter identifiability analysis was performed under multiple experimental constraints. Dynamic simulations of atorvastatin biotransformation considering the inter-individual variability of the two major involved enzymes CYP3A4 and UGT1A3 based on quantitative protein expression data in a large human liver bank (n = 150 highlighted the variability in the individual biotransformation profiles and therefore also points to the individuality of pharmacokinetics. Conclusions A dynamic model for the biotransformation of atorvastatin has been developed using quantitative metabolite measurements in primary human hepatocytes. The model comprises kinetics for transport processes and metabolic enzymes as well as population liver expression data allowing us to assess the impact of inter-individual variability of concentrations of key proteins. Application of computational tools for parameter sensitivity analysis enabled us to considerably improve the validity of the model and to create a consistent framework for precise computer-aided simulations in toxicology.

  19. A systems biology approach to dynamic modeling and inter-subject variability of statin pharmacokinetics in human hepatocytes.

    Science.gov (United States)

    Bucher, Joachim; Riedmaier, Stephan; Schnabel, Anke; Marcus, Katrin; Vacun, Gabriele; Weiss, Thomas S; Thasler, Wolfgang E; Nüssler, Andreas K; Zanger, Ulrich M; Reuss, Matthias

    2011-05-06

    The individual character of pharmacokinetics is of great importance in the risk assessment of new drug leads in pharmacological research. Amongst others, it is severely influenced by the properties and inter-individual variability of the enzymes and transporters of the drug detoxification system of the liver. Predicting individual drug biotransformation capacity requires quantitative and detailed models. In this contribution we present the de novo deterministic modeling of atorvastatin biotransformation based on comprehensive published knowledge on involved metabolic and transport pathways as well as physicochemical properties. The model was evaluated on primary human hepatocytes and parameter identifiability analysis was performed under multiple experimental constraints. Dynamic simulations of atorvastatin biotransformation considering the inter-individual variability of the two major involved enzymes CYP3A4 and UGT1A3 based on quantitative protein expression data in a large human liver bank (n = 150) highlighted the variability in the individual biotransformation profiles and therefore also points to the individuality of pharmacokinetics. A dynamic model for the biotransformation of atorvastatin has been developed using quantitative metabolite measurements in primary human hepatocytes. The model comprises kinetics for transport processes and metabolic enzymes as well as population liver expression data allowing us to assess the impact of inter-individual variability of concentrations of key proteins. Application of computational tools for parameter sensitivity analysis enabled us to considerably improve the validity of the model and to create a consistent framework for precise computer-aided simulations in toxicology.

  20. 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.

  1. Pharmacokinetics of flavanone glycosides after ingestion of single doses of fresh-squeezed orange juice versus commercially processed orange juice in healthy humans

    Science.gov (United States)

    Orange juice is a rich source of flavonoids known to be beneficial to cardiovascular health in humans. The objective of this study was to analyze the pharmacokinetics of the main flavanone glycosides, hesperidin and narirutin, in humans after the consumption of two types of orange juice, fresh squee...

  2. A pharmacokinetic model of drug-drug interaction between clopidogrel and omeprazole at CYP2C19 in humans.

    Science.gov (United States)

    Tangamornsuksan, Wimonchat; Thiansupornpong, Pongpak; Morasuk, Thirawut; Lohitnavy, Ornrat; Lohitnavy, Manupat

    2017-07-01

    Clopidogrel is a thienopryridine antiplatelet agent commonly used in the management of cardiovascular diseases. Clopidogrel is metabolized by hepatic CYP2C19 and CYP2B6, therefore, co-administration of clopidogrel and CYP2C19 inhibitors can alter pharmacokinetics of clopidogrel. Omeprazole is a proton pump inhibitor used for decreasing gastric acid production. Omeprazole is known to be a potent inhibitor of CYP2C19. Thus when the drugs are simultaneously administered, clopidogrel plasma concentration levels can be increased. However, plasma levels of the active metabolite of clopidogrel can be significantly decreased, thereby, its antiplatelet activity is reduced. We aimed to develop a mathematical model describing a drug-drug interaction between clopidogrel and omeprazole in humans. Searching for pharmacokinetic interaction studies between clopidogrel and omeprazole in humans was performed in PubMed. Six studies were selected into our modeling purposes to develop 3 mathematical models (i.e. 4 studies for clopidogrel alone, 1 study for omeprazole alone and 1 study for clopidogrel-omeprazole interaction). Subsequently, concentration-time course data from the selected studies were extracted. Computer codes and simulations were performed using the Advanced Continuous Simulating Language Extreme (ACSLX) program. We successfully developed 3 mathematical models which are able to describe all of the datasets. Our clopidogrel-omeprazole pharmacokinetic interaction model with a description of competitive inhibition at CYP2C19 could successfully describe concentration-time courses from the selected datasets. Our interaction model may be useful in predicting plasma levels of clopidogrel and its active metabolite.

  3. Acute passive cigarette smoke exposure and inhaled human insulin (Exubera) pharmacokinetics.

    Science.gov (United States)

    Fountaine, Robert; Milton, Ashley; Checchio, Tina; Wei, Greg; Stolar, Marilyn; Teeter, John; Jaeger, Rudolph; Fryburg, David

    2008-06-01

    Active cigarette smoking is associated with increased permeability of the pulmonary alveolar epithelium, resulting in faster absorption of inhaled drugs such as Exubera (EXU). Absorption of EXU is increased approximately twice to four times as much in chronic smokers compared with nonsmokers. The rate of clearance of radioaerosols such as technetium-labelled diethylenetriamine penta-acetic acid is decreased in response to passive smoke exposure. Passive smoke exposure causes a decrease in lung permeability, an effect opposite to that of active smoking. Acute passive smoke exposure results in a decrease in EXU bioavailability and does not create a risk of hypoglycaemia. These results are consistent with previous studies of radioaerosol lung clearance. AIMS Relative to nonsmokers, the bioavailability of inhaled human insulin (Exubera(R); EXU) is markedly increased in chronic smokers. The pharmacokinetics of EXU following passive cigarette smoke exposure is unknown. METHODS In an open-label, crossover study, healthy nonsmoking volunteers received two treatments in randomized sequence separated by a 2-week wash-out: (i) EXU 3 mg with no passive smoke exposure and (ii) EXU 3 mg after passive smoke exposure (atmospheric nicotine levels 75-125 mug m(-3)) for 2 h. Blood samples were obtained at prespecified times up to 6 h after EXU administration. Twenty-seven subjects completed both study periods. Mean plasma insulin AUC(0-360) decreased by 17% [ratio 83%, 95% confidence interval (CI) 68.8, 99.5] and mean C(max) by 29% (ratio 71%, 95% CI 59.8, 83.1) after passive cigarette smoke exposure. The median (range) t(max) was 60 min (20-120 min) and 75 min (20-360 min) in the EXU with no exposure and EXU passive exposure groups, respectively. EXU was well tolerated. Unlike active chronic smoking, acute passive cigarette smoke exposure modestly decreases EXU bioavailability and thus should not increase hypoglycaemia risk. These results are consistent with those from published

  4. Synthetic Cannabinoids: Epidemiology, Pharmacodynamics, and Clinical Implications*

    Science.gov (United States)

    Castaneto, Marisol S.; Gorelick, David A.; Desrosiers, Nathalie A.; Hartman, Rebecca L.; Pirard, Sandrine; Huestis, Marilyn A.

    2014-01-01

    Background Synthetic cannabinoids (SC) are a heterogeneous group of compounds developed to probe the endogenous cannabinoid system or as potential therapeutics. Clandestine laboratories subsequently utilized published data to develop SC variations marketed as abuseable “designer drugs.” In the early 2000’s, SC became popular as “legal highs” under brand names such as “Spice” and “K2,” in part due to their ability to escape detection by standard cannabinoid screening tests. The majority of SC detected in herbal products have greater binding affinity to the cannabinoid CB1 receptor than does Δ9-tetrahydrocannabinol (THC), the primary psychoactive compound in the cannabis plant, and greater affinity at the CB1 than the CB2 receptor. In-vitro and animal in-vivo studies show SC pharmacological effects 2-100 times more potent than THC, including analgesic, anti-seizure, weight-loss, anti-inflammatory, and anti-cancer growth effects. SC produce physiological and psychoactive effects similar to THC, but with greater intensity, resulting in medical and psychiatric emergencies. Human adverse effects include nausea and vomiting, shortness of breath or depressed breathing, hypertension, tachycardia, chest pain, muscle twitches, acute renal failure, anxiety, agitation, psychosis, suicidal ideation, and cognitive impairment. Long-term or residual effects are unknown. Due to these public health consequences, many SC are classified as controlled substances. However, frequent structural modification by clandestine laboratories results in a stream of novel SC that may not be legally controlled or detectable by routine laboratory tests. Methods We present here a comprehensive review, based on a systematic electronic literature search, of SC epidemiology and pharmacology and their clinical implications. PMID:25220897

  5. Synthetic cannabinoids: epidemiology, pharmacodynamics, and clinical implications.

    Science.gov (United States)

    Castaneto, Marisol S; Gorelick, David A; Desrosiers, Nathalie A; Hartman, Rebecca L; Pirard, Sandrine; Huestis, Marilyn A

    2014-11-01

    Synthetic cannabinoids (SC) are a heterogeneous group of compounds developed to probe the endogenous cannabinoid system or as potential therapeutics. Clandestine laboratories subsequently utilized published data to develop SC variations marketed as abusable designer drugs. In the early 2000s, SC became popular as "legal highs" under brand names such as Spice and K2, in part due to their ability to escape detection by standard cannabinoid screening tests. The majority of SC detected in herbal products have greater binding affinity to the cannabinoid CB1 receptor than does Δ(9)-tetrahydrocannabinol (THC), the primary psychoactive compound in the cannabis plant, and greater affinity at the CB1 than the CB2 receptor. In vitro and animal in vivo studies show SC pharmacological effects 2-100 times more potent than THC, including analgesic, anti-seizure, weight-loss, anti-inflammatory, and anti-cancer growth effects. SC produce physiological and psychoactive effects similar to THC, but with greater intensity, resulting in medical and psychiatric emergencies. Human adverse effects include nausea and vomiting, shortness of breath or depressed breathing, hypertension, tachycardia, chest pain, muscle twitches, acute renal failure, anxiety, agitation, psychosis, suicidal ideation, and cognitive impairment. Long-term or residual effects are unknown. Due to these public health consequences, many SC are classified as controlled substances. However, frequent structural modification by clandestine laboratories results in a stream of novel SC that may not be legally controlled or detectable by routine laboratory tests. We present here a comprehensive review, based on a systematic electronic literature search, of SC epidemiology and pharmacology and their clinical implications. Published by Elsevier Ireland Ltd.

  6. Flavonoids from Perovskia atriplicifolia and Their in Vitro Displacement of the Respective Radioligands for Human Opioid and Cannabinoid Receptors.

    Science.gov (United States)

    Tarawneh, Amer; León, Francisco; Pettaway, Sara; Elokely, Khaled M; Klein, Michael L; Lambert, Janet; Mansoor, Arsala; Cutler, Stephen J

    2015-06-26

    Bioassay-guided fractionation of the leaves of Perovskia atriplicifolia (Russian sage) resulted in the isolation of four previously known flavonoid derivatives, 5-hydroxy-6,7,3',4'-tetramethoxyflavone (1), 5,7-dihydroxy-6,3',4'-trimethoxyflavone (2), 5-hydroxy-6,7,4'-trimethoxyflavone (3), and 5,7-dihydroxy-6,4'-dimethoxyflavone (4). Compounds 1, 3, and 4 showed displacement of the radioligand for the cloned human δ opioid receptor with Ki values ranging from 3.1 to 26.0 μM. In addition, the binding mode of the compounds in the active site of the δ opioid receptor was investigated through molecular modeling algorithms. This study may have implications in better understanding non-nitrogenous δ opioid receptor ligands.

  7. A nonsynonymous polymorphism in cannabinoid CB2 receptor gene is associated with eating disorders in humans and food intake is modified in mice by its ligands.

    Science.gov (United States)

    Ishiguro, H; Carpio, O; Horiuchi, Y; Shu, A; Higuchi, S; Schanz, N; Benno, R; Arinami, T; Onaivi, E S

    2010-01-01

    Marijuana use activates cannabinoid receptors (CB-Rs) producing several behavioral effects related to addiction, mood, and appetite. We investigated the association between CNR2 gene, which encodes cannabinoid CB2 receptor (CB2-R) and eating disorders in 204 subjects with eating disorders and 1876 healthy volunteers in Japanese population. The effect of treatment with CB2-R ligands on mouse food consumption was also determined. The CB2-R ligands used suppressed food intake in a time- and strain-dependent manner when food was available ad libitum and during the 12-h fast except, AM 630-the CB2-R antagonist that stimulated food consumption in food-deprived mice. There is an association between the R63Q polymorphism of the CNR2 gene and eating disorders (P = 0.04; Odds ratio 1.24, 95% CI, (1.01-1.53). These results suggest that cannabinoid CB2-R is involved in the endocannabinoid signaling mechanisms associated with the regulation of food intake and in eating disorders.

  8. 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...... with 64Cu-ATSM and CT scans with contrast. Irreversible and reversible two-tissue compartment models were fitted to time activity curves (TACs) obtained from whole tumor volumes and compared using the Akaike information criterion (AIC). Based on voxel-wise pharmacokinetic analysis, parametric maps...... of model rate constants k₁, k₃ and Ki were generated and compared to 64Cu-ATSM uptake.RESULTS: Based on the AIC, an irreversible two-tissue compartment model was selected for voxel-wise pharmacokinetic analysis. Of the extracted parameters, k₁ (~perfusion) showed a strong correlation with early tracer...

  9. 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.

  10. Cannabinoid receptors in the kidney.

    Science.gov (United States)

    Hryciw, Deanne H; McAinch, Andrew J

    2016-09-01

    The endocannabinoid system modulates cell signaling targets that are essential for energy homeostasis. Endocannabinoids bind to G protein-coupled receptors in the central nervous system and periphery, including the kidney. Modulation of cannabinoid receptor 1 (CB1) and CB2 activity in the kidney in diabetes and obesity has been identified as potential therapeutic target to reduce albuminuria and renal fibrosis. This review will highlight the results of recent studies that have identified a role for CB1 and CB2 in normal and pathological renal conditions. CB1 and CB2 have been reported to play key roles in renal function and dysfunction. Recent studies have determined that antagonism of CB1 and agonism of CB2 in diabetic nephropathy and obesity associated kidney disease can reduce albuminuria, potentially by acting on both the glomeruli and tubules. Emerging studies have also identified a role for CB1 in renal diseases associated with fibrosis, with CB1 upregulated in multiple models of human nephropathies. Emerging studies using isolated cells, rodent models, and human studies have identified a critical role for the endocannabinoid system in renal function and disease. Thus, therapeutics that modulate the activity of CB1 and CB2 in renal disease could become clinically relevant.

  11. 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.

  12. 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...... harvested following a two-step perfusion protocol and the SCRH were prepared between layers of rat-tail collagen. The biliary efflux of 5F-PY-PICA and its metabolites was determined in three-day–cultured SCRH by differential efflux into either standard buffer from intact bile canaliculi or standard buffer...

  13. Engineering yeasts as platform organisms for cannabinoid biosynthesis.

    Science.gov (United States)

    Zirpel, Bastian; Degenhardt, Friederike; Martin, Chantale; Kayser, Oliver; Stehle, Felix

    2017-10-10

    Δ9-tetrahydrocannabinolic acid (THCA) is a plant derived secondary natural product from the plant Cannabis satival. The discovery of the human endocannabinoid system in the late 1980s resulted in a growing number of known physiological functions of both synthetic and plant derived cannabinoids. Thus, manifold therapeutic indications of cannabinoids currently comprise a significant area of research. Here we reconstituted the final biosynthetic cannabinoid pathway in yeasts. The use of the soluble prenyltransferase NphB from Streptomyces sp. strain CL190 enables the replacement of the native transmembrane prenyltransferase cannabigerolic acid synthase from C. sativa. In addition to the desired product cannabigerolic acid, NphB catalyzes an O-prenylation leading to 2-O-geranyl olivetolic acid. We show for the first time that the bacterial prenyltransferase and the final enzyme of the cannabinoid pathway tetrahydrocannabinolic acid synthase can both be actively expressed in the yeasts Saccharomyces cerevisiae and Komagataella phaffii simultaneously. While enzyme activities in S. cerevisiae were insufficient to produce THCA from olivetolic acid and geranyl diphosphate, genomic multi-copy integrations of the enzyme's coding sequences in K. phaffii resulted in successful synthesis of THCA from olivetolic acid and geranyl diphosphate. This study is an important step toward total biosynthesis of valuable cannabinoids and derivatives and demonstrates the potential for developing a sustainable and secure yeast bio-manufacturing platform. Copyright © 2017 Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Christoph W Michalski

    Full Text Available BACKGROUND: While cannabinoids have been shown to ameliorate liver fibrosis, their effects in chronic pancreatitis and on pancreatic stellate cells (PSC are unknown. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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.

  15. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes.

    Science.gov (United States)

    De Petrocellis, Luciano; Ligresti, Alessia; Moriello, Aniello Schiano; Allarà, Marco; Bisogno, Tiziana; Petrosino, Stefania; Stott, Colin G; Di Marzo, Vincenzo

    2011-08-01

    Cannabidiol (CBD) and Δ(9) -tetrahydrocannabinol (THC) interact with transient receptor potential (TRP) channels and enzymes of the endocannabinoid system. The effects of 11 pure cannabinoids and botanical extracts [botanical drug substance (BDS)] from Cannabis varieties selected to contain a more abundant cannabinoid, on TRPV1, TRPV2, TRPM8, TRPA1, human recombinant diacylglycerol lipase α (DAGLα), rat brain fatty acid amide hydrolase (FAAH), COS cell monoacylglycerol lipase (MAGL), human recombinant N-acylethanolamine acid amide hydrolase (NAAA) and anandamide cellular uptake (ACU) by RBL-2H3 cells, were studied using fluorescence-based calcium assays in transfected cells and radiolabelled substrate-based enzymatic assays. Cannabinol (CBN), cannabichromene (CBC), the acids (CBDA, CBGA, THCA) and propyl homologues (CBDV, CBGV, THCV) of CBD, cannabigerol (CBG) and THC, and tetrahydrocannabivarin acid (THCVA) were also tested. CBD, CBG, CBGV and THCV stimulated and desensitized human TRPV1. CBC, CBD and CBN were potent rat TRPA1 agonists and desensitizers, but THCV-BDS was the most potent compound at this target. CBG-BDS and THCV-BDS were the most potent rat TRPM8 antagonists. All non-acid cannabinoids, except CBC and CBN, potently activated and desensitized rat TRPV2. CBDV and all the acids inhibited DAGLα. Some BDS, but not the pure compounds, inhibited MAGL. CBD was the only compound to inhibit FAAH, whereas the BDS of CBC > CBG > CBGV inhibited NAAA. CBC = CBG > CBD inhibited ACU, as did the BDS of THCVA, CBGV, CBDA and THCA, but the latter extracts were more potent inhibitors. These results are relevant to the analgesic, anti-inflammatory and anti-cancer effects of cannabinoids and Cannabis extracts. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  16. 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.

  17. 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/106 cells in dog and 353.7 ng/g w.w. cell pellet or 6,809 pg/106 cells in human) and in hepatocytes (414.5 ng/g w.w. cell pellet or 14,005 pg/106 cells in dog and 813.5 ng/g w.w. cell pellet or 13,780 pg/106 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/106 cells, human: 201.5 ng/g w.w. cell pellet or 18.6 pg/106 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.

  18. Exploratory population pharmacokinetics (e-PPK) analysis for predicting human PK using exploratory ADME data during early drug discovery research.

    Science.gov (United States)

    Tabata, Kenji; Hamakawa, Nozomu; Sanoh, Seigo; Terashita, Shigeyuki; Teramura, Toshio

    2009-01-01

    We have proposed a novel method by population pharmacokinetics analysis for forecasting the drug concentration time-course in humans. This method is based on the non-linear mixed effect model (NONMEM) combined with in vitro-in vivo extrapolation (IVIVE). Eleven clinically tested compounds were selected for retrospective analysis. The in vivo pharmacokinetic (pk) profiles (rats, dogs, monkeys, and humans) and in vitro ADME data [intrinsic clearance (CLint), plasma unbound fraction (fp), and blood-plasma partition ratio (Rb)] for each compound was routinely tested via a screening system to account for inter-compound differences in pk properties. When evaluating the pk parameters, the hepatic plasma flow (Qph) and plasma volume (Vp) were taken into account to compensate for differences in body size among species. All these data were used to conduct population pk (PPK) analyses under the hypothesis that all species constituted one population. The two-compartment model (ADVAN4 TRANS3) and NONMEM software were used for this analysis. The fixed effect model for total body clearance (CL) and central distribution volume (Vd) were constructed as theta(CL)Qph x Eh and theta(Vd) x Vp, respectively, where the hepatic extraction ratio Eh was calculated using the traditional dispersion model. NONMEM generates both fixed and random effects (eta). The key point of this concept was to substitute the eta values of each species (rats, dogs, and monkeys) into the human PPK model to simulate three kinds of pk profiles, compound by compound, for use as a general scaling factor. The NONMEM post hoc option was used to perform the simulation, after which the concentration vs. time courses were compared with actual clinical pk data. The true values were almost within the dynamic range. Thus, the advantage of this concept is that it can generate time-courses without the detail of drug-specific parameters, from which the elimination half time can be determined. This proposed exploratory

  19. Multiple-Dose Pharmacokinetic Behavior of Elvucitabine, a Nucleoside Reverse Transcriptase Inhibitor, Administered over 21 Days with Lopinavir-Ritonavir in Human Immunodeficiency Virus Type 1-Infected Subjects

    NARCIS (Netherlands)

    Colucci, Philippe; Pottage, John C.; Robison, Heather; Turgeon, Jacques; Schuermann, Dirk; Hoepelman, I. M.; Ducharme, Murray P.

    The purpose of this study was to describe the plasma pharmacokinetics (PK) of elvucitabine at different doses when administered daily or every other day for 21 days with lopinavir-ritonavir ( Kaletra) in human immunodeficiency virus (HIV)-infected subjects. Three different dosing regimens of

  20. 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

    Objective: The aim of this study was to characterise the population pharmacokinetics of FE 999049, a novel recombinant human follicle-stimulating hormone (FSH), after multiple dosing in healthy women, taking into account endogenous FSH levels and the reproductive hormone dynamics. Methods...

  1. Combined analysis of pharmacokinetic and efficacy data of preclinical studies with statins markedly improves translation of drug efficacy to human trialss

    NARCIS (Netherlands)

    Steeg, E. van de; Kleemann, R.; Jansen, H.T.; Duyvenvoorde, W. van; Offerman, E.H.; Wortelboer, H.M.; DeGroot, J.

    2013-01-01

    Correct prediction of human pharmacokinetics (PK) and the safety and efficacy of novel compounds based on preclinical data, is essential but often fails. In the current study, we aimed to improve the predictive value of ApoE*3Leiden (E3L) trans-genic mice regarding the cholesterol-lowering efficacy

  2. 21 CFR 862.3870 - Cannabinoid test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cannabinoid test system. 862.3870 Section 862.3870 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

  3. Animal models of cannabinoid reward

    Science.gov (United States)

    Panlilio, Leigh V; Justinova, Zuzana; Goldberg, Steven R

    2010-01-01

    The endogenous cannabinoid system is involved in numerous physiological and neuropsychological functions. Medications that target this system hold promise for the treatment of a wide variety of disorders. However, as reward is one of the most prominent of these functions, medications that activate this system must be evaluated for abuse potential. Meanwhile, cannabis is already being used chronically by millions of people, many of whom eventually seek treatment for cannabis dependence. Therefore, there is a need for procedures that can be used to: (i) better understand the mechanisms of cannabinoid reward; (ii) evaluate the abuse potential of new medications; and (iii) evaluate the effectiveness of medications developed for treating cannabis dependence. Animal models of cannabinoid reward provide a means of accomplishing these goals. In this review, we briefly describe and evaluate these models, their advantages and their shortcomings. Special emphasis is placed on intravenous cannabinoid self-administration in squirrel monkeys, a valid, reliable and flexible model that we have developed over the past decade. Although the conditions under which cannabinoid drugs have rewarding effects may be more restricted than with other drugs of abuse such as cocaine and heroin, work with these models indicates that cannabinoid reward involves similar brain mechanisms and produces the same kinds of reward-related behaviour. By continuing to use these animal models as tools in the development of new medications, it should be possible to take advantage of the potential benefits provided by the endocannabinoid system while minimizing its potential for harm. This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x PMID:20590560

  4. 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

  5. Cannabinoid pharmacology: the first 66 years

    OpenAIRE

    Pertwee, Roger G.

    2006-01-01

    Research into the pharmacology of individual cannabinoids that began in the 1940s, several decades after the presence of a cannabinoid was first detected in cannabis, is concisely reviewed. Also described is how this pharmacological research led to the discovery of cannabinoid CB1 and CB2 receptors and of endogenous ligands for these receptors, to the development of CB1- and CB2-selective agonists and antagonists and to the realization that the endogenous cannabinoid system has significant ro...

  6. 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

  7. Cannabinoids: occurrence and medicinal chemistry.

    Science.gov (United States)

    Appendino, G; Chianese, G; Taglialatela-Scafati, O

    2011-01-01

    With an inventory of several hundreds secondary metabolites identified, Cannabis sativa L. (hemp) is one of the phytochemically best characterized plant species. The biomedical relevance of hemp undoubtedly underlies the wealth of data on its constituents and their biological activities, and cannabinoids, a class of unique meroterpenoids derived from the alkylation of an olivetollike alkyl resorcinol with a monoterpene unit, are the most typical constituents of Cannabis. In addition to the well-known psychotropic properties of Δ(9)-THC, cannabinoids have been reported to show potential in various fields of medicine, with the capacity to address unmet needs like the relief of chemotherapy-derived nausea and anorexia, and symptomatic mitigation of multiple sclerosis. Many of the potential therapeutic uses of cannabinoids are related to the interaction with (at least) two cannabinoid G-protein coupled receptors (CB1 and CB2). However, a number of activities, like the antibacterial or the antitumor properties are non totally dependent or fully independent from the interaction with these proteins. These pharmacological activities are particularly interesting since, in principle, they could be easily dissociated by the unwanted psychotropic effects. This review aims at giving readers a survey of the more recent advances in both phytochemistry of C. sativa, the medicinal chemistry of cannabinoids, and their distribution in plants, highlighting the impact that research in these hot fields could have for modern medicinal chemistry and pharmacology.

  8. Thermolytic Degradation of Synthetic Cannabinoids: Chemical Exposures and Pharmacological Consequences.

    Science.gov (United States)

    Thomas, Brian F; Lefever, Timothy W; Cortes, Ricardo A; Grabenauer, Megan; Kovach, Alexander L; Cox, Anderson O; Patel, Purvi R; Pollard, Gerald T; Marusich, Julie A; Kevin, Richard C; Gamage, Thomas F; Wiley, Jenny L

    2017-04-01

    Synthetic cannabinoids are manufactured clandestinely with little quality control and are distributed as herbal "spice" for smoking or as bulk compound for mixing with a solvent and inhalation via electronic vaporizers. Intoxication with synthetic cannabinoids has been associated with seizure, excited delirium, coma, kidney damage, and other disorders. The chemical alterations produced by heating these structurally novel compounds for consumption are largely unknown. Here, we show that heating synthetic cannabinoids containing tetramethylcyclopropyl-ring substituents produced thermal degradants with pharmacological activity that varied considerably from their parent compounds. Moreover, these degradants were formed under conditions simulating smoking. Some products of combustion retained high affinity at the cannabinoid 1 (CB1) and CB2 receptors, were more efficacious than (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55,940) in stimulating CB1 receptor-mediated guanosine 5'-O-(3-thiotriphosphate) (GTPγS) binding, and were potent in producing Δ9-tetrahydrocannabinol-like effects in laboratory animals, whereas other compounds had low affinity and efficacy and were devoid of cannabimimetic activity. Degradants that retained affinity and efficacy also substituted in drug discrimination tests for the prototypical synthetic cannabinoid 1-pentyl-3-(1-naphthoyl)indole (JWH-018), and are likely to produce psychotropic effects in humans. Hence, it is important to take into consideration the actual chemical exposures that occur during use of synthetic cannabinoid formulations to better comprehend the relationships between dose and effect. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  9. 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.

  10. [Evaluation of an on-site drug-testing device for the detection of synthetic cannabinoids in illegal herbal products].

    Science.gov (United States)

    Uchiyama, Nahoko; Kikura-Hanajiri, Ruri; Hakamatsuka, Takashi

    2015-01-01

    Recently, illegal herbal or liquid products containing psychoactive compounds have been a serious problem damaging human health and causing numerous traffic accidents. Reports indicate that most of those herbal products contain various types of synthetic cannabinoids. There are many on-site drug-testing devices; however, synthetic cannabinoids are not targeted compounds for such devices. In this study, we evaluated the on-site drug-testing device "K2/Spice Test" for the detection of 12 different types of 38 synthetic cannabinoids (including 13 naphthoylindole-type synthetic cannabinoids) and a natural cannabinoid (Δ(9)-tetrahydrocannabinol). Although this device is primarily used for the detection of metabolites of naphthoylindole-type synthetic cannabinoids in urine samples, we applied it to detect synthetic cannabinoids in illegal herbal products for rapid screening analyses. As a result of the on-site examination of synthetic cannabinoids, 10 naphthoylindole-type synthetic cannabinoids [five narcotics (JWH-018, JWH-073, AM-2201, MAM-2201, and JWH-122); five designated substances (JWH-015, JWH-200, AM-1220, JWH-019, and JWH-020)], and two other types of synthetic cannabinoid [designated substances (a benzoylindole AM-694 and a naphthoylnaphthalene CB-13)] showed positive results (the limit of detection ranged from 50 to 250 μg/mL). Furthermore, MeOH extracts of illegal herbal products containing naphthoylindole-type synthetic cannabinoids also showed positive results (the limit of detection ranged from 2.5 to 10 mg herbal products/mL). Therefore, we found that this device may be useful for the on-site examination of some naphthoylindole-type synthetic cannabinoids not only in urine samples but also in illegal herbal products.

  11. [Determination of levodropropizine and its pharmacokinetics in human plasma using LC/MS/MS].

    Science.gov (United States)

    Zhao, Li-mei; Zhao, Li; Sun, Ya-xin; Qiu, Feng; Guo, Shan-bin

    2004-12-01

    To develop a rapid and sensitive LC/MS/MS method for the analysis of levodropropizine in plasma and study the pharmacokinetics of levodropropizine in healthy Chinese volunteers. Levodropropizine and zolmitriptan (internal standard, IS) were extracted from plasma samples and chromatographed on a C18 column and detected using a tandem mass spectrometer with a TurboIon Spray ionization interface. Quantitation was performed using multiple reaction monitoring (MRM) of the transitions of the m/z 237 --> m/z 120 for levodropropizine and m/z 288 --> m/z 58 for the IS. The limit of quantification of the method for levodropropizine was 0.25 microg x L(-1). The assay was linear over the concentration range from 0.25 to 500.0 microg x L(-1) and intra- and inter-day precision over this range were levodropropizine.

  12. Pharmacokinetics of Dapsone Administered Daily and Weekly in Human Immunodeficiency Virus-Infected Children

    Science.gov (United States)

    Mirochnick, Mark; Cooper, Ellen; McIntosh, Ken; Xu, Jing; Lindsey, Jane; Jacobus, David; Mofenson, Lynne; Sullivan, John L.; Dankner, Wayne; Frenkel, Lisa M.; Nachman, Sharon; Wara, Diane W.; Johnson, Daniel; Bonagura, Vincent R.; Rathore, Mobeen H.; Cunningham, Coleen K.; McNamara, James

    1999-01-01

    Although dapsone is a commonly used alternative agent for prophylaxis against Pneumocystis carinii pneumonia in children intolerant to trimethoprim-sulfamethoxazole, there are few data that describe dapsone pharmacokinetics in children. We studied dapsone pharmacokinetics in 30 children (median age, 2.8 years; age range, 0.3 to 12 years) receiving a new proprietary liquid preparation by three dosing regimens (1 mg/kg of body weight daily, 2 mg/kg daily, or 4 mg/kg weekly). Dosing of children with 2 mg/kg daily or 4 mg/kg weekly resulted in peak concentrations equivalent to those reached in adults receiving 100-mg tablets daily. For the entire population, the median half-life was 22.2 h (range, 7.1 to 40.3 h), the median oral clearance was 0.0365 liter/kg/h (range, 0.0104 to 0.1021 liter/kg/h), and the median oral apparent volume of distribution was 1.13 liters/kg (range, 0.50 to 2.32 liters/kg). The median dapsone oral clearance was significantly increased in those infants less than 2 years of age compared to the oral clearance in those over 2 years of age (0.0484 versus 0.0278 liter/kg/h; P = 0.011). These data suggest that absorption of this liquid preparation is adequate and that the concentrations in the sera of children receiving 2 mg/kg daily or 4 mg/kg weekly are equivalent to those seen in adults receiving standard dapsone dosing. Dapsone oral clearance appears to be increased in children under 2 years of age. PMID:10543733

  13. Cannabinoid pharmacology: the first 66 years.

    Science.gov (United States)

    Pertwee, Roger G

    2006-01-01

    Research into the pharmacology of individual cannabinoids that began in the 1940s, several decades after the presence of a cannabinoid was first detected in cannabis, is concisely reviewed. Also described is how this pharmacological research led to the discovery of cannabinoid CB(1) and CB(2) receptors and of endogenous ligands for these receptors, to the development of CB(1)- and CB(2)-selective agonists and antagonists and to the realization that the endogenous cannabinoid system has significant roles in both health and disease, and that drugs which mimic, augment or block the actions of endogenously released cannabinoids must have important therapeutic applications. Some goals for future research are identified.

  14. 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.

  15. Cannabinoids and the regulation of ingestive behaviour.

    Science.gov (United States)

    Vickers, S P; Kennett, G A

    2005-03-01

    Over past centuries, Cannabis sativa (Delta(9)-tetrahydrocannabinol being the principal active ingredient) has been used extensively for both medicinal and recreational uses, and one widely reported effect is the onset of a ravenous appetite and eating behaviour. The pharmacological properties of such exogenous cannabinoids are mediated through the activation of two receptor subtypes, the CB(1) and CB(2) receptors. A number of endogenous ligands for these receptors, the endocannabinoids, have now also been identified allowing their effects on ingestive behaviour to be determined. In a number of species, including man, the administration of exogenous and endogenous cannabinoids leads to robust increases in food intake and can promote body weight gain. These effects are believed to be mediated through activation of the CB(1) receptor. Conversely, experiments with selective CB(1) receptor antagonists have demonstrated reductions in food intake and body weight with repeated compound administration. These reductions in body weight appear to be greater in obese animals and may be the result of a dual effect on both food intake and metabolic processes. Such findings have led to a number of pharmaceutical companies developing selective CB(1) receptor antagonists for the treatment of obesity. The most advanced compound is Sanofi-Synthelabo's inverse agonist, rimonabant (Acomplia; SR-141716), and early Phase III results have recently demonstrated significant reductions in body weight, waist circumference and improvement of lipid and glucose metabolism in overweight and obese humans. Accordingly, the cannabinoid system appears to have an important role in the regulation of ingestive behaviour in man and animals.

  16. 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.

  17. Establishing in vitro in vivo correlations to screen monoclonal antibodies for physicochemical properties related to favorable human pharmacokinetics.

    Science.gov (United States)

    Avery, Lindsay B; Wade, Jason; Wang, Mengmeng; Tam, Amy; King, Amy; Piche-Nicholas, Nicole; Kavosi, Mania S; Penn, Steve; Cirelli, David; Kurz, Jeffrey C; Zhang, Minlei; Cunningham, Orla; Jones, Rhys; Fennell, Brian J; McDonnell, Barry; Sakorafas, Paul; Apgar, James; Finlay, William J; Lin, Laura; Bloom, Laird; O'Hara, Denise M

    2017-12-22

    Implementation of in vitro assays that correlate with in vivo human pharmacokinetics (PK) would provide desirable preclinical tools for the early selection of therapeutic monoclonal antibody (mAb) candidates with minimal non-target-related PK risk. Use of these tools minimizes the likelihood that mAbs with unfavorable PK would be advanced into costly preclinical and clinical development. In total, 42 mAbs varying in isotype and soluble versus membrane targets were tested in in vitro and in vivo studies. MAb physicochemical properties were assessed by measuring non-specific interactions (DNA- and insulin-binding ELISA), self-association (affinity-capture self-interaction nanoparticle spectroscopy) and binding to matrix-immobilized human FcRn (surface plasmon resonance and column chromatography). The range of scores obtained from each in vitro assay trended well with in vivo clearance (CL) using both human FcRn transgenic (Tg32) mouse allometrically projected human CL and observed human CL, where mAbs with high in vitro scores resulted in rapid CL in vivo. Establishing a threshold value for mAb CL in human of 0.32 mL/hr/kg enabled refinement of thresholds for each in vitro assay parameter, and using a combinatorial triage approach enabled the successful differentiation of mAbs at high risk for rapid CL (unfavorable PK) from those with low risk (favorable PK), which allowed mAbs requiring further characterization to be identified. Correlating in vitro parameters with in vivo human CL resulted in a set of in vitro tools for use in early testing that would enable selection of mAbs with the greatest likelihood of success in the clinic, allowing costly late-stage failures related to an inadequate exposure profile, toxicity or lack of efficacy to be avoided.

  18. 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.

  19. Pharmacokinetic and pharmacodynamic profiles of recombinant human erythropoietin-loaded poly(lactic-co-glycolic acid) microspheres in rats.

    Science.gov (United States)

    Zhou, Xiang-lian; He, Jin-tian; Du, Hui-juan; Fan, Yang-yang; Wang, Ying; Zhang, Hong-xia; Jiang, Yang

    2012-01-01

    To characterize the pharmacokinetic and pharmacodynamic profiles of the recombinant human erythropoietin (rhEPO)-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres in rats. The rhEPO-loaded microspheres were prepared using a solid-in-oil-in-water emulsion method. Pharmacokinetics and pharmacodynamics of the rhEPO-loaded microspheres were evaluated in male Sprague-Dawley rats. The serum rhEPO level was determined with ELISA. The level of anti-rhEPO antibody in the serum was measured to assess the immunogenicity of rhEPO released from the microspheres. rhEPO was almost completely released from the PLGA microspheres in vitro, following zero-order release kinetics over approximately 30 d. After intramuscular injection (10,000 or 30,000 IU rhEPO/kg) in the rats, the serum rhEPO concentration reached maximum levels on d 1, then decreased gradually and was maintained at nearly steady levels for approximately 4 weeks. Furthermore, the release of rhEPO from the PLGA microspheres was found to be controlled mainly by a dissolution/diffusion mechanism. A good linear correlation (R(2)=0.98) was obtained between the in vitro and in vivo release data. A single intramuscular injection of the rhEPO-loaded PLGA microspheres (10,000 or 30,000 IU rhEPO/kg) in the rats resulted in elevated hemoglobin and red blood cell concentrations for more than 28 d. Moreover, the immunogenicity of rhEPO released from the PLGA microspheres was comparable with that of the unencapsulated rhEPO. The results prove the feasibility of using the PLGA-based microspheres to deliver rhEPO for approximately 1 month.

  20. Pharmacokinetics and safety of letermovir, a novel anti-human cytomegalovirus drug, in patients with renal impairment.

    Science.gov (United States)

    Kropeit, Dirk; Scheuenpflug, Jürgen; Erb-Zohar, Katharina; Halabi, Atef; Stobernack, Hans-Peter; Hulskotte, Ellen G J; van Schanke, Arne; Zimmermann, Holger; Rübsamen-Schaeff, Helga

    2017-09-01

    Human cytomegalovirus remains a significant issue for immunocompromised patients and existing viral polymerase targeting therapies are associated with significant toxicity. Accordingly, the viral terminase complex inhibitor, letermovir, is in development. We assessed letermovir pharmacokinetics in renal impairment. This was a Phase 1, open-label, nonrandomised trial. Estimated glomerular filtration rate based on the Modification of Diet Renal Disease equation was used to create three groups of eight subjects: healthy function (estimated glomerular filtration rate ≥ 90 ml min(-1)  1.73m(-2) ), moderate (30-59 ml min(-1)  1.73m(-2) ) and severe (letermovir 120 mg was dosed once-daily for 8 days and blood collected for pharmacokinetic analyses. All 24 subjects enrolled completed the trial. Moderate and severe renal impairment increased mean unbound letermovir fractions by 11% and 26%, respectively, vs. healthy subjects. Exposure (AUCτ,ss and Css,max ) was increased with renal impairment [least square mean ratios (90% confidence intervals) total letermovir vs. healthy subjects, AUCτ,ss 192% (143-258%) and 142% (83-243%) for moderate and severe impairment, respectively; Css,max 125% (87-182%) and 106% (75-151%), respectively]. Clearance was decreased vs. healthy subjects. Correlation analyses indicated a correlation between decreasing renal function and increased unbound letermovir concentration (R(2)  = 0.5076, P letermovir 120 mg was well tolerated across groups. Renal impairment increased exposure to letermovir, although age was a confounding factor. © 2017 The British Pharmacological Society.

  1. Incorporation of the genetic control of alcohol dehydrogenase into a physiologically based pharmacokinetic model for ethanol in humans.

    Science.gov (United States)

    Sultatos, Lester G; Pastino, Gina M; Rosenfeld, Clint A; Flynn, Edward J

    2004-03-01

    The assessment of the variability of human responses to foreign chemicals is an important step in characterizing the public health risks posed by nontherapeutic hazardous chemicals and the risk of encountering adverse reactions with drugs. Of the many sources of interindividual variability in chemical response identified to date, hereditary factors are some of the least understood. Physiologically based pharmacokinetic modeling linked with Monte Carlo sampling has been shown to be a useful tool for the quantification of interindividual variability in chemical disposition and/or response when applied to biological processes that displayed single genetic polymorphisms. The present study has extended this approach by modeling the complex hereditary control of alcohol dehydrogenase, which includes polygenic control and polymorphisms at two allelic sites, and by assessing the functional significance of this hereditary control on ethanol disposition. The physiologically based pharmacokinetic model for ethanol indicated that peak blood ethanol levels and time-to-peak blood ethanol levels were marginally affected by alcohol dehydrogenase genotypes, with simulated subjects possessing the B2 subunit having slightly lower peak blood ethanol levels and shorter times-to-peak blood levels compared to subjects without the B2 subunit. In contrast, the area under the curve (AUC) of the ethanol blood decay curve was very sensitive to alcohol dehydrogenase genotype, with AUCs from any genotype including the ADH1B2 allele considerably smaller than AUCs from any genotype without the ADH1B2 allele. Furthermore, the AUCs in the ADH1C1/C1 genotype were moderately lower than the AUCs from the corresponding ADH1C2/C2 genotype. Moreover, these simulations demonstrated that interindividual variability of ethanol disposition is affected by alcohol dehydrogenase and that the degree of this variability was a function of the ethanol dose.

  2. Pharmacokinetic Properties and Human Use Characteristics of an FDA-Approved Intranasal Naloxone Product for the Treatment of Opioid Overdose.

    Science.gov (United States)

    Krieter, Philip; Chiang, Nora; Gyaw, Shwe; Skolnick, Phil; Crystal, Roger; Keegan, Fintan; Aker, Julie; Beck, Melissa; Harris, Jennifer

    2016-10-01

    Parenteral naloxone has been approved to treat opiate overdose for over 4 decades. Intranasal naloxone, administered "off label" using improvised devices, has been widely used by both first responders and the lay public to treat overdose. However, these improvised devices require training for effective use, and the recommended volumes (2 to 4 mL) exceed those considered optimum for intranasal administration. The present study compared the pharmacokinetic properties of intranasal naloxone (2 to 8 mg) delivered in low volumes (0.1 to 0.2 mL) using an Aptar Unit-Dose device to an approved (0.4 mg) intramuscular dose. A parallel study assessed the ease of use of this device in a simulated overdose situation. All doses of intranasal naloxone resulted in plasma concentrations and areas under the curve greater than those observed following the intramuscular dose; the time to reach maximum plasma concentrations was not different following intranasal and intramuscular administration. Plasma concentrations of naloxone were dose proportional between 2 and 8 mg and independent of whether drug was administered to 1 or both nostrils. In a study using individuals representative of the general population, >90% were able to perform both critical tasks (inserting nozzle into a nostril and pressing plunger) needed to deliver a simulated dose of naloxone without prior training. Based on both pharmacokinetic and human use studies, a 4-mg dose delivered in a single device (0.1 mL) was selected as the final product. This product can be used by first responders and the lay public, providing an important and potentially life-saving intervention for victims of an opioid overdose. © 2016, The American College of Clinical Pharmacology.

  3. Quantitative Detection of Ambroxol in Human Plasma Using HPLC-APCI-MS/MS: Application to a Pharmacokinetic Study.

    Science.gov (United States)

    Mao, Zhengsheng; Wang, Xin; DI, Xin; Liu, Yangdan; Zang, Yanan; Ma, Dongke; Liu, Youping; DI, Xin

    2017-01-01

    In this study, a rapid and reliable high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the determination of ambroxol in human plasma was developed and validated using palmatine as an internal standard (IS). Ambroxol and IS were extracted from 200 μL of human plasma via a simple protein precipitation preparation. Chromatographic separation was achieved on a Platisil C18 column (150 × 4.6 mm, 5 μm) using methanol-0.01% formic acid (70:30, v/v) as the mobile phase at a flow rate of 0.6 mL/min under an isocratic condition. The MS acquisition m/z 379 → 264 for ambroxol and 352 → 336 for IS was performed by atmospheric-pressure chemical ionization (APCI) mass spectrometry in selected reaction monitoring mode. The calibration curve for ambroxol was linear over the concentration range of 2.500 - 180.0 ng/mL. The matrix effects of ambroxol ranged from 104.6 to 112.7%. This fully validated method was successfully applied to a pharmacokinetic study of ambroxol in humans after oral administration of ambroxol at a single dose of 75 mg.

  4. Structural determinants in the second intracellular loop of the human cannabinoid CB1 receptor mediate selective coupling to Gs and Gi

    Science.gov (United States)

    Chen, XP; Yang, W; Fan, Y; Luo, JS; Hong, K; Wang, Z; Yan, JF; Chen, X; Lu, JX; Benovic, JL; Zhou, NM

    2010-01-01

    BACKGROUND AND PURPOSE The cannabinoid CB1 receptor is primarily thought to be functionally coupled to the Gi form of G proteins, through which it negatively regulates cAMP accumulation. Here, we investigated the dual coupling properties of CB1 receptors and characterized the structural determinants that mediate selective coupling to Gs and Gi. EXPERIMENTAL APPROACH A cAMP-response element reporter gene system was employed to quantitatively analyze cAMP change. CB1/CB2 receptor chimeras and site-directed mutagenesis combined with functional assays and computer modelling were used to determine the structural determinants mediating selective coupling to Gs and Gi. KEY RESULTS CB1 receptors could couple to both Gs-mediated cAMP accumulation and Gi-induced activation of ERK1/2 and Ca2+ mobilization, whereas CB2 receptors selectively coupled to Gi and inhibited cAMP production. Using CB1/CB2 chimeric receptors, the second intracellular loop (ICL2) of the CB1 receptor was identified as primarily responsible for mediating Gs and Gi coupling specificity. Furthermore, mutation of Leu-222 in ICL2 to either Ala or Pro switched G protein coupling from Gs to Gi, while to Ile or Val led to balanced coupling of the mutant receptor with Gs and Gi. CONCLUSIONS AND IMPLICATIONS The ICL2 of CB1 receptors and in particular Leu-222, which resides within a highly conserved DRY(X)5PL motif, played a critical role in Gs and Gi protein coupling and specificity. Our studies provide new insight into the mechanisms governing the coupling of CB1 receptors to G proteins and cannabinoid-induced tolerance. PMID:20735408

  5. 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

  6. 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.

  7. 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.

  8. 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.

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

    Science.gov (United States)

    Ladin, Daniel A; Soliman, Eman; Griffin, LaToya; Van Dross, Rukiyah

    2016-01-01

    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 by the endocannabinoid system (ECS), 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 cell proliferation and death. However, many studies investigated these effects 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 animal models and to examine the current standing of cannabinoids that are being tested in human cancer patients.

  10. 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

  11. 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

  12. Clinical pharmacokinetics of melatonin

    DEFF Research Database (Denmark)

    Harpsøe, Nathja Groth; Andersen, Lars Peter Holst; Gögenur, Ismail

    2015-01-01

    PURPOSE: The aim of the review was to provide an overview of studies investigating the pharmacokinetics of exogenous melatonin in humans and if possible, to provide recommendations for clinical use. METHODS: The review was conducted in accordance to PRISMA guidelines. A systematic literature search...

  13. Comparative Inter-Species Pharmacokinetics of Phenoxyacetic Acid Herbicides and Related Organic Acids. Evidence that the Dog is Not a Relevant Species for Evaluation of Human Health Risk.

    Energy Technology Data Exchange (ETDEWEB)

    Timchalk, Chuck

    2004-07-15

    Phenoxyacetic acids including 2,4-dichlorophenoxyacetic acid (2,4-D) and 4-chloro-2-methylphenoxyacetic acid (MCPA) are widely utilized organic acid herbicides that have undergone extensive toxicity and pharmacokinetic analyses. The dog is particularly susceptible to the toxicity of phenoxyacetic acids and related organic acids relative to other species. Active renal clearance mechanisms for organic acids are ubiquitous in mammalian species, and thus a likely mechanism responsible for the increased sensitivity of the dog to these agents is linked to a lower capacity to secrete organic acids from the kidney. Using published data describing the pharmacokinetics of phenoxyacetic and structurally related organic acids in a variety of species including humans, inter-species comparative pharmacokinetics were evaluated using allometic parameter scaling. For both 2,4-D and MCPA the dog plasma half-life (t1/2) and renal clearance (Clr; ml hr-1) rates did not scale as a function of body weight across species; whereas for all other species evaluated, including humans, these pharmacokinetic parameters reasonably scaled. This exceptional response in the dog is clearly illustrated by comparing the plasma t1/2 at comparable doses of 2,4-D and MCPA, across several species. At a dosage of 5 mg/kg, in dogs the plasma t1/2 for 2,4-D and MCPA were {approx}92 - 106 hr and 63 hr, respectively, which is substantially longer than in the rat ({approx}1 and 6 hr, respectively) or in humans (12 and 11 hr, respectively). This longer t1/2, and slower elimination in the dog, results in substantially higher body burdens of these organic acids, at comparable doses, relative to other species. Although these results indicate the important role of renal transport clearance mechanisms as determinants of the clearance and potential toxicity outcomes of phenoxyacetic acid herbicides across several species, other contributing mechanisms such as reabsorption from the renal tubules is highly likely. These

  14. Pharmacokinetic study of amaranth extract in healthy humans: A randomized trial.

    Science.gov (United States)

    Subramanian, Deepa; Gupta, Swati

    2016-01-01

    Nitric oxide (NO) is one of the most important signaling molecules produced within the body. Continuous generation of NO is essential for the integrity of the cardiovascular system. The aim of this study was to assess whether oral intake of a nitrate (NO3-)-rich dietary supplement (amaranth extract) is able to increase NO3- and nitrite (NO2-) levels in blood plasma and saliva of healthy adults. In the present study, bioavailability and pharmacokinetics of NO3- and NO2- from amaranth extract (2 g as single dose) was studied in 16 healthy individuals and compared with placebo in a crossover design. The NO3- and NO2- levels in plasma as well as saliva were measured up to 24 h. After administration of amaranth extract, the NO3- levels in plasma as well as saliva were found to be significantly (P amaranth group (test group) compared with that in the placebo group, whereas the saliva NO2- level was significantly high (P amaranth extract-treated group than the placebo group. These results clearly indicate that a single oral dose of amaranth extract is able to increase the NO3- and NO2- levels in the body for at least 8 h. The increase in NO3- and NO2- levels can help to improve the overall performance of people involved in vigorous physical activities or sports. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Pharmacokinetics and metabolism of an intravenously administered penem (Sch 34343) in humans.

    Science.gov (United States)

    Lin, C C; Lim, J; Radwanski, E; Kim, H K; Marco, A; Lapiguera, A; DiGiore, C; Symchowicz, S

    1987-01-01

    The pharmacokinetics of Sch 34343, a new broad-spectrum penem antibiotic, was studied in subjects receiving 1 g of 14C-labeled drug by intravenous administration. At the end of a 30-min intravenous infusion, the mean maximum concentration of drug in serum was 39 micrograms/ml for unchanged Sch 34343 and 49 mu eq/ml for total radioactivity. The mean serum half-lives of Sch 34343 were 0.16 h for the distribution phase and 0.80 h for the elimination phase. The total body clearance of Sch 34343 was 7.52 ml/min per kg, and the mean apparent volume of distribution was 525 ml/kg. Over a 4-day period, mean urinary excretion of radioactivity accounted for 87.9% of the dose, and mean urinary excretion of unchanged Sch 34343 accounted for 23.6% of the dose. The total radioactivity in feces on days 0 to 6 accounted for only 0.8% of the dose. In serum from 0.5 and 1 h, unchanged Sch 34343 represented the major radioactive peak, with negligible amounts of several metabolites. In urine, there were at least six metabolites in addition to Sch 34343. The amount of unchanged Sch 34343 accounted for 33% of radioactivity in samples of urine from 0 to 2 h, 22% in urine from 2 to 4 h, 15% in urine from 4 to 8 h, and 0% in urine from 8 to 12 h. PMID:3566242

  16. Pharmacokinetics and metabolism of an intravenously administered penem (Sch 34343) in humans

    Energy Technology Data Exchange (ETDEWEB)

    Lin, C.C.; Lim, J.; Radwanski, E.; Kim, H.K.; Marco, A.; Lapiguera, A.; DiGiore, C.; Symchowicz, S.

    1987-01-01

    The pharmacokinetics of Sch 34343, a new broad-spectrum penem antibiotic, was studied in subjects receiving 1 g of /sup 14/C-labeled drug by intravenous administration. At the end of a 30-min intravenous infusion, the mean maximum concentration of drug in serum was 39 micrograms/ml for unchanged Sch 34343 and 49 mu eq/ml for total radioactivity. The mean serum half-lives of Sch 34343 were 0.16 h for the distribution phase and 0.80 h for the elimination phase. The total body clearance of Sch 34343 was 7.52 ml/min per kg, and the mean apparent volume of distribution was 525 ml/kg. Over a 4-day period, mean urinary excretion of radioactivity accounted for 87.9% of the dose, and mean urinary excretion of unchanged Sch 34343 accounted for 23.6% of the dose. The total radioactivity in feces on days 0 to 6 accounted for only 0.8% of the dose. In serum from 0.5 and 1 h, unchanged Sch 34343 represented the major radioactive peak, with negligible amounts of several metabolites. In urine, there were at least six metabolites in addition to Sch 34343. The amount of unchanged Sch 34343 accounted for 33% of radioactivity in samples of urine from 0 to 2 h, 22% in urine from 2 to 4 h, 15% in urine from 4 to 8 h, and 0% in urine from 8 to 12 h.

  17. A novel LC–MS/MS assay for methylprednisolone in human plasma and its pharmacokinetic application

    Directory of Open Access Journals (Sweden)

    Sridhar Siddiraju

    2016-06-01

    Full Text Available Methylprednisolone is a synthetic glucocorticoid. In our report, the authors proposed a sensitive and selective liquid chromatography/tandem mass spectrometry (LC–MS/MS assay for the determination of methylprednisolone applying budesonide as internal standard. Liquid–liquid extraction (LLE having tert–butyl methyl ether (TBME have been employed to extract methylprednisolone from the plasma samples. Immediately after reconstitution, the samples were chromatographed on a C18 column using an isocratic mobile phase composed of 10 mM ammonium formate buffer and acetonitrile (35:65, v/v. A flow rate of 1.00 ml/min was used to elute the analyte form the column. Analysis was carried out with an API–4000 LC–MS/MS instrument operated in multiple reaction-monitoring (MRM mode. The linearity has been proven within the concentration range of 10.1–804 ng/ml in plasma samples. The precision (%CV and accuracy results in five validation batches across five concentration levels were well within the acceptance limits. The drug was stable under different conditions. The particular assay has been proficiently put on pharmacokinetic study in healthy male subjects.

  18. Pharmacokinetics of fexofenadine

    DEFF Research Database (Denmark)

    Lappin, Graham; Shishikura, Yoko; Jochemsen, Roeline

    2010-01-01

    with an oral unlabelled therapeutic dose (120mg). Plasma was collected from all 3 periods and analysed for both total (14)C content and parent drug by accelerator mass spectrometry (AMS). For period 3, plasma samples were also analysed using HPLC-fluorescence to determine total drug concentration. Urine......A human pharmacokinetic study was performed to assess the ability of a microdose to predict the pharmacokinetics of a therapeutic dose of fexofenadine and to determine its absolute oral bioavailability. Fexofenadine was chosen to represent an unmetabolized transporter substrate (P-gP and OATP...

  19. High performance liquid chromatography-tandem mass spectrometric determination of rupatadine in human plasma and its pharmacokinetics.

    Science.gov (United States)

    Tian, Yuan; Zhang, Jingjing; Lin, Hui; Liang, Jiabi; Zhang, Zunjian; Chen, Yun

    2008-08-05

    A simple, rapid, sensitive and selective liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the quantification of rupatadine in human plasma using estazolam as internal standard (IS). Following liquid-liquid extraction, the analytes were separated using a mobile phase of methanol-ammonium acetate (pH 2.2; 5mM) (50:50, v/v) on a reverse phase C18 column and analyzed by a triple-quadrupole mass spectrometer in the positive ion and multiple reaction monitoring (MRM) mode, m/z 416-->309 for rupatadine and m/z 295-->267 for the IS. The assay exhibited a linear dynamic range of 0.1-100 ng/ml for rupatadine in human plasma. The lower limit of quantification (LLOQ) was 0.1 ng/ml with a relative standard deviation of less than 20%. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. The validated LC-MS/MS method has been successfully applied to study the pharmacokinetics of rupatadine in healthy volunteers.

  20. Analysis of rocuronium in human plasma by liquid chromatography-tandem mass spectrometry with application in clinical pharmacokinetics.

    Science.gov (United States)

    de Moraes, Natália Valadares; Lauretti, Gabriela Rocha; Filgueira, Gabriela Campos de Oliveira; Lopes, Bruno Carvalho Portes; Lanchote, Vera Lucia

    2014-03-01

    Rocuronium (ROC) is a neuromuscular blocking agent used in surgical procedures which is eliminated primarily by biliary excretion. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for analysis of ROC in human plasma. Separation of ROC and IS (verapamil) was performed using an endcapped C-18 column and a mixture of water:acetonitrile:trifluoracetic acid (50:50:0.1, v/v) as mobile phase. Aliquots of 100 μL of human plasma were extracted at pH 3, using dichloromethane. The lower limit of quantification of 5 ng/mL shows the high sensitivity of this method. Intra- and inter-assay precision (as relative standard deviation) was all ≤14.2% and accuracy (as relative standard error) did not exceed 10.1%. The validated method was successfully applied to quantify ROC concentrations in patients under surgical procedures up to 6h after the administration of the 0.4-0.9 mg/kg ROC. The pharmacokinetic parameter estimations of ROC showed AUC/dose of 563 μg min/mL, total clearance of 2.5 mL/min/kg, volume of distribution at steady state of 190 mL/kg and mean residence time of 83 min. Copyright © 2013 Elsevier B.V. All rights reserved.

  1. Characterization of Pharmacokinetics in the Göttingen Minipig with Reference Human Drugs: An In Vitro and In Vivo Approach.

    Science.gov (United States)

    Lignet, Floriane; Sherbetjian, Eva; Kratochwil, Nicole; Jones, Russell; Suenderhauf, Claudia; Otteneder, Michael B; Singer, Thomas; Parrott, Neil

    2016-10-01

    This study aims to expand our understanding of the mechanisms of drug absorption, distribution, metabolism and excretion in the Göttingen minipig to aid a knowledge-driven selection of the optimal species for preclinical pharmaceutical research. The pharmacokinetics of seven reference compounds (antipyrine, atenolol, cimetidine, diazepam, hydrochlorothiazide, midazolam and theophylline) was investigated after intravenous and oral dosing in minipigs. Supportive in vitro data were generated on hepatocellularity, metabolic clearance in hepatocytes, blood cell and plasma protein binding and metabolism routes. Systemic plasma clearance for the seven drugs ranged from low (1.1 ml/min/kg, theophylline) to close to liver blood flow (37.4 ml/min/kg, cimetidine). Volume of distribution in minipigs ranged from 0.7 L/kg for antipyrine to 3.2 L/kg for hydrochlorothiazide. A gender-related difference of in vivo metabolic clearance was observed for antipyrine. The hepatocellularity for minipig was determined as 124 Mcells/g liver, similar to the values reported for human. Based on these data a preliminary in vitro to in vivo correlation (IVIVC) for metabolic clearance measured in hepatocytes was investigated. Metabolite profiles of diazepam and midazolam compared well between minipig and human. The results of the present study support the use of in vitro metabolism data for the evaluation of minipig in preclinical research and safety testing.

  2. 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

  3. Cannabinoids in medicine: A review of their therapeutic potential.

    Science.gov (United States)

    Ben Amar, Mohamed

    2006-04-21

    In order to assess the current knowledge on the therapeutic potential of cannabinoids, a meta-analysis was performed through Medline and PubMed up to July 1, 2005. The key words used were cannabis, marijuana, marihuana, hashish, hashich, haschich, cannabinoids, tetrahydrocannabinol, THC, dronabinol, nabilone, levonantradol, randomised, randomized, double-blind, simple blind, placebo-controlled, and human. The research also included the reports and reviews published in English, French and Spanish. For the final selection, only properly controlled clinical trials were retained, thus open-label studies were excluded. Seventy-two controlled studies evaluating the therapeutic effects of cannabinoids were identified. For each clinical trial, the country where the project was held, the number of patients assessed, the type of study and comparisons done, the products and the dosages used, their efficacy and their adverse effects are described. Cannabinoids present an interesting therapeutic potential as antiemetics, appetite stimulants in debilitating diseases (cancer and AIDS), analgesics, and in the treatment of multiple sclerosis, spinal cord injuries, Tourette's syndrome, epilepsy and glaucoma.

  4. Cannabinoids attenuate cancer pain and proliferation in a mouse model.

    Science.gov (United States)

    Saghafi, Negin; Lam, David K; Schmidt, Brian L

    2011-01-25

    We investigated the effects of cannabinoid receptor agonists on (1) oral cancer cell viability in vitro and (2) oral cancer pain and tumor growth in a mouse cancer model. We utilized immunohistochemistry and Western blot to show that human oral cancer cells express CBr1 and CBr2. When treated with WIN55,212-2 (non-selective), ACEA (CBr1-selective) or AM1241 (CBr2-selective) agonists in vitro, oral cancer cell proliferation was significantly attenuated in a dose-dependent manner. In vivo, systemic administration (0.013M) of WIN55,212-2, ACEA, or AM1241 significantly attenuated cancer-induced mechanical allodynia. Tumor growth was also significantly attenuated with systemic AM1241 administration. Our findings suggest a direct role for cannabinoid mechanisms in oral cancer pain and proliferation. The systemic administration of cannabinoid receptor agonists may have important therapeutic implications wherein cannabinoid receptor agonists may reduce morbidity and mortality of oral cancer. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  5. Plasma and cerebrospinal fluid pharmacokinetics of select chemotherapeutic agents following intranasal delivery in a non-human primate model.

    Science.gov (United States)

    League-Pascual, James C; Lester-McCully, Cynthia M; Shandilya, Shaefali; Ronner, Lukas; Rodgers, Louis; Cruz, Rafael; Peer, Cody J; Figg, William D; Warren, Katherine E

    2017-05-01

    The blood-brain barrier (BBB) limits entry of most chemotherapeutic agents into the CNS, resulting in inadequate exposure within CNS tumor tissue. Intranasal administration is a proposed means of delivery that can bypass the BBB, potentially resulting in more effective chemotherapeutic exposure at the tumor site. The objective of this study was to evaluate the feasibility and pharmacokinetics (plasma and CSF) of intranasal delivery using select chemotherapeutic agents in a non-human primate (NHP) model. Three chemotherapeutic agents with known differences in CNS penetration were selected for intranasal administration in a NHP model to determine proof of principle of CNS delivery, assess tolerability and feasibility, and to evaluate whether certain drug characteristics were associated with increased CNS exposure. Intravenous (IV) temozolomide (TMZ), oral (PO) valproic acid, and PO perifosine were administered to adult male rhesus macaques. The animals received a single dose of each agent systemically and intranasally in separate experiments, with each animal acting as his own control. The dose of the agents administered systemically was the human equivalent of a clinically appropriate dose, while the intranasal dose was the maximum achievable dose based on the volume limitation of 1 mL. Multiple serial paired plasma and CSF samples were collected and quantified using a validated uHPLC/tandem mass spectrometry assay after each drug administration. Pharmacokinetic parameters were estimated using non-compartmental analysis. CSF penetration was calculated from the ratio of areas under the concentration-time curves for CSF and plasma (AUCCSF:plasma). Intranasal administration was feasible and tolerable for all agents with no significant toxicities observed. For TMZ, the degrees of CSF drug penetration after intranasal and IV administration were 36 (32-57) and 22 (20-41)%, respectively. Although maximum TMZ drug concentration in the CSF (Cmax) was lower after intranasal

  6. Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans.

    Science.gov (United States)

    Manini, Alex F; Yiannoulos, Georgia; Bergamaschi, Mateus M; Hernandez, Stephanie; Olmedo, Ruben; Barnes, Allan J; Winkel, Gary; Sinha, Rajita; Jutras-Aswad, Didier; Huestis, Marilyn A; Hurd, Yasmin L

    2015-01-01

    Cannabidiol (CBD) is hypothesized as a potential treatment for opioid addiction, with safety studies an important first step for medication development. We determined CBD safety and pharmacokinetics when administered concomitantly with a high-potency opioid in healthy subjects. This double-blind, placebo-controlled cross-over study of CBD, coadministered with intravenous fentanyl, was conducted at the Clinical Research Center in Mount Sinai Hospital, a tertiary care medical center in New York City. Participants were healthy volunteers aged 21 to 65 years with prior opioid exposure, regardless of the route. Blood samples were obtained before and after 400 or 800 mg of CBD pretreatment, followed by a single 0.5 (session 1) or 1.0 μg/kg (session 2) of intravenous fentanyl dose. The primary outcome was the Systematic Assessment for Treatment Emergent Events (SAFTEE) to assess safety and adverse effects. CBD peak plasma concentrations, time to reach peak plasma concentrations (tmax), and area under the curve (AUC) were measured. SAFTEE data were similar between groups without respiratory depression or cardiovascular complications during any test session. After low-dose CBD, tmax occurred at 3 and 1.5 hours in sessions 1 and 2, respectively. After high-dose CBD, tmax occurred at 3 and 4 hours in sessions 1 and 2, respectively. There were no significant differences in plasma CBD or cortisol (AUC P = NS) between sessions. Cannabidiol does not exacerbate adverse effects associated with intravenous fentanyl administration. Coadministration of CBD and opioids was safe and well tolerated. These data provide the foundation for future studies examining CBD as a potential treatment for opioid abuse.

  7. Voclosporin food effect and single oral ascending dose pharmacokinetic and pharmacodynamic studies in healthy human subjects.

    Science.gov (United States)

    Mayo, Patrick R; Huizinga, Robert B; Ling, Spencer Y; Freitag, Derrick G; Aspeslet, Launa J; Foster, Robert T

    2013-08-01

    Voclosporin (VCS) is a novel calcineurin (CN) inhibitor intended for prevention of organ graft rejection and treatment of lupus nephritis. These studies evaluated the single ascending dose pharmacokinetics (PK) and pharmacodynamics (PD, CN activity) of VCS and the effect of food. VCS was administered orally in single doses of 0.25 through 4.5 mg/kg in 62 subjects in the single ascending dose study and as a single oral 1.5 mg/kg dose to 18 subjects after fasting, consumption of a low-fat and high-fat meal. Non-compartmental PK, PD, and PKPD correlation were evaluated. Following single oral doses, systemic exposure increased in a linear manner and demonstrated 1:1 dose-proportional, first-order linear PK above 1.5 mg/kg. VCS inhibited CN activity in a dose-related fashion with maximal inhibition peaking at 3.0 mg/kg. PKPD correlation indicated an EC50 of 78.3 ± 6.8 ng/mL. Administration of VCS with a low-fat and high-fat meal decreased C(max) by 29% and 53%, respectively, and AUC(inf) by 15% and 25%, respectively. Following ascending single doses of VCS, exposure increased in a linear fashion. A food effect on exposure was demonstrated, with a more pronounced effect following a high-fat meal. VCS concentrations were also found to correlate with CN activity. © The Author(s) 2013.

  8. Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics.

    Science.gov (United States)

    Riba, Jordi; Valle, Marta; Urbano, Gloria; Yritia, Mercedes; Morte, Adelaida; Barbanoj, Manel J

    2003-07-01

    The effects of the South American psychotropic beverage ayahuasca on subjective and cardiovascular variables and urine monoamine metabolite excretion were evaluated, together with the drug's pharmacokinetic profile, in a double-blind placebo-controlled clinical trial. This pharmacologically complex tea, commonly obtained from Banisteriopsis caapi and Psychotria viridis, combines N,N-dimethyltryptamine (DMT), an orally labile psychedelic agent showing 5-hydroxytryptamine2A agonist activity, with monoamine oxidase (MAO)-inhibiting beta-carboline alkaloids (harmine, harmaline, and tetrahydroharmine). Eighteen volunteers with prior experience in the use of psychedelics received single oral doses of encapsulated freeze-dried ayahuasca (0.6 and 0.85 mg of DMT/kg of body weight) and placebo. Ayahuasca produced significant subjective effects, peaking between 1.5 and 2 h, involving perceptual modifications and increases in ratings of positive mood and activation. Diastolic blood pressure showed a significant increase at the high dose (9 mm Hg at 75 min), whereas systolic blood pressure and heart rate were moderately and nonsignificantly increased. Cmax values for DMT after the low and high ayahuasca doses were 12.14 ng/ml and 17.44 ng/ml, respectively. Tmax (median) was observed at 1.5 h after both doses. The Tmax for DMT coincided with the peak of subjective effects. Drug administration increased urinary normetanephrine excretion, but, contrary to the typical MAO-inhibitor effect profile, deaminated monoamine metabolite levels were not decreased. This and the negligible harmine plasma levels found suggest a predominantly peripheral (gastrointestinal and liver) site of action for harmine. MAO inhibition at this level would suffice to prevent first-pass metabolism of DMT and allow its access to systemic circulation and the central nervous system.

  9. A comprehensive quantitative and qualitative evaluation of extrapolation of intravenous pharmacokinetic parameters from rat, dog, and monkey to humans. II. Volume of distribution and mean residence time.

    Science.gov (United States)

    Ward, Keith W; Smith, Brian R

    2004-06-01

    Our laboratory is engaged in an ongoing analysis of a 103-compound data set containing reliable intravenous pharmacokinetic parameters in the rat, dog, monkey, and human, and we have previously reported our findings regarding extrapolation of clearance. In this article, we report on our findings regarding volume of distribution and mean residence time. Various allometric and nonallometric methods were used to predict human volume of distribution based on preclinical pharmacokinetic data; clearance and volume of distribution values generated by various means were then used to estimate mean residence time. From both a quantitative and qualitative perspective, estimating human volume and mean residence time based on monkey data alone was the most accurate approach evaluated. For volume, estimation based on monkey data alone was quantitatively the least biased of all approaches evaluated. Additionally, prediction of mean residence time based on clearance and volume from the monkey was the only extrapolation method that exhibited a positive, rather than negative, bias. None of the allometric scaling approaches investigated afforded optimal predictivity for either volume or mean residence time, and neither the correlation coefficient nor the allometric exponent allowed a prospective estimation of predictive success or failure. These observations regarding volume and mean residence time confirm our earlier results with clearance, and further confirm the value of the monkey as a species for pharmacokinetic lead optimization.

  10. Male-female differences in the effects of cannabinoids on sexual behavior and gonadal hormone function.

    Science.gov (United States)

    Gorzalka, Boris B; Hill, Matthew N; Chang, Sabrina C H

    2010-06-01

    The putative role of the endocannabinoid system and the effects of cannabis use in male and female sexual functioning are summarized. The influence of cannabis intake on sexual behavior and arousability appear to be dose-dependent in both men and women, although women are far more consistent in reporting facilitatory effects. Furthermore, evidence from nonhuman species indicate somewhat more beneficial than debilitating effects of cannabinoids on female sexual proceptivity and receptivity while suggesting predominantly detrimental effects on male sexual motivation and erectile functioning. Data from human and nonhuman species converge on the ephemeral nature of THC-induced testosterone decline. However, it is clear that cannabinoid-induced inhibition of male sexual behavior is independent of concurrent declines in testosterone levels. Investigations also reveal a suppression of gonadotropin release by cannabinoids across various species. Historical milestones and promising future directions in the area of cannabinoid and sexuality research are also outlined in this review. Copyright 2009 Elsevier Inc. All rights reserved.

  11. Pharmacokinetics, pharmacodynamics, metabolism, toxicology and residues of phenylbutazone in humans and horses.

    OpenAIRE

    Lees, Peter

    2013-01-01

    The presence of horse meat in food products destined for human consumption and labelled as beef has raised several concerns of public interest. This review deals solely with one aspect of these concerns; samples of equine tissue from horses destined for the human food chain have tested positive for the non-steroidal anti-inflammatory drug, phenylbutazone. The safety of some or all such foods for human consumers is a major concern, because it was shown many years ago that phenylbutazone therap...

  12. The use of cannabinoids as anticancer agents.

    Science.gov (United States)

    Velasco, Guillermo; Hernández-Tiedra, Sonia; Dávila, David; Lorente, Mar

    2016-01-04

    It is well-established that cannabinoids exert palliative effects on some cancer-associated symptoms. In addition evidences obtained during the last fifteen years support that these compounds can reduce tumor growth in animal models of cancer. Cannabinoids have been shown to activate an ER-stress related pathway that leads to the stimulation of autophagy-mediated cancer cell death. In addition, cannabinoids inhibit tumor angiogenesis and decrease cancer cell migration. The mechanisms of resistance to cannabinoid anticancer action as well as the possible strategies to develop cannabinoid-based combinational therapies to fight cancer have also started to be explored. In this review we will summarize these observations (that have already helped to set the bases for the development of the first clinical studies to investigate the potential clinical benefit of using cannabinoids in anticancer therapies) and will discuss the possible future avenues of research in this area. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  13. An update on PPAR activation by cannabinoids.

    Science.gov (United States)

    O'Sullivan, Saoirse Elizabeth

    2016-06-01

    Some cannabinoids activate the different isoforms of PPARs (α, β and γ), as shown through the use of reporter gene assays, binding studies, selective antagonists and knockout studies. Activation of all isoforms, but primarily PPARα and γ, mediates some (but not all) of the analgesic, neuroprotective, neuronal function modulation, anti-inflammatory, metabolic, anti-tumour, gastrointestinal and cardiovascular effects of some cannabinoids, often in conjunction with activation of the more traditional target sites of action such as the cannabinoid CB1 and CB2 receptors and the TRPV1 ion channel. PPARs also mediate some of the effects of inhibitors of endocannabinoid degradation or transport. Cannabinoids may be chaperoned to the PPARs by fatty acid binding proteins. The aims of this review are to update the evidence supporting PPAR activation by cannabinoids and to review the physiological responses to cannabinoids that are mediated, and not mediated, by PPAR activation. © 2016 The British Pharmacological Society.

  14. Behavioral, metabolic, and immune consequences of chronic alcohol or cannabinoids on HIV/AIDs: Studies in the Non-Human Primate SIV model

    Science.gov (United States)

    Molina, Patricia E.; Amedee, Angela M.; Winsauer, Peter; Nelson, Steve; Bagby, Gregory; Simon, Liz

    2015-01-01

    HIV-associated mortality has been significantly reduced with antiretroviral therapy (ART), and HIV infection has become a chronic disease that frequently coexists with many disorders, including substance abuse (Azar et al. 2010; Phillips et al. 2001). Alcohol and drugs of abuse may modify host-pathogen interactions at various levels including behavioral, metabolic, and immune consequences of HIV infection, as well as the ability of the virus to integrate into the genome and replicate in host cells. Identifying mechanisms responsible for these interactions is complicated by many factors, such as the tissue specific responses to viral infection, multiple cellular mechanisms involved in inflammatory responses, neuroendocrine and localized responses to infection, and kinetics of viral replication. An integrated physiological analysis of the biomedical consequences of chronic alcohol and drug use or abuse on disease progression is possible using rhesus macaques infected with simian immunodeficiency virus (SIV), a relevant model of HIV infection. This review will provide an overview of the data gathered using this model to show that chronic administration of two of the most commonly abused substances, alcohol and cannabinoids (Δ9-Tetrahydrocannabinol; THC), affect host-pathogen interactions. PMID:25795088

  15. Beyond THC: The New Generation of Cannabinoid Designer Drugs

    National Research Council Canada - National Science Library

    Fattore, Liana; Fratta, Walter

    2011-01-01

    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...

  16. Determination of ipriflavone in human plasma by LC-MS and its application in a pharmacokinetic study.

    Science.gov (United States)

    Yun, Changhong; Ding, Li; Leng, Ye; Zhu, He; Wen, Aidong; Yang, Lin

    2012-01-01

    A sensitive liquid chromatography-mass spectrometric method was developed for the quantification of ipriflavone in human plasma. The method utilized liquid-liquid extraction of plasma with ethyl acetate. A gradient elution was performed on a Hedera ODS-2 column (150×2.1 mm i.d., 5 µm), using a mobile phase consisting of 0.1% formic acid solution and methanol at a flow rate of 0.5 mL/min. The single quadrupole mass spectrometer was operated in selected-ion monitoring mode via positive electrospray ionization interface detecting m/z 239.1 and 285.1 for ipriflavone and diazepam (the internal standard), respectively. To improve the selectivity and sensitivity, the fragment ion m/z 239.1, which was produced by in-source collision-induced dissociation, was chosen as the quantitative ion for ipriflavone. The method was fully validated and applied to a pharmacokinetic study of ipriflavone. After oral administration of a single 200 mg ipriflavone tablet, the C(max,) AUC(0-72 h) , t(1/2) and T(max) were 6.3±6.3 ng/mL, 80.0±69.1 µg h/L, 23.0±8.6 h and 3.4±2.1 h, respectively. Copyright © 2011 John Wiley & Sons, Ltd.

  17. 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.

  18. 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

  19. 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

  20. Quantitative Evaluation of Dichloroacetic Acid Kinetics in Human -- A Physiologically-Based Pharmacokinetic Modeling Investigation

    Science.gov (United States)

    2008-01-01

    model (Keys, 2004). Not active in Human Model DCA Model: !CONSTANT KFC = 0.0 !First order metabolism rate constant (/hr /kg) !Urinary...8217 VMAX = VMAXC*BW**0.75 !KF = KFC /BW**0.25 : Proposed 1st order pathway (Keys, 2004; Not active in Human Model) Clr = Clrc*BW

  1. Cannabinoids for cancer treatment: progress and promise.

    Science.gov (United States)

    Sarfaraz, Sami; Adhami, Vaqar M; Syed, Deeba N; Afaq, Farrukh; Mukhtar, Hasan

    2008-01-15

    Cannabinoids are a class of pharmacologic compounds that offer potential applications as antitumor drugs, based on the ability of some members of this class to limit inflammation, cell proliferation, and cell survival. In particular, emerging evidence suggests that agonists of cannabinoid receptors expressed by tumor cells may offer a novel strategy to treat cancer. Here, we review recent work that raises interest in the development and exploration of potent, nontoxic, and nonhabit forming cannabinoids for cancer therapy.

  2. 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.

  3. Gemcitabine/cannabinoid combination triggers autophagy in pancreatic cancer cells through a ROS-mediated mechanism

    Science.gov (United States)

    Donadelli, M; Dando, I; Zaniboni, T; Costanzo, C; Dalla Pozza, E; Scupoli, M T; Scarpa, A; Zappavigna, S; Marra, M; Abbruzzese, A; Bifulco, M; Caraglia, M; Palmieri, M

    2011-01-01

    Gemcitabine (GEM, 2′,2′-difluorodeoxycytidine) is currently used in advanced pancreatic adenocarcinoma, with a response rate of cannabinoids. Here, we show that GEM induces both cannabinoid receptor-1 (CB1) and cannabinoid receptor-2 (CB2) receptors by an NF-κB-dependent mechanism and that its association with cannabinoids synergistically inhibits pancreatic adenocarcinoma cell growth and increases reactive oxygen species (ROS) induced by single treatments. The antiproliferative synergism is prevented by the radical scavenger N-acetyl--cysteine and by the specific NF-κB inhibitor BAY 11-7085, demonstrating that the induction of ROS by GEM/cannabinoids and of NF-κB by GEM is required for this effect. In addition, we report that neither apoptotic nor cytostatic mechanisms are responsible for the synergistic cell growth inhibition, which is strictly associated with the enhancement of endoplasmic reticulum stress and autophagic cell death. Noteworthy, the antiproliferative synergism is stronger in GEM-resistant pancreatic cancer cell lines compared with GEM-sensitive pancreatic cancer cell lines. The combined treatment strongly inhibits growth of human pancreatic tumor cells xenografted in nude mice without apparent toxic effects. These findings support a key role of the ROS-dependent activation of an autophagic program in the synergistic growth inhibition induced by GEM/cannabinoid combination in human pancreatic cancer cells. PMID:21525939

  4. Cannabinoid CB1 receptor antagonists in therapeutic and structural perspectives.

    Science.gov (United States)

    Lange, Jos H M; Kruse, Chris G

    2008-01-01

    The observed antiobesity effect of rimonabant (1) in a pharmacological rodent model 10 years ago has led to a surge in the search for novel cannabinoid CB1 antagonists as a new therapeutic target for the treatment of obesity. Rimonabant showed clinical efficacy in the treatment of obesity and also improved cardiovascular and metabolic risk factors. Cannabinoid CB1 receptor antagonists have also good prospects in other therapeutic areas, including smoking and alcohol addiction as well as cognitive impairment. Solvay's research achievements in this fast-moving field are reported in relation with the current state of the art. Several medicinal chemistry strategies have been pursued. The application of the concept of conformational constraint led to the discovery of more rigid analogs of the prototypic CB1 receptor antagonist rimonabant. Replacement of the central heterocyclic pyrazole ring in rimonabant yielded imidazoles, triazoles, and thiazoles as selective CB1 receptor antagonists. Dedicated medium-throughput screening efforts delivered one 3,4-diarylpyrazoline hit. Its poor pharmacokinetic properties were successfully optimized which led to the discovery of orally active and highly CB1/CB2 receptor selective analogs in this series. Regioisomeric 1,5-diarylpyrazolines, 1,2-diarylimidazolines, and water-soluble imidazoles have been designed as novel CB1 receptor antagonist structure classes. Copyright 2008 The Japan Chemical Journal Forum and Wiley Periodicals, Inc.

  5. The role of cannabinoids in adult neurogenesis

    Science.gov (United States)

    Prenderville, Jack A; Kelly, Áine M; Downer, Eric J

    2015-01-01

    The processes underpinning post-developmental neurogenesis in the mammalian brain continue to be defined. Such processes involve the proliferation of neural stem cells and neural progenitor cells (NPCs), neuronal migration, differentiation and integration into a network of functional synapses within the brain. Both intrinsic (cell signalling cascades) and extrinsic (neurotrophins, neurotransmitters, cytokines, hormones) signalling molecules are intimately associated with adult neurogenesis and largely dictate the proliferative activity and differentiation capacity of neural cells. Cannabinoids are a unique class of chemical compounds incorporating plant-derived cannabinoids (the active components of Cannabis sativa), the endogenous cannabinoids and synthetic cannabinoid ligands, and these compounds are becoming increasingly recognized for their roles in neural developmental processes. Indeed, cannabinoids have clear modulatory roles in adult neurogenesis, probably through activation of both CB1 and CB2 receptors. In recent years, a large body of literature has deciphered the signalling networks involved in cannabinoid-mediated regulation of neurogenesis. This timely review summarizes the evidence that the cannabinoid system is intricately associated with neuronal differentiation and maturation of NPCs and highlights intrinsic/extrinsic signalling mechanisms that are cannabinoid targets. Overall, these findings identify the central role of the cannabinoid system in adult neurogenesis in the hippocampus and the lateral ventricles and hence provide insight into the processes underlying post-developmental neurogenesis in the mammalian brain. PMID:25951750

  6. Cannabinoids in the treatment of cancer.

    Science.gov (United States)

    Alexander, Amy; Smith, Paul F; Rosengren, Rhonda J

    2009-11-18

    Cannabinoids, the active components of the hemp plant Cannabis sativa, along with their endogenous counterparts and synthetic derivatives, have elicited anti-cancer effects in many different in vitro and in vivo models of cancer. While the various cannabinoids have been examined in a variety of cancer models, recent studies have focused on the role of cannabinoid receptor agonists (both CB(1) and CB(2)) in the treatment of estrogen receptor-negative breast cancer. This review will summarize the anti-cancer properties of the cannabinoids, discuss their potential mechanisms of action, as well as explore controversies surrounding the results.

  7. Nicotine delivery to rats via lung alveolar region-targeted aerosol technology produces blood pharmacokinetics resembling human smoking.

    Science.gov (United States)

    Shao, Xuesi M; Xu, Bin; Liang, Jing; Xie, Xinmin Simon; Zhu, Yifang; Feldman, Jack L

    2013-07-01

    Nicotine is a heavily used addictive drug acquired through smoking tobacco. Nicotine in cigarette smoke is deposited and absorbed in the lungs, which results in a rapidly peaked slowly declining arterial concentration. This pattern plays an important role in initiation of nicotine addiction. A method and device were developed for delivering nicotine to rodents with lung alveolar region-targeted aerosol technology. The dose of delivery can be controlled by the nicotine aerosol concentration and duration of exposure. Our data showed that, in the breathing zone of the nose-only exposure chamber, the aerosol droplet size distribution was within the respirable diameter range. Rats were exposed to nicotine aerosol for 2 min. The arterial blood nicotine concentration reached 43.2 ± 15.7 ng/ml (mean ± SD) within 1-4 min and declined over the next 20 min, closely resembling the magnitude and early pharmacokinetics of a human smoking a cigarette. The acute inhalation toxicity of nicotine: LC50 = 2.3mg/L was determined; it was affected by pH, suggesting that acidification decreases nicotine absorption and/or bioavailability. A noninvasive method and toolkit were developed for delivering nicotine to rodents that enable rapid delivery of a controllable amount of nicotine into the systemic circulation and brain-inducing dose-dependent pharmacological effects, even a lethal dose. Aerosol inhalation can produce nicotine kinetics in both arterial and venous blood resembling human smoking. This method can be applied to studies of the effects of chronic intermittent nicotine exposure, nicotine addiction, toxicology, tobacco-related diseases, teratogenicity, and for discovery of pharmacological therapeutics.

  8. Simultaneous determination of pioglitazone and candesartan in human plasma by LC-MS/MS and its application to a human pharmacokinetic study

    Directory of Open Access Journals (Sweden)

    Vijaya Kumari Karra

    2012-06-01

    Full Text Available A simple and rapid liquid chromatography-tandem mass spectrometric (LC-MS/MS assay method has been developed and fully validated for simultaneous quantification of pioglitazone and candesartan in human plasma. Irbesartan was used as an internal standard. The analytes were extracted from human plasma samples by solid-phase extraction technique using a Strata-X 33 μm polymeric sorbent. The reconstituted samples were chromatographed on a C18 column by using a 80:20 (v/v mixture of acetonitrile and 0.1% formic acid as the mobile phase at a flow rate of 0.8 mL/min. The calibration curves obtained were linear (r≥0.99 over the concentration range of 15–3000 ng/mL for pioglitazone and 5–608 ng/mL for candesartan. The results of the intra- and inter-day precision and accuracy studies were well within the acceptable limits. A run time of 2.7 min for each sample made it possible to analyze more than 300 plasma samples per day. The proposed method was found to be applicable to clinical studies. Keywords: Pioglitazone, Candesartan, Human plasma, Solid-phase extraction, LC-MS/MS, Pharmacokinetics

  9. Cannabinoids as treatment for nausea and vomiting

    Directory of Open Access Journals (Sweden)

    Erin M. Rock

    2016-07-01

    Full Text Available Despite the advent of classic anti-emetics, chemotherapy-induced nausea is still problematic, with vomiting being somewhat better managed in the clinic. If post-treatment nausea and vomiting are not properly controlled, anticipatory nausea—a conditioned response to the contextual cues associated with illness-inducing chemotherapy— can develop. Once it develops, anticipatory nausea is refractive to current anti-emetics, highlighting the need for alternative treatment options. One of the first documented medicinal uses of Δ9-tetrahydrocannabinol (Δ9-THC was for the treatment of chemotherapy-induced nausea and vomiting, and recent evidence is accumulating to suggest a role for the endocannabinoid system in modulating chemotherapy-induced nausea and vomiting. Here, we review studies assessing the therapeutic potential of cannabinoids and manipulations of the endocannabinoid system in human patients and pre-clinical animal models of nausea and vomiting.

  10. 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.)

  11. 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.

  12. PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 2: comparative assessment of prediction methods of human volume of distribution.

    Science.gov (United States)

    Jones, Rhys Do; Jones, Hannah M; Rowland, Malcolm; Gibson, Christopher R; Yates, James W T; Chien, Jenny Y; Ring, Barbara J; Adkison, Kimberly K; Ku, M Sherry; He, Handan; Vuppugalla, Ragini; Marathe, Punit; Fischer, Volker; Dutta, Sandeep; Sinha, Vikash K; Björnsson, Thorir; Lavé, Thierry; Poulin, Patrick

    2011-10-01

    The objective of this study was to evaluate the performance of various empirical, semimechanistic and mechanistic methodologies with and without protein binding corrections for the prediction of human volume of distribution at steady state (Vss ). PhRMA member companies contributed a set of blinded data from preclinical and clinical studies, and 18 drugs with intravenous clinical pharmacokinetics (PK) data were available for the analysis. In vivo and in vitro preclinical data were used to predict Vss by 24 different methods. Various statistical and outlier techniques were employed to assess the predictability of each method. There was not simply one method that predicts Vss accurately for all compounds. Across methods, the maximum success rate in predicting human Vss was 100%, 94%, and 78% of the compounds with predictions falling within tenfold, threefold, and twofold error, respectively, of the observed Vss . Generally, the methods that made use of in vivo preclinical data were more predictive than those methods that relied solely on in vitro data. However, for many compounds, in vivo data from only two species (generally rat and dog) were available and/or the required in vitro data were missing, which meant some methods could not be properly evaluated. It is recommended to initially use the in vitro tissue composition-based equations to predict Vss in preclinical species and humans, putting the assumptions and compound properties into context. As in vivo data become available, these predictions should be reassessed and rationalized to indicate the level of confidence (uncertainty) in the human Vss prediction. The top three methods that perform strongly at integrating in vivo data in this way were the Øie-Tozer, the rat -dog-human proportionality equation, and the lumped-PBPK approach. Overall, the scientific benefit of this study was to obtain greater characterization of predictions of human Vss from several methods available in the literature. Copyright

  13. 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.

  14. Biodistribution and translational pharmacokinetic modeling of a human recombinant alkaline phosphatase

    NARCIS (Netherlands)

    Peters, Esther; Stevens, Jasper; Arend, Jacques; Guan, Zheng; Raaben, Willem; Laverman, Peter; Elsas, Andrea van; Masereeuw, R.; Pickkers, Peter

    2015-01-01

    Clinical trials showed renal protective effects of bovine intestinal alkaline phosphatase (AP) in patients with sepsis-associated Acute Kidney Injury (AKI). Subsequently, a human recombinant chimeric AP (recAP) was developed as a pharmaceutically acceptable alternative. Here, we investigated the

  15. Triphasic blood pressure responses to cannabinoids: do we understand the mechanism?

    Science.gov (United States)

    Malinowska, Barbara; Baranowska-Kuczko, Marta; Schlicker, Eberhard

    2012-01-01

    The cannabinoids comprise three major classes of substances, including compounds derived from the cannabis plant (e.g. Δ9-tetrahydrocannabinol and the chemically related substances CP55940 and HU210), endogenously formed (e.g. anandamide) and synthetic compounds (e.g. WIN55212-2). Beyond their psychotropic effects, cannabinoids have complex effects on blood pressure, including biphasic changes of Δ9-tetrahydrocannabinol and WIN55212-2 and an even triphasic effect of anandamide. The differing pattern of blood pressure changes displayed by the three types of compounds is not really surprising since, although they share an agonistic effect at cannabinoid CB1 and CB2 receptors, some compounds have additional effects. In particular, anandamide is known for its pleiotropic effects, and there is overwhelming evidence that anandamide influences blood pressure via (i) CB1 receptors, (ii) TRPV1 receptors, (iii) endothelial cannabinoid receptors and (iv) degradation products. This review is dedicated to the description of the effects of externally added cannabinoids on cardiovascular parameters in vivo. First, the cardiovascular effects of cannabinoids in anaesthetized animals will be highlighted since most data have been generated in experiments of that type. The text will follow the three phases of anandamide on blood pressure, and we will check to which extent cardiovascular changes elicited by other cannabinoids show overlap with those effects or differ. The second part will be dedicated to the cardiovascular effects of the cannabinoids in conscious animals. In the third part, cardiovascular effects in humans will be discussed, and similarities and differences with respect to the data from animals will be examined. PMID:22022923

  16. Thujone exhibits low affinity for cannabinoid receptors but fails to evoke cannabimimetic responses.

    Science.gov (United States)

    Meschler, J P; Howlett, A C

    1999-03-01

    Absinthe, an abused drug in the early 1900s, has been speculated to activate the receptors responsible for marijuana intoxication (the CB1 cannabinoid receptor) (Nature 253:365-356; 1975). To test this hypothesis, we investigated oil of wormwood (Artemisia absinthium) the active plant product found in absinthe, and thujone, the active compound found in oil of wormwood. Radioligand receptor binding assays employing membrane preparations from rat brains containing CB1 cannabinoid receptors, and human tonsils containing CB2 receptors, demonstrated that thujone displaced [3H]CP55940, a cannabinoid agonist, only at concentrations above 10 microM. HPLC analysis of oil of wormwood revealed that only the fractions having mobility close to thujone displaced [3H]CP55940 from the CB1 cannabinoid receptor. [35S]GTPgammaS binding assays revealed that thujone failed to stimulate G-proteins even at 0.1 mM. Thujone failed to inhibit forskolin-stimulated adenylate cyclase activity in N18TG2 membranes at 1 mM. Rats administered thujone exhibited different behavioral characteristics compared with rats administered a potent cannabinoid agonist, levonantradol. Therefore, the hypothesis that activation of cannabinoid receptors is responsible for the intoxicating effects of thujone is not supported by the present data.

  17. Pharmacokinetics & Neurophysiology

    Science.gov (United States)

    Davis, Andrew S.; Salpekar, Jay A.

    2009-01-01

    Medications administered in clinical practice obtain their therapeutic effect only to the extent that the drug is present in the appropriate concentration at the desired site. To achieve this goal, the prescribing clinician must be aware of how a drug may interact with the physiology of the patient. Pharmacokinetics is the study of this process…

  18. Pharmacology, Toxicology, and Adverse Effects of Synthetic Cannabinoid Drugs.

    Science.gov (United States)

    Gurney, S M R; Scott, K S; Kacinko, S L; Presley, B C; Logan, B K

    2014-01-01

    Synthetic cannabinoid drugs have become an established part of the recreational drug landscape in the United States and internationally. These drugs are manufactured in clandestine laboratories internationally and distributed in the United States in smoking mixtures, use of which produces effects very similar to use of marijuana. The adverse-effect profile of the drugs has not been studied in humans and infrequently in animal models, so much of the information about their toxicity comes from emergency department and treatment reports and forensic case studies. This review considers the discovery and characterization of the endocannabinoid system, approaches to receptor-binding studies of various synthetic cannabinoids from the first wave of naphthoylindoles (e.g., JWH-018) to the emerging adamantoylindole drugs (e.g., AKB-48), and their analogs, to evaluate the potential activity of drugs in this class. Currently employed approaches to assessing functional activity of the drugs using in vitro and in vivo models is also described, and comparisons made to the effects of THC. The physiological effects of activation of the endocannabinoid system in humans are reviewed, and the physiological effects of cannabinoid use are described. Case reports of adverse events including emergency department admissions, mental health admissions, and clinical and forensic case reports are presented in detail and discussed to summarize the current state of knowledge of adverse effects, both clinical and forensic in humans, including effects on driving ability, and tissue injury and death. The greatest weight is accorded to those reports that include toxicological confirmation of use. Finally, we discuss the current status of attempts to schedule and control the distribution of synthetic cannabinoids and the relevance of receptor binding and functional activity in this context. There is growing toxicological and pharmacological evidence of impairment, psychosis, tissue injury, and

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

    Science.gov (United States)

    2013-01-13

    has the advantage of adapting to real- world administration routes (the IM A B C Fig. 11 Time courses of sensitivity coefficients for 12 model...very water soluble, the charge and large size of TMB-4 molecules could slow their movement into tissues. The brain compartment requires the smallest ...human, Cynomolgus monkey , swine and guinea pig acetylcholinesterase by MMB-4: a modified kinetic approach. Toxicol Appl Pharmacol 249(3):231–237 Wu AHB

  20. 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...

  1. An extended range generic immunoassay for total human therapeutic antibodies in preclinical pharmacokinetic studies.

    Science.gov (United States)

    Hall, Colin M; Pearson, Josh T; Patel, Vimal; Wienkers, Larry C; Greene, Robert J

    2013-07-31

    Bioanalytical support of discovery programs for human monoclonal antibody therapies involves quantitation by immunoassay. Historically, preclinical samples have been analyzed by the traditional Enzyme-Linked Immuno-Sorbent Assay (ELISA). We investigated transferring our generic ELISA for quantitating human IgG constructs in preclinical serum samples to an automated microfluidics immunoassay platform based on nanoscale streptavidin bead columns. Transfer of our immunoassay to the automated platform resulted in not only the anticipated reduction in analysts' time required for manual manipulation (ELISA) but also a substantial increase in the dynamic range of the immunoassay. The generic nature and wide dynamic range of this automated microcolumn immunoassay permit bioanalytical support of novel therapeutic candidates without the need to develop new, specific assay reagents and minimize the chances that sample reassays will be required due to out of range concentration results. Improved process efficiencies and enhanced workflow during the analysis of preclinical PK samples that enable high throughput assessment of a human monoclonal antibody lead in early discovery programs. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. 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.

  3. 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.

  4. First-in-human, pharmacokinetic and pharmacodynamic phase I study of Resminostat, an oral histone deacetylase inhibitor, in patients with advanced solid tumors.

    Science.gov (United States)

    Brunetto, André T; Ang, Joo Ern; Lal, Rohit; Olmos, David; Molife, L Rhoda; Kristeleit, Rebecca; Parker, Ann; Casamayor, Isabel; Olaleye, Muyibat; Mais, Anna; Hauns, Bernhard; Strobel, Vera; Hentsch, Bernd; de Bono, Johann S

    2013-10-01

    This first-in-human dose-escalating trial investigated the safety, tolerability, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of the novel histone deacetylase (HDAC) inhibitor resminostat in patients with advanced solid tumors. Resminostat was administered orally once-daily on days 1 to 5 every 14 days at 5 dose levels between 100 and 800 mg. Safety, pharmacokinetics, pharmacodynamics including histone acetylation and HDAC enzyme activity, and antitumor efficacy were assessed. Nineteen patients (median age 58 years, range 39-70) were treated. At 800 mg, 1 patient experienced grade 3 nausea and vomiting, grade 2 liver enzyme elevation, and grade 1 hypokalemia and thrombocytopenia; these were declared as a combined DLT. No other DLT was observed. Although an MTD was not reached and patients were safely dosed up to 800 mg, 3 of 7 patients treated with 800 mg underwent dose reductions after the DLT-defining period due to cumulative gastrointestinal toxicities and fatigue. All toxicities resolved following drug cessation. No grade 4 treatment-related adverse event was observed. The pharmacokinetic profile was dose-proportional with low inter-patient variability. Pharmacodynamic inhibition of HDAC enzyme was dose-dependent and reached 100% at doses ≥400 mg. Eleven heavily pretreated patients had stable disease and 1 patient with metastatic thymoma had a 27% reduction in target lesion dimensions. Resminostat was safely administered with a dose-proportional pharmacokinetic profile, optimal on-target pharmacodynamic activity at dose levels ≥400 mg and signs of antitumor efficacy. The recommended phase II dose is 600 mg once-daily on days 1 to 5 every 14 days.

  5. Safety Pharmacology, Toxicology and Pharmacokinetic Assessment of Human Gc Globulin (Vitamin D Binding Protein)

    DEFF Research Database (Denmark)

    Pihl, Tina Holberg; Jørgensen, Charlotte Svaerke; Santoni-Rugiu, Eric

    2010-01-01

    potentially be life-saving. This article presents pre-clinical toxicology experiments conducted on purified plasma-derived human Gc globulin. The Gc globulin formulation was shown to be stable for at least 4 years with full retention of actin-binding capacity. In vitro studies did not reveal activation...... toxicity studies in rats and horses did not show any unwanted reactions. In a 14-day toxicology study in beagle dogs, formation of antibodies was seen and in the end of the study period, three out of four dogs showed clinical immunological reactions, which could be ascribed to the formation of antibodies...

  6. Safety pharmacology, toxicology and pharmacokinetic assesment of human Gc globulin (vitamin d binding protein)

    DEFF Research Database (Denmark)

    Pihl, Tina Holberg; Jørgensen, Charlotte Sværke; Santoni Rugiu, Eric

    2010-01-01

    potentially be life-saving. This article presents pre-clinical toxicology experiments conducted on purified plasma-derived human Gc globulin. The Gc globulin formulation was shown to be stable for at least 4 years with full retention of actin-binding capacity. In vitro studies did not reveal activation...... toxicity studies in rats and horses did not show any unwanted reactions. In a 14-day toxicology study in beagle dogs, formation of antibodies was seen and in the end of the study period, three out of four dogs showed clinical immunological reactions, which could be ascribed to the formation of antibodies...

  7. 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.

  8. Simultaneous determination of telmisartan and amlodipine in human plasma by LC–MS/MS and its application in a human pharmacokinetic study

    Directory of Open Access Journals (Sweden)

    Vasu Babu Ravi

    2012-10-01

    Full Text Available A rapid and sensitive liquid chromatography–tandem mass spectrometric (LC–MS/MS assay method has been developed and fully validated for the simultaneous quantification of telmisartan and amlodipine in human plasma. Carbamazepine was used as an internal standard. Analytes and the internal standard were extracted from human plasma by solid-phase extraction technique using Waters Oasis® HLB 1 cm3 (30 mg extraction cartridge. The reconstituted samples were chromatographed on a Hypurity advance C18 column (50 mm×4.6 mm, 5 μm using a mixture of acetonitrile–5 mM ammonium acetate buffer (pH-4.0 (50:50, v/v as the mobile phase at a flow rate of 0.8 mL/min. The calibration curve obtained was linear (r≥0.99 over the concentration range of 2.01–400.06 ng/mL for telmisartan and 0.05–10.01 ng/mL for amlodipine. Method validation was performed as per FDA guidelines and the results met the acceptance criteria. A run time of 2.5 min for each sample made it possible to analyze more than 400 human plasma samples per day. The proposed method was found to be applicable to clinical studies. Keywords: Telmisartan, Amlodipine, Human plasma, Solid-phase extraction, LC–MS/MS, Pharmacokinetics

  9. 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.

    Science.gov (United States)

    Mardal, Marie; Annaert, Pieter; Noble, Carolina; Oorts, Marlies; Linnet, Kristian

    2017-11-07

    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 5F-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 harvested following a two-step perfusion protocol and the SCRH were prepared between layers of rat-tail collagen. The biliary efflux of 5F-PY-PICA and its metabolites was determined in three-day-cultured SCRH by differential efflux into either standard buffer from intact bile canaliculi or standard buffer without divalent cations, which disrupts the bile canaliculi. The metabolites were identified using liquid chromatography-high resolution mass spectrometry/mass spectrometry (LC-HR-MS/MS). The main metabolites were the COOH-ω-metabolite (M4) in pHH, the defluoro-HO-ω-metabolite (M3) in pHLM, and the COOH-pyrrolidine-metabolite (M6) in rat hepatocytes. Efflux into standard buffer without divalent cations was significantly higher (pPICA, M4, and the HO-indole-glucuronide-metabolite (M22). M6 did not undergo significant biliary efflux, indicating that basolateral efflux dominates for this metabolite. 5F-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. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. 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...... that 125I-rIL-1 beta was localized to the proximal tubules in the kidney and to the hepatocytes in the liver. Furthermore, grains were localized to the islets of Langerhans in the pancreas. Tracer-bound proteins corresponding to intact 125I-rIL-1 beta were found in the circulation after i...

  11. High-performance liquid chromatographic determination of rivastigmine in human plasma for application in pharmacokinetic studies.

    Science.gov (United States)

    Amini, Hossein; Ahmadiani, Abolhassan

    2010-01-01

    A simple and reproducible HPLC method with spectrophotometric detection was developed for determination of rivastigmine in human plasma. Liquid-liquid extraction of rivastigmine and donepezil (as internal standard) from plasma samples was performed with 1-butanol/n-hexane (2:98 v/v) in alkaline condition followed by back-extraction into diluted acetic acid. Chromatography was carried out using a Silica column (250 mm × 4.6 mm, 5 μm) under isocratic elution with acetonitrile-50 mM aqueous sodium dihydrogen phosphate (17: 83 v/v, pH 3.1. Analyses were run at a flow-rate of 1.3 mL/min at of 50°C. The recovery was 90.8% and 95.7% for rivastigmine and the internal standard donepezil, respectively. The precision of the method was 2.6% to 9.1% over the concentration range of 0.5-16 ng/mL for rivastigmine in plasma with a linearity greater than 0.999. The method was specific and sensitive, with a quantification limit of 0.5 ng/mL and a detection limit of 0.2 ng/mL in plasma. The method was used for a bioequivalence study in healthy subjects.

  12. 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.

  13. 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.

  14. Immunoactive effects of cannabinoids: considerations for the therapeutic use of cannabinoid receptor agonists and antagonists

    Science.gov (United States)

    Greineisen, William E.; Turner., Helen

    2013-01-01

    The active constituents of Cannabis sativa have been used for centuries as recreational drugs and medicinal agents. Today, marijuana is the most prevalent drug of abuse in the United States and, conversely, therapeutic use of marijuana constituents are gaining mainstream clinical and political acceptance. Given the documented contributions of endocannabinoid signaling to a range of physiological systems, including cognitive function, and the control of eating behaviors, it is unsurprising that cannabinoid receptor agonists and antagonists are showing significant clinical potential. In addition to the neuroactive effects of cannabinoids, an emerging body of data suggests that both endogenous and exogenous cannabinoids are potently immunoactive. The central premise of this review article is that the immunological effects of cannabinoids should be considered in the context of each prescribing decision. We present evidence that the immunological effects of cannabinoid receptor agonists and antagonists are highly relevant to the spectrum of disorders for which cannabinoid therapeutics are currently offered. PMID:20219697

  15. Antiaversive Effects of Cannabinoids: Is the Periaqueductal Gray Involved?

    Directory of Open Access Journals (Sweden)

    F. S. Guimarães

    2008-12-01

    Full Text Available Cannabinoids play an important role in activity-dependent changes in synaptic activity and can interfere in several brain functions, including responses to aversive stimuli. The regions responsible for their effects, however, are still unclear. Cannabinoid type 1 (CB1 receptors are widely distributed in the central nervous system and are present in the periaqueductal gray (PAG, a midbrain structure closely involved in responses related to aversive states. Accordingly, exposure to stressful stimuli increases endocannabinoid (eCB levels in the PAG, and local administration of CB1 agonists or drugs that facilitate eCB-mediated neurotransmission produces antinociceptive and antiaversive effects. To investigate if these drugs would also interfere in animal models that are sensitive to anxiolytic drugs, we verified the responses to intra-PAG injection of CB1 agonists in rats submitted to the elevated plus-maze, the Vogel punished licking test, or contextual aversive conditioning model. The drugs induced anxiolytic-like effects in all tests. The same was observed with the transient receptor potential vanilloid type 1 (TRPV1 antagonist capsazepine and with cannabidiol, a nonpsychotomimetic phytocannabinoid that produces anxiolytic-like effects after systemic administration in humans and laboratory animals. These results, therefore, suggest that the PAG could be an important site for the antiaversive effects of cannabinoids.

  16. Antiaversive effects of cannabinoids: is the periaqueductal gray involved?

    Science.gov (United States)

    Moreira, F A; Aguiar, D C; Campos, A C; Lisboa, S F; Terzian, A L; Resstel, L B; Guimarães, F S

    2009-01-01

    Cannabinoids play an important role in activity-dependent changes in synaptic activity and can interfere in several brain functions, including responses to aversive stimuli. The regions responsible for their effects, however, are still unclear. Cannabinoid type 1 (CB1) receptors are widely distributed in the central nervous system and are present in the periaqueductal gray (PAG), a midbrain structure closely involved in responses related to aversive states. Accordingly, exposure to stressful stimuli increases endocannabinoid (eCB) levels in the PAG, and local administration of CB1 agonists or drugs that facilitate eCB-mediated neurotransmission produces antinociceptive and antiaversive effects. To investigate if these drugs would also interfere in animal models that are sensitive to anxiolytic drugs, we verified the responses to intra-PAG injection of CB1 agonists in rats submitted to the elevated plus-maze, the Vogel punished licking test, or contextual aversive conditioning model. The drugs induced anxiolytic-like effects in all tests. The same was observed with the transient receptor potential vanilloid type 1 (TRPV1) antagonist capsazepine and with cannabidiol, a nonpsychotomimetic phytocannabinoid that produces anxiolytic-like effects after systemic administration in humans and laboratory animals. These results, therefore, suggest that the PAG could be an important site for the antiaversive effects of cannabinoids.

  17. 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.

  18. New Trend in Narcotic Drugs Synthetic Cannabinoids

    Directory of Open Access Journals (Sweden)

    Selahattin Artuç

    2014-12-01

    Full Text Available Natural cannabis (Δ9-THC, tetrahydrocannabinol is obtained from Indian hemp plant (Cannabis sativa and it acts on cannabinoid receptors expressed as CB1, CB2. The therapeutic effects of cannabis is known from far away times. At the present time, some drugs containing kannabinoid are used for medical purposes. Synthetic cannabinoids’ chemical structure is quite different than natural cannabis. Cannabinoid receptor affinity and activity are greater than the natural cannabis. Substances containing synthetic cannabinoids are generally called “Spice”, “K2” abroad and, “Bonzai” or “Jamaica” in Turkey. Legal sale of herbal mixtures containing synthetic cannabinoids at places called “head shop” and “smart shop” in some countries and having easily access to them from the internet is an attractive feature for users. Moreover the impact stronger than cannabis, affordability, easy accessibility and getting rid of standard material tests contribute to increasing use of synthetic cannabinoids. As there is absence of reference standards of synthetic cannabinoids, it is not easy to identify them. In order to overcome legal barriers, new cannabinomimetic analogs are presented to market constantly. When taking into consideration of the increase of the use of synthetic cannabinoids, it is expected to be one of the most problematic drugs in the near future. Due to the widespread abuse of synthetic cannabinoids, further investigation of these substances is needed for better identification of their pharmacology and toxicology and to make appropriate legal planning and arrangements. Keywords: Synthetic cannabinoid, bonzai, narcotic drug.

  19. Pharmacokinetic evaluation of the tau PET radiotracer 18F-T807 (18F-AV-1451) in human subjects

    Science.gov (United States)

    Wooten, Dustin W.; Guehl, Nicolas J.; Verwer, Eline E.; Shoup, Timothy M.; Yokell, Daniel L.; Zubcevik, Nevena; Vasdev, Neil; Zafonte, Ross D.; Johnson, Keith A.; Fakhri, Georges El; Normandin, Marc D.

    2017-01-01

    18F-T807 is a PET radiotracer developed for imaging tau protein aggregates, which are implicated in neurological disorders including Alzheimer's disease (AD) and traumatic brain injury (TBI). The current study characterizes 18F-T807 pharmacokinetics in human subjects using dynamic PET imaging and metabolite-corrected arterial input functions. Methods Nine subjects (4 control, 3 with history of TBI, 2 mild cognitive impairment (MCI) due to suspected AD) underwent dynamic PET imaging for up to 120 minutes after bolus injection of 18F-T807 with arterial blood sampling. Total volume of distribution (VT) was estimated using compartmental modeling (one- and two-tissue configurations) and graphical analysis techniques (Logan and MA1 regression methods). Reference region-based methods of quantification were explored including Logan distribution volume ratio (DVR) and static standardized uptake value ratio (SUVR) utilizing the cerebellum as a reference tissue. Results Percent unmetabolized 18F-T807 in plasma followed a single exponential with T1/2 of 17.0±4.2 minutes. Metabolite corrected plasma radioactivity concentration fit a bi-exponential (T1/2: 18.1±5.8; 2.4±0.5 minutes). 18F-T807 in gray matter peaked quickly (SUV >2 at ∼5 minutes). Compartmental modeling resulted in good fits and the two-tissue model with estimated blood volume correction (2Tv) performed best, particularly in regions with elevated binding. VT was greater in MCI subjects than controls in the occipital, parietal, and temporal cortices as well as the posterior cingulate gyrus, precuneus, and mesial temporal cortex. High focal uptake was found in the posterior corpus callosum of a TBI subject. Plots from Logan and MA1 graphical methods became linear by 30 minutes, yielding regional estimates of VT in excellent agreement with compartmental analysis and providing high quality parametric maps when applied in voxelwise fashion. Reference region based approaches including Logan DVR (t*=55 min) and SUVR

  20. Role of the endogenous cannabinoid system in nicotine addiction: novel insights

    Directory of Open Access Journals (Sweden)

    Islam Hany Gamaleddin

    2015-03-01

    Full Text Available Several lines of evidence have shown that the endogenous cannabinoids are implicated in several neuropsychiatric diseases. Notably, preclinical and human clinical studies have shown a pivotal role of the cannabinoid system in nicotine addiction. The CB1 receptor inverse agonist/antagonist rimonabant (also known as SR141716 was effective to decrease nicotine-taking and nicotine-seeking in rodents, as well as the elevation of dopamine induced by nicotine in brain reward area. Rimonabant has been shown to improve the ability of smokers to quit smoking in randomized clinical trials. However, rimonabant was removed from the market due to increased risk of psychiatric side effects observed in humans. Recently, other components of the endogenous cannabinoid system have been explored. Here, we present the recent advances on the understanding of the role of the different components of the cannabinoid system on nicotine’s effects. Those recent findings suggest possible alternative ways of modulating the cannabinoid system that could have implication for nicotine dependence treatment.

  1. Cannabinoids in intestinal inflammation and cancer.

    Science.gov (United States)

    Izzo, Angelo A; Camilleri, Michael

    2009-08-01

    Emerging evidence suggests that cannabinoids may exert beneficial effects in intestinal inflammation and cancer. Adaptive changes of the endocannabinoid system have been observed in intestinal biopsies from patients with inflammatory bowel disease and colon cancer. Studies on epithelial cells have shown that cannabinoids exert antiproliferative, antimetastatic and apoptotic effects as well as reducing cytokine release and promoting wound healing. In vivo, cannabinoids - via direct or indirect activation of CB(1) and/or CB(2) receptors - exert protective effects in well-established models of intestinal inflammation and colon cancer. Pharmacological elevation of endocannabinoid levels may be a promising strategy to counteract intestinal inflammation and colon cancer.

  2. PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 3: comparative assessement of prediction methods of human clearance.

    Science.gov (United States)

    Ring, Barbara J; Chien, Jenny Y; Adkison, Kimberly K; Jones, Hannah M; Rowland, Malcolm; Jones, Rhys Do; Yates, James W T; Ku, M Sherry; Gibson, Christopher R; He, Handan; Vuppugalla, Ragini; Marathe, Punit; Fischer, Volker; Dutta, Sandeep; Sinha, Vikash K; Björnsson, Thorir; Lavé, Thierry; Poulin, Patrick

    2011-10-01

    The objective of this study was to evaluate the performance of various allometric and in vitro-in vivo extrapolation (IVIVE) methodologies with and without plasma protein binding corrections for the prediction of human intravenous (i.v.) clearance (CL). The objective was also to evaluate the IVIVE prediction methods with animal data. Methodologies were selected from the literature. Pharmaceutical Research and Manufacturers of America member companies contributed blinded datasets from preclinical and clinical studies for 108 compounds, among which 19 drugs had i.v. clinical pharmacokinetics data and were used in the analysis. In vivo and in vitro preclinical data were used to predict CL by 29 different methods. For many compounds, in vivo data from only two species (generally rat and dog) were available and/or the required in vitro data were missing, which meant some methods could not be properly evaluated. In addition, 66 methods of predicting oral (p.o.) area under the curve (AUCp.o. ) were evaluated for 107 compounds using rational combinations of i.v. CL and bioavailability (F), and direct scaling of observed p.o. CL from preclinical species. Various statistical and outlier techniques were employed to assess the predictability of each method. Across methods, the maximum success rate in predicting human CL for the 19 drugs was 100%, 94%, and 78% of the compounds with predictions falling within 10-fold, threefold, and twofold error, respectively, of the observed CL. In general, in vivo methods performed slightly better than IVIVE methods (at least in terms of measures of correlation and global concordance), with the fu intercept method and two-species-based allometry (rat-dog) being the best performing methods. IVIVE methods using microsomes (incorporating both plasma and microsomal binding) and hepatocytes (not incorporating binding) resulted in 75% and 78%, respectively, of the predictions falling within twofold error. IVIVE methods using other combinations of

  3. Delta(9)-tetrahydrocannabinol, 11-hydroxy-delta(9)-tetrahydrocannabinol and 11-nor-9-carboxy-delta(9)-tetrahydrocannabinol in human plasma after controlled oral administration of cannabinoids.

    Science.gov (United States)

    Goodwin, Robert S; Gustafson, Richard A; Barnes, Allan; Nebro, Wesenyalsh; Moolchan, Eric T; Huestis, Marilyn A

    2006-08-01

    A clinical study to investigate the pharmacokinetics and pharmacodynamics of oral tetrahydrocannabinol was performed. This randomized, double-blind, placebo-controlled, within-subject, inpatient study compared the effects of THC-containing hemp oils in liquid and capsule form to dronabinol (synthetic THC) in doses used for appetite stimulation. The National Institute on Drug Abuse Institutional Review Board approved the protocol and each participant provided informed consent. Detection times and concentrations of THC, 11-hydroxy-Delta-tetrahydrocannabinol (11-OH-THC), and 11-nor-9-carboxy-Delta-tetrahydrocannabinol (THCCOOH) in plasma were determined by gas chromatography-mass spectrometry [limits of quantification (LOQ)=0.5, 0.5, and 1.0 ng/mL, respectively] after oral THC administration. Six volunteers ingested liquid hemp oil (0.39 and 14.8 mg THC/d), hemp oil in capsules (0.47 mg THC/d), dronabinol capsules (7.5 mg THC/d), and placebo. Plasma specimens were collected during and after each dosing condition. THC and 11-OH-THC concentrations were low and never exceeded 6.1 ng/mL. Analytes were detectable 1.5 hour after initiating dosing with the 7.5 mg THC/d regimen and 4.5 hour after starting the 14.8 mg THC/d sessions. THCCOOH was detected 1.5 hour after the first dose, except for the 0.47 mg THC/d session, which required 4.5 hour for concentrations to reach the LOQ. THCCOOH concentrations peaked at 3.1 ng/mL during dosing with the low-dose hemp oils. Plasma THC and 11-OH-THC concentrations were negative for all participants at all doses within 15.5 hours after the last THC dose. Plasma THCCOOH persisted for at least 39.5 hours after the end of dosing and at much higher concentrations (up to 43.0 ng/mL). This study demonstrated that subjects who used high THC content hemp oil (347 mug/mL) as a dietary supplement had THC and metabolites in plasma in quantities comparable to those of patients using dronabinol for appetite stimulation. There was a significant

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

    Science.gov (United States)

    Caffarel, María M; Andradas, Clara; Mira, Emilia; Pérez-Gómez, Eduardo; Cerutti, Camilla; Moreno-Bueno, Gema; Flores, Juana M; García-Real, Isabel; Palacios, José; Mañes, Santos; Guzmán, Manuel; Sánchez, Cristina

    2010-07-22

    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. Our results show that both Delta9-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. Taken together, these results provide a strong preclinical evidence for the use of cannabinoid-based therapies for the management of ErbB2-positive breast cancer.

  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. 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].

  7. 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...

  8. Cannabinoids, Endocannabinoids, and Related Analogs in Inflammation

    National Research Council Canada - National Science Library

    Burstein, Sumner H; Zurier, Robert B

    2009-01-01

    ..., and finally, noncannabinoid components of Cannabis that show anti-inflammatory action. It is intended to be an update on the topic of the involvement of cannabinoids in the process of inflammation...

  9. Antitumorigenic effects of cannabinoids beyond apoptosis.

    Science.gov (United States)

    Freimuth, Nadine; Ramer, Robert; Hinz, Burkhard

    2010-02-01

    According to the World Health Organization, the cases of death caused by cancer will have been doubled until the year 2030. By 2010, cancer is expected to be the number one cause of death. Therefore, it is necessary to explore novel approaches for the treatment of cancer. Over past years, the antitumorigenic effects of cannabinoids have emerged as an exciting field in cancer research. Apart from their proapoptotic and antiproliferative action, recent research has shown that cannabinoids may likewise affect tumor cell angiogenesis, migration, invasion, adhesion, and metastasization. This review will summarize the data concerning the influence of cannabinoids on these locomotive processes beyond modulation of cancer cell apoptosis and proliferation. The findings discussed here provide a new perspective on the antitumorigenic potential of cannabinoids.

  10. Determination of tigecycline in human plasma by LC-MS/MS and its application to population pharmacokinetics study in Chinese patients with hospital-acquired pneumonia.

    Science.gov (United States)

    Shao, Rong; Li, Xingang; Hu, Yangmin; Chen, Jinliang; Lou, Honggang; Dai, Haibin

    2018-02-01

    A selective, sensitive and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination of tigecycline (TGC) in human plasma, using tigecycline-d9 as an internal standard (IS). Analytical samples were prepared using a protein precipitation method coupled with a concentration process. The analyte and IS were separated on a reversed-phase Waters Acquity UPLC® BEH-C18 column (2.1 × 50 mm i.d., 1.7 μm) with a flow rate of 0.25 mL/min. The mobile phase consisted of water, containing 0.2% formic acid (v/v) with 10 mm ammonium formate (A) and acetonitrile (B). The mass spectrometer was operated in selected reaction monitoring mode through electrospray ionization ion mode using the transitions of m/z 586.2 → 513.1 and m/z 595.1 → 514.0 for TGC and IS, respectively. The linearity of the method was in the range of 10-5000 ng/mL. Intra- and inter-batch precision (CV) for TGC was <9.27%, and the accuracy ranged from 90.06 to 107.13%. This method was successfully applied to the analysis of samples from hospital-acquired pneumonia patients treated with TGC, and a validated population pharmacokinetic model was established. This developed method could be useful to predict pharmacokinetics parameters and valuable for further pharmacokinetics/pharmacodynamics studies. Copyright © 2017 John Wiley & Sons, Ltd.

  11. 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)

  12. Phase 1 safety, tolerability, and pharmacokinetic study of single ascending doses of XM17 (recombinant human follicle-stimulating hormone in downregulated healthy women

    Directory of Open Access Journals (Sweden)

    Lammerich A

    2015-07-01

    Full Text Available Andreas Lammerich, Peter Bias, Beate Gertz Merckle GmbH, Ulm, Germany Background: XM17 is a recombinant human follicle-stimulating hormone (follitropin alfa for stimulation of multifollicular development in women undergoing controlled ovarian hyperstimulation during assisted reproductive therapy and for treatment of anovulation. Manufactured using Chinese hamster ovary cells transfected with the human follicle-stimulating hormone gene, XM17 has an identical amino acid sequence to that of the human protein as well as to those of the other approved recombinant human follicle-stimulating hormone products. Glycosylation patterns may differ slightly between products. The objectives of this first-in-human study were to assess the safety, tolerability, pharmacokinetics, and dose-proportionality of single ascending subcutaneous doses of XM17 in healthy young female volunteers.Methods: Endogenous follicle-stimulating hormone was downregulated by implanting a 1-month depot of goserelin acetate 3.6 mg on day 0 in eligible subjects. On day 14 of the experimental period, subjects received one of four ascending doses of XM17. Blood sampling to obtain the pharmacokinetic profile of XM17 was done at frequent intervals until 168 hours post-dose.Results: Following downregulation of endogenous follicle-stimulating hormone to <4 IU/L, 40 subjects (of mean age 29±5.4 years received single subcutaneous doses of 37.5 (n=4, pilot group, 75, 150, or 300 IU (n=12 each of XM17. The mean serum concentration-time profiles of XM17 revealed dose-related increases in maximum concentration (Cmax within 24 hours followed by monoexponential decay for the three higher dose levels. Slopes estimated by linear regression for Cmax and AUC0–168h were ~1.0 (0.9052 IU/L and 1.0964 IU·h/L, respectively. For each IU of XM17 administered, Cmax and AUC0–168h rose by 0.032 IU/L and 2.60 IU·h/L, respectively. Geometric mean elimination half-life ranged from 54 to 90 hours. No antibodies

  13. Cannabinoids and Cytochrome P450 Interactions.

    Science.gov (United States)

    Zendulka, Ondřej; Dovrtělová, Gabriela; Nosková, Kristýna; Turjap, Miroslav; Šulcová, Alexandra; Hanuš, Lumír; Juřica, Jan

    2016-01-01

    This review consists of three parts, representing three different possibilities of interactions between cannabinoid receptor ligands of both exogenous and endogenous origin and cytochrome P450 enzymes (CYPs). The first part deals with cannabinoids as CYP substrates, the second summarizes current knowledge on the influence of various cannabinoids on the metabolic activity of CYP, and the third outline a possible involvement of the endocannabinoid system and cannabinoid ligands in the regulation of CYP liver activity. We performed a structured search of bibliographic and drug databases for peer-reviewed literature using focused review questions. Biotransformation via a hydrolytic pathway is the major route of endocannabinoid metabolism and the deactivation of substrates is characteristic, in contrast to the minor oxidative pathway via CYP involved in the bioactivation reactions. Phytocannabinoids are extensively metabolized by CYPs. The enzymes CYP2C9, CYP2C19, and CYP3A4 catalyze most of their hydroxylations. Similarly, CYP represents a major metabolic pathway for both synthetic cannabinoids used therapeutically and drugs that are abused. In vitro experiments document the mostly CYP inhibitory activity of the major phytocannabinoids, with cannabidiol as the most potent inhibitor of many CYPs. The drug-drug interactions between cannabinoids and various drugs at the CYP level are reported, but their clinical relevance remains unclear. The direct activation/inhibition of nuclear receptors in the liver cells by cannabinoids may result in a change of CYP expression and activity. Finally, we hypothesize the interplay of central cannabinoid receptors with numerous nervous systems, resulting in a hormone-mediated signal towards nuclear receptors in hepatocytes.

  14. Cannabinoid modulation of fear extinction brain circuits: a novel target to advance anxiety treatment.

    Science.gov (United States)

    Rabinak, Christine A; Phan, K Luan

    2014-01-01

    Anxiety disorders, such as post-traumatic stress (PTSD), panic, and phobic disorders, can be conceptualized as a failure to inhibit inappropriate fear responses. A common, effective treatment strategy involves repeated presentations to the feared cue without any danger (extinction). However, extinction learning has a number of important limitations, and enhancing its effects, generalizability and durability via cognitive enhancers may improve its therapeutic impact. In this review we focus specifically on the role of the cannabinoid system in fear extinction learning and its retention. We address the following questions: What are the neural circuits mediating fear extinction?; Can we make fear extinction more effective?; Can cannabinoids facilitate fear extinction in humans?; How might the cannabinoid system effect fear extinction? Collectively, translational evidence suggest that enhancing cannabinoid transmission may facilitate extinction learning and its recall, and that the cannabinoid system is a potential pharmacological target for improving the active learning that occurs during exposure-based behavioral treatments prompting future research in terms of mechanisms research, novel treatment approaches ('cognitive enhancers'), and pharmacotherapeutic drug discovery.

  15. Comparing the effects of endogenous and synthetic cannabinoid receptor agonists on survival of gastric cancer cells.

    Science.gov (United States)

    Ortega, A; García-Hernández, V M; Ruiz-García, E; Meneses-García, A; Herrera-Gómez, A; Aguilar-Ponce, J L; Montes-Servín, E; Prospero-García, O; Del Angel, S A

    2016-11-15

    Anti-neoplastic activity induced by cannabinoids has been extensively documented for a number of cancer cell types; however, this topic has been explored in gastric cancer cells only in a limited number of approaches. Thus, the need of integrative and comparative studies still persists. In this study we tested and compared the effects of three different cannabinoid receptor agonists-anandamide (AEA), (R)-(+)-methanandamide (Meth-AEA) and CP 55,940 (CP)- on gastric cancer cell morphology, viability and death events in order to provide new insights to the use of these agents for therapeutic purposes. The three agents tested exhibited similar concentration-dependent effects in the induction of changes in cell morphology and cell loss, as well as in the decrease of cell viability and DNA laddering in the human gastric adenocarcinoma cell line (AGS). Differences among the cannabinoids tested were mostly observed in the density of cells found in early and late apoptosis and necrosis, favoring AEA and CP as the more effective inducers of apoptotic mechanisms, and Meth-AEA as a more effective inducer of necrosis through transient and rapid apoptosis. Through a comparative approach, our results support and confirm the therapeutic potential that cannabinoid receptor agonists exert in gastric cancer cells and open possibilities to use cannabinoids as part of a new gastric cancer therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Cannabinoids - a new weapon against cancer?

    Science.gov (United States)

    Pokrywka, Małgorzata; Góralska, Joanna; Solnica, Bogdan

    2016-12-29

    Cannabis has been cultivated by man since Neolithic times. It was used, among others for fiber and rope production, recreational purposes and as an excellent therapeutic agent. The isolation and characterization of the structure of one of the main active ingredients of cannabis - Δ9 - tetrahydrocannabinol as well the discovery of its cannabinoid binding receptors CB1 and CB2, has been a milestone in the study of the possibilities of the uses of Cannabis sativa and related products in modern medicine. Many scientific studies indicate the potential use of cannabinoids in the fight against cancer. Experiments carried out on cell lines in vitro and on animal models in vivo have shown that phytocannabinoids, endocannabinoids, synthetic cannabinoids and their analogues can lead to inhibition of the growth of many tumor types, exerting cytostatic and cytotoxic neoplastic effect on cells thereby negatively influencing neo-angiogenesis and the ability of cells to metastasize. The main molecular mechanism leading to inhibition of proliferation of cancer cells by cannabinoids is apoptosis. Studies have shown, however, that the process of apoptosis in cells, treated with recannabinoids, is a consequence of induction of endoplasmic reticulum stress and autophagy. On the other hand, in the cellular context and dosage dependence, cannabinoids may enhance the proliferation of tumor cells by suppressing the immune system or by activating mitogenic factors. Leading from this there is a an obvious need to further explore cannabinoid associated molecular pathways making it possible to develop safe therapeutic drug agents for patients in the future.

  17. A validated high-resolution accurate mass LC-MS assay for quantitative determination of metoprolol and α-hydroxymetoprolol in human serum for application in pharmacokinetics

    Directory of Open Access Journals (Sweden)

    Sjoukje Postma-Kunnen

    2017-06-01

    Full Text Available To determine metoprolol and its metabolite α-hydroxymetoprolol in human serum we validated a method on an LC system with an Exactive® Orbitrap mass spectrometer (Thermo Scientific as detector and isotope-labelled metoprolol-d7 as internal standard. A simple sample preparation was used with water-acetonitrile (15:85, v/v as precipitation reagent. This method has a chromatographic run time of 15 min and linear calibration curves in the range of 5.0-250 μg/L for both metoprolol and α-hydroxymetoprolol. Validation showed the method to be accurate, with a good precision, selective and with a lower limit of quantitation of 2.0 μg/L for metoprolol and 1.0 μg/L for α-hydroxymetoprolol, respectively. This validated LC-Orbitrap MS analysis for metoprolol and α-hydroxymetoprolol can be used for application in human pharmacokinetics.

  18. Are cannabinoids effective for epilepsy?

    Directory of Open Access Journals (Sweden)

    Javier Peña

    2017-03-01

    Full Text Available Resumen En el último tiempo se han descrito diversos beneficios con el uso de canabinoides en diferentes situaciones clínicas. Dentro de ellas se ha planteado un posible efecto en el control de la epilepsia, pero la real utilidad clínica es tema de debate. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en múltiples bases de datos, identificamos cinco revisiones sistemáticas que en conjunto incluyen cuatro estudios aleatorizados. Extrajimos los datos y realizamos una síntesis mediante tablas de resumen de los resultados utilizando el método GRADE. Concluimos que no está claro si los cannabinoides disminuyen la frecuencia de las convulsiones porque la certeza de la evidencia es muy baja, pero probablemente se asocian a efectos adversos frecuentes.

  19. Synthesis of deuterium labeled cannabinoids

    Energy Technology Data Exchange (ETDEWEB)

    Banijamali, A.R.; Abou-Taleb, N.; Van der Schyf, C.J.; Charalambous, A.; Makriyannis, A.

    1988-01-01

    Several methods for the specific deuteration of cannabinoids are described. Deuteration of the phenolic ring was accomplished by treatment with BF/sub 3/center dotEt/sub 2/O followed by quenching with a solution of Na/sub 2/ CO/sub 3/ in D/sub 2/ O resulting in deuterium incorporation in both the 2 and 4 positions. Regioselective incorporation of deuterium into either the 2 or 4 position of ..delta../sup 8/-THC was achieved using Florisil spiked with either D/sub 2/O or H/sub 2/O. Deuteration at positions 8, 10 and 11 was achieved by addition of DC1 gas to the appropriate tetrahydrocannabinol to form 9-chlorohexahydrocannabinol labeled at either of the above positions, followed by elimination of hydrogen- or deuterium chloride with potassium-tert-amylate. UV irradiation of specifically labeled ..delta../sup 8/-THC gave the correspondingly labeled ..delta..sup(9,11)-THC.

  20. Cannabinoids: novel medicines for the treatment of Huntington's disease.

    Science.gov (United States)

    Sagredo, Onintza; Pazos, M Ruth; Valdeolivas, Sara; Fernandez-Ruiz, Javier

    2012-04-01

    Cannabinoid pharmacology has experienced a notable increase in the last 3 decades which is allowing the development of novel cannabinoid-based medicines for the treatment of different human pathologies, for example, Cesamet® (nabilone) or Marinol® (synthetic Δ9-tetrahydrocannabinol for oral administration) that were approved in 80s for the treatment of nausea and vomiting associated with chemotherapy treatment in cancer patients and in 90s for anorexiacachexia associated with AIDS therapy. Recently, the british company GW Pharmaceuticals plc has developed an oromucosal spray called Sativex®, which is constituted by an equimolecular combination of Δ9-tetrahydrocannabinol- and cannabidiol- enriched botanical extracts. Sativex® has been approved for the treatment of specific symptoms (i.e. spasticity and pain) of multiple sclerosis patients in various countries (i.e. Canada, UK, Spain, New Zealand). However, this cannabis- based medicine has been also proposed to be useful in other neurological disorders given the analgesic, antitumoral, anti-inflammatory, and neuroprotective properties of their components demonstrated in preclinical models. Numerous clinical trials are presently being conducted to confirm this potential in patients. We are particularly interested in the case of Huntington's disease (HD), an autosomal-dominant inherited disorder caused by an excess of CAG repeats in the genomic allele resulting in a polyQ expansion in the encoded protein called huntingtin, and that affects primarily striatal and cortical neurons thus producing motor abnormalities (i.e. chorea) and dementia. Cannabinoids have been studied for alleviation of hyperkinetic symptoms, given their inhibitory effects on movement, and, in particular, as disease-modifying agents due to their anti-inflammatory, neuroprotective and neuroregenerative properties. This potential has been corroborated in different experimental models of HD and using different types of cannabinoid agonists

  1. High-performance liquid chromatography-tandem mass spectrometry for the determination of pidotimod in human plasma and its application to a pharmacokinetic study.

    Science.gov (United States)

    Zhang, Yi; Xiong, Zhili; Qin, Feng; Lu, Shan; Liu, Wei; Li, Famei

    2009-08-15

    A selective, rapid and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for the first time to determine pidotimod in human plasma and applied to a pharmacokinetic study. Diphenhydramine was used as the internal standard (I.S.). Sample pretreatment involved in one-step protein precipitation (PPT) with methanol of 0.1 mL plasma. The analysis was carried out on an Ultimate XB-C(8) column with mobile phase of methanol-water containing 0.5% formic acid (65:35, v/v). The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via electrospray ionization (ESI) source. Each plasma sample was chromatographed within 4.5 min. The linear calibration curves were obtained in the concentration range of 0.05-20.00 microg/mL (r(2) > or = 0.99) with the lower limit of quantification (LLOQ) of 0.0500 microg/mL. The intra- and inter-day precision (relative standard deviation, R.S.D.) values were below 15% and accuracy (relative error, R.E.) was from -5.1% to 3.9% at all quality control (QC) levels. The method was applicable to clinical pharmacokinetic study of pidotimod in healthy volunteers after oral administration.

  2. A physiologically based pharmacokinetic model characterizing mechanism-based inhibition of CYP1A2 for predicting theophylline/antofloxacin interaction in both rats and humans.

    Science.gov (United States)

    Pan, Xian; Wang, Ping; Hu, Nan; Liu, Li; Liu, Xiaodong; Xie, Lin; Wang, Guangji

    2011-01-01

    Clinical studies have revealed that some fluoroquinolones may cause severe adverse effects when co-administered with substrates of CYP1A2. Our previous study showed antofloxacin (ATFX) was responsible for mechanism-based inhibition (MBI) of the metabolism of phenacetin in rats. In the clinical setting, ATFX is likely to be administrated with theophylline (TP), which is mainly metabolized by CYP1A2. The aim of the present study was to investigate the possible mechanism of TP/ATFX interaction. In vitro studies showed that the inhibitory effect of ATFX on the formation of three TP metabolites depended on NADPH, the pre-inhibition time, and ATFX concentration, i.e., factors which characterize MBI. In vivo studies demonstrated that single-dose ATFX (20 mg/kg) did not affect the pharmacokinetic behavior of TP, but multidose ATFX (20 mg/kg b.i.d. for 7.5 days) significantly increased the AUC of TP, decreased the amount of three TP metabolites in urine, and suppressed hepatic microsomal activity. A physiologically based pharmacokinetic (PBPK) model characterizing MBI of the three TP metabolites was developed for predicting TP/ATFX interaction in rats; this model was further extrapolated to humans. The predicted results were in good agreement with observed data. All the results indicated that ATFX was responsible for MBI of the metabolism of TP, and the PBPK model characterizing MBI may give good prediction of TP/ATFX interaction.

  3. Cannabinoids for the treatment of dementia.

    Science.gov (United States)

    Krishnan, Sarada; Cairns, Ruth; Howard, Robert

    2009-04-15

    Following the discovery of an endogenous cannabinoid system and the identification of specific cannabinoid receptors in the central nervous system, much work has been done to investigate the main effects of these compounds. There is increasing evidence that the cannabinoid system may regulate neurodegenerative processes such as excessive glutamate production, oxidative stress and neuroinflammation. Neurodegeneration is a feature common to the various types of dementia and this has led to interest in whether cannabinoids may be clinically useful in the treatment of people with dementia. Recent studies have also shown that cannabinoids may have more specific effects in interrupting the pathological process in Alzheimer's disease. To determine from available research whether cannabinoids are clinically effective in the treatment of dementia. The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on 11 April 2008 using the terms: cannabis or cannabinoid* or endocannabinoid* or cannabidiol or THC or CBD or dronabinol or delta-9-tetrahydrocannabinol or marijuana or marihuana or hashish. The CDCIG Specialized Register contains records from all major health care databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many clinical trials registries and grey literature sources. All double-blind and single (rater)-blind randomized placebo controlled trials assessing the efficacy of cannabinoids at any dose in the treatment of people with dementia. Two reviewers independently examined the retrieved studies for inclusion according to the selection criteria. They then independently assessed the methodological quality of selected trials and extracted data where possible. Only one study met the inclusion criteria. The data in the study report were presented in such a way that they could not be extracted for further analysis and

  4. 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 45...... min are well established. Several questions relate to what constitutes a clinically effective plasma concentration, the choice of ideal administration route, and the optimal method of analysis. Furthermore, investigations of melatonin metabolites in humans are urgently needed in order to characterize...

  5. Evaluation of principal cannabinoids in airborne particulates

    Energy Technology Data Exchange (ETDEWEB)

    Balducci, C., E-mail: balducci@iia.cnr.it [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.

  6. Evaluation of principal cannabinoids in airborne particulates.

    Science.gov (United States)

    Balducci, C; Nervegna, G; Cecinato, A

    2009-05-08

    The determination of delta(9)-tetrahydrocannabinol (Delta9-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.

  7. Multitarget cannabinoids as novel strategy for Alzheimer disease.

    Science.gov (United States)

    González-Naranjo, Pedro; Campillo, Nuria E; Pérez, Concepción; Páez, Juan A

    2013-03-01

    During the last years the development of approaches to multitarget drug design and discovery is gaining acceptance. The cannabinoids are potentially excellent multi-target drug candidates because of their interesting pharmacological profiles, among which stands out the dual capacity of cannabinoid ligands to act as cannabinoid agonist and cholinesterase inhibitors. In this article, inhibition, kinetics studies and docking simulations with a representative set of cannabinoids are presented. The results of these studies showed the inhibitory capacity of some agonist cannabinoids with selectivity at AChE or BuChE enzymes. The kinetic and modelling studies allowed us to postulate the potential mode of action and the binding site of the cannabinoids. In general, the studied cannabinoids showed a mixed type inhibition mode of action. The exception to this behaviour was found for the agonist CP-55,940 that showed a non-competitive inhibition, suggesting that this cannabinoid only binds to the peripheral site.

  8. 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

  9. Effects of polymorphisms of the SLCO2B1 transporter gene on the pharmacokinetics of montelukast in humans.

    Science.gov (United States)

    Kim, Kyoung-Ah; Lee, Hye-Mi; Joo, Hyun-Jin; Park, In-Bae; Park, Ji-Young

    2013-11-01

    Montelukast, a leukotriene receptor antagonist, is a substrate of organic anion transporting OATP2B1 encoded by the SLCO2B1. We evaluated the effects of six non-synonymous (c.1175C>T, c.1457C>T, c.43C>T, c.935G>A, c.601G>A, and c.644A>T) polymorphisms and one promoter (g.-282G>A) polymorphism on the pharmacokinetics of montelukast. A single dose of 10 mg montelukast was administered in 24 healthy subjects. Its levels were measured up to 24 hours and a pharmacokinetic analysis was performed based on the SLCO2B1 polymorphisms. We did not encounter subjects with c.1175C>T, c.43C>T, or c.644A>T polymorphisms. The remaining SLCO2B1 polymorphisms did not affect plasma levels of montelukast, and pharmacokinetic parameters of montelukast did not differ among genotype groups. Oral clearance results were as follows: (1) 3.3 L/h for c.935GG, 3.0 L/h for c.935GA, and 3.5 L/h for c.935AA; (2) 3.4 L/h for c.1457CC, 2.9 L/h for c.1457CT, and 3.2 L/h for c.1457TT; (3) 3.2 L/h for c.601GG, 3.4 L/h for c.601GA, and 3.4 L/h for c.601AA; (4) 3.2 L/h for g.-282GG, 3.4 L/h for g.-282GA, and 3.2 L/h for g.-282AA. The findings suggest that SLCO2B1 polymorphisms do not affect the pharmacokinetics of montelukast and that SLCO2B1 polymorphisms appear to be a minor determinant of inter-individual variability of montelukast. © 2013, The American College of Clinical Pharmacology.

  10. 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.

  11. Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity

    NARCIS (Netherlands)

    Boon, M.R.; Kooijman, S.; Dam, A.D. van; Pelgrom, L.R.; Berbée, J.F.P.; Visseren, C.A.R.; Aggele, R.C. van; Hoek, A.M. van den; Sips, H.C.M.; Lombès, M.; Havekes, L.M.; Tamsma, J.T.; Guigas, B.; Meijer, O.C.; Jukema, J.W.; Rensen, P.C.N.

    2014-01-01

    The endocannabinoid system is an important player in energy metabolism by regulating appetite, lipolysis, and energy expenditure. Chronic blockade of the cannabinoid 1 receptor (CB1R) leads to long-term maintenance of weight loss and reduction of dyslipidemia in experimental and human obesity. The

  12. Antiretroviral Pharmacokinetics in Pregnant Women.

    Science.gov (United States)

    Gilbert, Elise M; Darin, Kristin M; Scarsi, Kimberly K; McLaughlin, Milena M

    2015-09-01

    For women infected with the human immunodeficiency virus (HIV) who become pregnant, the use of combination antiretroviral therapy (ART) significantly reduces transmission of HIV from mother to child. Selection of an appropriate ART regimen for use among pregnant women requires consideration of numerous factors including maternal and fetal safety, antiretroviral pharmacokinetics, and regimen efficacy. Optimization of antiretroviral pharmacokinetics during pregnancy requires special consideration because pregnancy-associated changes in drug absorption, distribution, metabolism, and excretion are known to occur throughout pregnancy and postpartum. Understanding antiretroviral placental transfer may offer additional insight into each drug's potential role in preventing HIV transmission in utero and may also have implications regarding viral resistance in cases where transmission does occur. In this review, we summarize key published data describing antiretroviral pharmacokinetics in pregnant women, providing suggestions for clinical application of these data where appropriate. © 2015 Pharmacotherapy Publications, Inc.

  13. Safety, pharmacokinetics, and pharmacodynamics of AMG 102, a fully human hepatocyte growth factor-neutralizing monoclonal antibody, in a first-in-human study of patients with advanced solid tumors.

    Science.gov (United States)

    Gordon, Michael S; Sweeney, Christopher S; Mendelson, David S; Eckhardt, S Gail; Anderson, Abraham; Beaupre, Darrin M; Branstetter, Daniel; Burgess, Teresa L; Coxon, Angela; Deng, Hongjie; Kaplan-Lefko, Paula; Leitch, Ian M; Oliner, Kelly S; Yan, Lucy; Zhu, Min; Gore, Lia

    2010-01-15

    The aims were to assess the safety, pharmacokinetics, maximum tolerated dose, and antitumor activity of AMG 102, a fully human hepatocyte growth factor/scatter factor (HGF/SF)-neutralizing monoclonal antibody, in patients with solid tumors. Patients (N = 40) with refractory advanced solid tumors were enrolled into six sequential dose-escalation cohorts (0.5, 1, 3, 5, 10, or 20 mg/kg AMG 102 i.v. every 2 weeks) and a dose-expansion cohort (20 mg/kg AMG 102 every 2 weeks). Safety, anti-AMG 102 antibody formation, pharmacokinetics, tumor response, and exploratory biomarkers were assessed. AMG 102 was well tolerated up to the planned maximum dose of 20 mg/kg, and the maximum tolerated dose was not reached. Treatment-related adverse events were generally mild and included fatigue (13%), constipation (8%), nausea (8%), vomiting (5%), anorexia (5%), myalgia (5%), and hypertension (5%). Two patients experienced dose-limiting toxicities: one patient (0.5 mg/kg cohort) experienced grade 3 hypoxia and grade 3 dyspnea and one patient (1 mg/kg cohort) experienced grade 3 upper gastrointestinal hemorrhage. No anti-AMG 102 antibodies were detected, and AMG 102 had linear pharmacokinetics within the dose range investigated. Sixteen of 23 (70%) evaluable patients had a best response of stable disease with progression-free survival ranging from 7.9 to 40 weeks. Circulating levels of the biomarker HGF/SF (bound and unbound) increased in a dose-dependent manner, whereas soluble c-Met concentrations were generally similar across doses. AMG 102 is safe and well tolerated, has a favorable pharmacokinetic profile, and will be further investigated as a monotherapy and in combination with other agents.

  14. 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.

  15. 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

    AIMS: To determine the effect of CYP2C8 genotype and of fluvoxamine on the pharmacokinetics of rosiglitazone. METHODS: Twenty-three healthy subjects with the following genotypes were included in a two-phase, open-label, cross-over trial: CYP2C8*3/ *3 (n = 3), CYP2C8*1/ *3 (n = 10) and CYP2C8*1/ *1...... (n = 10). In Phase A, the subjects were given 4 mg rosiglitazone as a single oral dose. In Phase B, the subjects were treated with multiple oral doses of 50 mg fluvoxamine maleate for 3 days prior to the single oral administration of 4 mg rosiglitazone. Plasma concentrations of rosiglitazone...... and relative amounts of N-desmethylrosiglitazone were measured in both phases for 24 h after drug administration. RESULTS: The pharmacokinetics of rosiglitazone and N-desmethylrosiglitazone were not significantly different between the CYP2C8 genotypic groups. Fluvoxamine caused a statistically significant (P...

  16. Efficacy, pharmacokinetics, safety, and tolerability of Flebogamma 10% DIF, a high-purity human intravenous immunoglobulin, in primary immunodeficiency.

    Science.gov (United States)

    Berger, Melvin; Pinciaro, Paul J; Althaus, Arthur; Ballow, Mark; Chouksey, Akhilesh; Moy, James; Ochs, Hans; Stein, Mark

    2010-03-01

    Flebogamma 10% DIF represents an evolution of intravenous immune globulin from the previous 5% product to be administered at higher rates and with smaller infusion volumes. Pathogen safety is enhanced by the combination of multiple methods with different mechanisms of action. The objective of this study as to evaluate the efficacy, pharmacokinetics, and safety of Flebogamma 10% DIF for immunoglobulin replacement therapy in primary immunodeficiency diseases (PIDD). Flebogamma 10% DIF was administered to 46 subjects with well-defined PIDD at a dose of 300-600 mg/kg every 21-28 days for 12 months. Serious bacterial infection rate was 0.025/subject/year. Half-life in serum of the administered IgG was approximately 35 days. No serious treatment-related adverse event (AE) occurred in any patient. Most of the potentially treatment-related AEs occurred during the infusion, accounting for 20% of the 601 infusions administered. Flebogamma 10% DIF is efficacious and safe, has adequate pharmacokinetic properties, and is well-tolerated for the treatment of PIDD.

  17. 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.

  18. Cannabinoids therapeutic use: what is our current understanding following the introduction of THC, THC:CBD oromucosal spray and others?

    Science.gov (United States)

    Maccarrone, Mauro; Maldonado, Rafael; Casas, Miguel; Henze, Thomas; Centonze, Diego

    2017-04-01

    The complexity of the endocannabinoid (eCB) system is becoming better understood and new drivers of eCB signaling are emerging. Modulation of the activities of the eCB system can be therapeutic in a number of diseases. Research into the eCB system has been paralleled by the development of agents that interact with cannabinoid receptors. In this regard it should be remembered that herbal cannabis contains a myriad of active ingredients, and the individual cannabinoids have quite distinct biological activities requiring independent studies. Areas covered: This article reviews the most important current data involving the eCB system in relation to human diseases, to reflect the present (based mainly on the most used prescription cannabinoid medicine, THC/CBD oromucosal spray) and potential future uses of cannabinoid-based therapy. Expert commentary: From the different therapeutic possibilities, THC/CBD oromucosal spray has been in clinical use for approximately five years in numerous countries world-wide for the management of multiple sclerosis (MS)-related moderate to severe resistant spasticity. Clinical trials have confirmed its efficacy and tolerability. Other diseases in which different cannabinoids are currently being investigated include various pain states, Alzheimer's disease, Parkinson's disease, Huntington's disease and epilepsy. The continued characterization of individual cannabinoids in different diseases remains important.

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

    Science.gov (United States)

    2007-02-01

    cannabinoids, the active components of Cannabis sativa linnaeus (marijuana) and their derivatives are drawing renewed attention because of their diverse...its treatment has become a challenging issue. In recent years, cannabinoids, the active components of Cannabis sativa linnaeus (marijuana) and their...the therapeutic potential of cannabinoids under in vivo situation on cell proliferation, apoptosis, markers of angiogenesis and PSA levels. We

  20. Analysis of nifedipine in human plasma and amniotic fluid by liquid chromatography-tandem mass spectrometry and its application to clinical pharmacokinetics in hypertensive pregnant women.

    Science.gov (United States)

    Filgueira, Gabriela Campos de Oliveira; Filgueira, Osmany Alberto Silva; Carvalho, Daniela Miarelli; Marques, Maria Paula; Moisés, Elaine Christine Dantas; Duarte, Geraldo; Lanchote, Vera Lucia; Cavalli, Ricardo Carvalho

    2015-07-01

    Nifedipine is a dihydropyridine calcium channel blocker used for the treatment of hypertension in pregnant women. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for analysis of nifedipine in human plasma and amniotic fluid. Separation of nifedipine and nitrendipine (IS) was performed using a LiChroCART(®) RP-Select B column and a mixture of water:acetonitrile:glacial acetic acid (30:70:0.5 v/v) as the mobile phase. Aliquots of 500μL of biological samples were extracted at pH 13 using dichloromethane:n-pentane (3:7 v/v). The validated method was applied to a study of the pharmacokinetics of nifedipine in human plasma and amniotic fluid samples collected up to 12h after administration of the last slow-release nifedipine (20mg/12h) dose to 12 hypertensive pregnant women. The estimated pharmacokinetic parameters of nifedipine showed a mean AUC(0-12) of 250.2ngh/mL, ClT/F of 89.2L/h, Vd/F of 600.0L and t1/2 5.1h. The mean amniotic fluid/plasma concentration ratio was 0.05. The methods proved to be highly sensitive by showing a lower quantification limit of 0.1ng/mL for both matrices. And this study reports for the first time the complete development and validation of the method to quantify nifedipine in amniotic fluid using LC-MS-MS. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Prediction of clinical pharmacokinetics of AMG 181, a human anti-α 4 β 7 monoclonal antibody for treating inflammatory bowel diseases.

    Science.gov (United States)

    Li, Hong; Köck, Kathleen; Wisler, John A; Rees, William A; Prince, Peter J; Reynhardt, Kai O; Hsu, Hailing; Yu, Zhigang; Borie, Dominic C; Salinger, David H; Pan, Wei-Jian

    2015-02-01

    The purpose of this study was to predict a safe starting dose of AMG 181, a human anti-α 4 β 7 antibody for treating inflammatory bowel diseases, based on cynomolgus monkey pharmacokinetic (PK) and pharmacodynamic (PD) data. A two-compartment model with parallel linear and target-mediated drug disposition for AMG 181 PK in cynomolgus monkey was developed. The estimated parameters were allometrically scaled to predict human PK. An E max PD model was used to relate AMG 181 concentration and free α 4 β 7 receptor data in cynomolgus monkey. AMG 181 clinical doses were selected based on observed exposures at the no adverse effect level of 80 mg·kg(-1) in monkeys, the predicted human exposures, and AMG 181 concentration expected to produce greater than 50% α 4 β 7 receptor occupancy in humans. The predicted human AMG 181 clearance and central volume of distribution were 144 mL·day(-1) and 2900 mL, respectively. The estimated EC50 for free α 4 β 7 receptor was 14 ng·mL(-1). At the 0.7 mg starting dose in humans, the predicted exposure margins were greater than 490,000 and AMG 181 concentrations were predicted to only briefly cover the free α 4 β 7 receptor EC10. Predictions for both C max and AUC matched with those observed in the first-in-human study within the 7 mg subcutaneous to 420 mg intravenous dose range. The developed model aided in selection of a safe starting dose and a pharmacological relevant dose escalation strategy for testing of AMG 181 in humans. The clinically observed human AMG 181 PK data validated the modeling approach based on cynomolgus monkey data alone.

  2. 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.

  3. Leaner and greener analysis of cannabinoids.

    Science.gov (United States)

    Mudge, Elizabeth M; Murch, Susan J; Brown, Paula N

    2017-05-01

    There is an explosion in the number of labs analyzing cannabinoids in marijuana (Cannabis sativa L., Cannabaceae) but existing methods are inefficient, require expert analysts, and use large volumes of potentially environmentally damaging solvents. The objective of this work was to develop and validate an accurate method for analyzing cannabinoids in cannabis raw materials and finished products that is more efficient and uses fewer toxic solvents. An HPLC-DAD method was developed for eight cannabinoids in cannabis flowers and oils using a statistically guided optimization plan based on the principles of green chemistry. A single-laboratory validation determined the linearity, selectivity, accuracy, repeatability, intermediate precision, limit of detection, and limit of quantitation of the method. Amounts of individual cannabinoids above the limit of quantitation in the flowers ranged from 0.02 to 14.9% w/w, with repeatability ranging from 0.78 to 10.08% relative standard deviation. The intermediate precision determined using HorRat ratios ranged from 0.3 to 2.0. The LOQs for individual cannabinoids in flowers ranged from 0.02 to 0.17% w/w. This is a significant improvement over previous methods and is suitable for a wide range of applications including regulatory compliance, clinical studies, direct patient medical services, and commercial suppliers.

  4. Inhibition of cancer cell invasion by cannabinoids via increased expression of tissue inhibitor of matrix metalloproteinases-1.

    Science.gov (United States)

    Ramer, Robert; Hinz, Burkhard

    2008-01-02

    Cannabinoids, in addition to having palliative benefits in cancer therapy, have been associated with anticarcinogenic effects. Although the antiproliferative activities of cannabinoids have been intensively investigated, little is known about their effects on tumor invasion. Matrigel-coated and uncoated Boyden chambers were used to quantify invasiveness and migration, respectively, of human cervical cancer (HeLa) cells that had been treated with cannabinoids (the stable anandamide analog R(+)-methanandamide [MA] and the phytocannabinoid delta9-tetrahydrocannabinol [THC]) in the presence or absence of antagonists of the CB1 or CB2 cannabinoid receptors or of transient receptor potential vanilloid 1 (TRPV1) or inhibitors of p38 or p42/44 mitogen-activated protein kinase (MAPK) pathways. Reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoblotting were used to assess the influence of cannabinoids on the expression of matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs). The role of TIMP-1 in the anti-invasive action of cannabinoids was analyzed by transfecting HeLa, human cervical carcinoma (C33A), or human lung carcinoma cells (A549) cells with siRNA targeting TIMP-1. All statistical tests were two-sided. Without modifying migration, MA and THC caused a time- and concentration-dependent suppression of HeLa cell invasion through Matrigel that was accompanied by increased expression of TIMP-1. At the lowest concentrations tested, MA (0.1 microM) and THC (0.01 microM) led to a decrease in invasion (normalized to that observed with vehicle-treated cells) of 61.5% (95% CI = 38.7% to 84.3%, P cannabinoid-induced TIMP-1 expression by siRNA led to a reversal of the cannabinoid-elicited decrease in tumor cell invasiveness in HeLa, A549, and C33A cells. Increased expression of TIMP-1 mediates an anti-invasive effect of cannabinoids. Cannabinoids may therefore offer a therapeutic option in the treatment of highly invasive cancers.

  5. Incorporation of Therapeutic Interventions in Physiologically Based Pharmacokinetic Modeling of Human Clinical Case Reports of Accidental or Intentional Overdosing with Ethylene Glycol

    Energy Technology Data Exchange (ETDEWEB)

    Corley, Rick A.; McMartin, K. E.

    2005-05-16

    Ethylene glycol is a high production volume chemical used in the manufacture of resins and fibers, antifreeze, deicing fluids, heat transfer and hydraulic fluids. Although occupational uses of ethylene glycol have not been associated with adverse effects, there are case reports where humans have either intentionally or accidentally ingested large quantities of ethylene glycol, primarily from antifreeze. The acute toxicity of ethylene glycol in humans and animals and can proceed through three stages, each associated with a different metabolite: central nervous system depression (ethylene glycol), cardiopulmonary effects associated with metabolic acidosis (glycolic acid) and ultimately renal toxicity (oxalic acid), depending upon the total amounts consumed and effectiveness of therapeutic interventions. A physiologically based pharmacokinetic (PBPK) model developed in a companion paper (Corley et al., 2004) was refined in this study to include clinically relevant treatment regimens for ethylene glycol poisoning such as hemodialysis or metabolic inhibition with either ethanol or fomepizole. Such modifications enabled the model to describe several human case reports which included analysis of ethylene glycol and/or glycolic acid. Such data and model simulations provide important confirmation that the PBPK model developed previously can adequately describe the pharmacokinetics of ethylene glycol in humans following low, occupational or environmentally relevant inhalation exposures, as well as massive oral doses even under conditions where treatments have been employed that markedly affect the disposition of ethylene glycol and glycolic acid. By integrating the case report data sets with controlled studies in this PBPK model, it was demonstrated that fomepizole, if administered early enough in a clinical situation, can be more effective than ethanol or hemodialysis in preventing the metabolism of ethylene glycol to more toxic metabolites. Hemodialysis remains an

  6. Pharmacokinetics of mitragynine in man.

    Science.gov (United States)

    Trakulsrichai, Satariya; Sathirakul, Korbtham; Auparakkitanon, Saranya; Krongvorakul, Jatupon; Sueajai, Jetjamnong; Noumjad, Nantida; Sukasem, Chonlaphat; Wananukul, Winai

    2015-01-01

    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. 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. Ten male subjects completed the study without adverse reactions. The median duration of abuse was 1.75 years. We analyzed one subject separately due to the abnormal behavior of blood concentration. From data of nine subjects, the pharmacokinetic parameters established were time to reach the maximum plasma concentration (0.83±0.35 hour), terminal half-life (23.24±16.07 hours), and the apparent volume of distribution (38.04±24.32 L/kg). The urine excretion of unchanged form was 0.14%. The pharmacokinetics were observed to be oral two-compartment model. This was the first pharmacokinetic study in humans, which demonstrated linearity and was consistent with the oral two-compartment model with a terminal half-life of about 1 day. The pharmacokinetic

  7. 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.

  8. The effects of the SLCO2B1 c.1457C > T polymorphism and apple juice on the pharmacokinetics of fexofenadine and midazolam in humans.

    Science.gov (United States)

    Imanaga, Junko; Kotegawa, Tsutomu; Imai, Hiromitsu; Tsutsumi, Kimiko; Yoshizato, Tsuneaki; Ohyama, Tetsuji; Shirasaka, Yoshiyuki; Tamai, Ikumi; Tateishi, Tomonori; Ohashi, Kyoichi

    2011-02-01

    The objective was to determine the effects of the SLCO2B1 c.1457C> T polymorphism and apple juice on the pharmacokinetics of fexofenadine and midazolam in humans. Individuals were divided based on the genotype of SLCO2B1 c.1457C> T (n = 14, c.[1457C]+ c.[= ] 5,c.[1457C]+ c.[1457C> T] 5, and c.[1457C> T]+c.[1457C> T] 4). The oral pharmacokinetics of 60 mg fexofenadine and 5mg midazolam were assessed with water or apple juice (1200 ml/day) in a randomized crossover study. OATP2B1-mediated uptake of fexofenadine and midazolam was evaluated with Xenopus laevis oocyte gene-expression system. When fexofenadine was administered with water, subjects with c.[1457C> T] allele showed a significant decrease in fexofenadine in the area under the plasma concentration-time curve (AUC) compared with c.[1457C] + c[= ] subjects (1110 ± 347 vs. 1762 ± 542 ng . h/ml, Papple juice, a significant decrease in the fexofenadine AUC was observed compared with water (1342 ± 519 vs. 284 ± 79.2 ng . h/ml, P apple juice induced decrease in fexofenadine AUC was significantly lower in subjects carrying the c.[1457C> T] allele. Neither the genotype nor the apple juice showed significant effects on the pharmacokinetics of midazolam except for a marginally significant decrease in Cmax after administration with apple juice. The uptake of fexofenadine by OATP2B1 cRNA-injected oocytes was significantly higher than that by water-injected oocytes. Apple juice, but not midazolam, significantly decreased the uptake of fexofenadine by OATP2B1 cRNA-injected oocytes. The results suggest that fexofenadine is a substrate of OATP2B1, and the transport function of OATP2B1 is subject to the genotype of SLCO2B1 c.1457C> T and apple juice. It is likely that apple juice has little effect on CYP3A.

  9. Cannabinoids – a new weapon against cancer?

    Directory of Open Access Journals (Sweden)

    Małgorzata Pokrywka

    2016-12-01

    Full Text Available Cannabis has been cultivated by man since Neolithic times. It was used, among others for fiber and rope production, recreational purposes and as an excellent therapeutic agent. The isolation and characterization of the structure of one of the main active ingredients of cannabis – Δ9 – tetrahydrocannabinol as well the discovery of its cannabinoid binding receptors CB1 and CB2, has been a milestone in the study of the possibilities of the uses of Cannabis sativa and related products in modern medicine. Many scientific studies indicate the potential use of cannabinoids in the fight against cancer. Experiments carried out on cell lines in vitro and on animal models in vivo have shown that phytocannabinoids, endocannabinoids, synthetic cannabinoids and their analogues can lead to inhibition of the growth of many tumor types, exerting cytostatic and cytotoxic neoplastic effect on cells thereby negatively influencing neo-angiogenesis and the ability of cells to metastasize.The main molecular mechanism leading to inhibition of proliferation of cancer cells by cannabinoids is apoptosis. Studies have shown, however, that the process of apoptosis in cells, treated with recannabinoids, is a consequence of induction of endoplasmic reticulum stress and autophagy. On the other hand, in the cellular context and dosage dependence, cannabinoids may enhance the proliferation of tumor cells by suppressing the immune system or by activating mitogenic factors. Leading from this there is a an obvious need to further explore cannabinoid associated molecular pathways making it possible to develop safe therapeutic drug agents for patients in the future.

  10. 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

  11. 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

  12. 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.

  13. Cannabinoids and the endocannabinoid system in lower urinary tract function and dysfunction.

    Science.gov (United States)

    Hedlund, Petter

    2014-01-01

    To review knowledge on cannabinoids and the endocannabinoid system in lower urinary tract function and dysfunction. Review of MEDLINE using defined search terms, and manual analysis. Articles published in English were included. Components of the endocannabinoid system—cannabinoid (CB)receptor types 1 and 2, anandamide, and fatty acid amide hydrolase (FAAH), which degrades anandamide and related fatty-acid amides—have been located to lower urinary tract tissues of mice, rats, monkeys, and humans. Studies have located CB receptors in urothelium and sensory nerves and FAAH in the urothelium. CB receptor- and FAAH-related activities have also been reported in the lumbosacral spinal cord. Data on supraspinal CB functions in relation to micturition are lacking. Cannabinoids are reported to reduce sensory activity of isolated tissues, cause antihyperalgesia in animal studies of bladder inflammation, affect urodynamics parameters reflecting sensory functions in animals models, and appear to have effects on storage symptoms in humans. FAAH inhibitors have affected sensory bladder functions and reduced bladder overactivity in rat models. Cannabinoids may modify nerve-mediated functions of isolated lower urinary tract tissues. Evidence suggests components of the endocannabinoid system are involved in regulation of bladder function, possibly at several levels of the micturition pathway. It is unclear if either CB receptor has a dominant role in modification of sensory signals or if differences exist at peripheral and central nervous sites. Amplification of endocannabinoid activity by FAAH inhibitors may be an attractive drug target in specific pathways involved in LUTS.

  14. Cannabinoid Markers in Biological Fluids and Tissues: Revealing Intake.

    Science.gov (United States)

    Huestis, Marilyn A; Smith, Michael L

    2018-02-01

    Understanding cannabis and synthetic cannabinoid intake history is vital for treating drug dependence, investigating cannabinoid effects, and providing information to healthcare personnel, medical examiners, and public health officials; this is particularly relevant today with cannabis medicalization and legalization. Required information includes identifying exposure, time of use, frequency of use, relapse, withdrawal, and predicting cannabinoid effects. Recent controlled cannabinoid administration studies enable the development of models and markers to better identify patterns of intake and exposure. Future challenges include developing behavioral markers of cannabis impairment, bringing to market breathalyzers for cannabinoid detection, and identifying markers of recent cannabis intake in diverse biological matrices. We posit that biological monitoring of cannabinoids and metabolites will improve the characterization of cannabis and synthetic cannabinoid intake history. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Cannabinoids and post-traumatic stress disorder: clinical and preclinical evidence for treatment and prevention.

    Science.gov (United States)

    Mizrachi Zer-Aviv, Tomer; Segev, Amir; Akirav, Irit

    2016-10-01

    There is substantial evidence from studies in humans and animal models for a role of the endocannabinoid system in the control of emotional states. Several studies have shown an association between exposure to trauma and substance use. Specifically, it has been shown that there is increased prevalence of cannabis use in post-traumatic stress disorder (PTSD) patients and vice versa. Clinical studies suggest that PTSD patients may cope with their symptoms by using cannabis. This treatment-seeking strategy may explain the high prevalence of cannabis use among individuals with PTSD. Preliminary studies in humans also suggest that treatment with cannabinoids may decrease PTSD symptoms including sleep quality, frequency of nightmares, and hyperarousal. However, there are no large-scale, randomized, controlled studies investigating this specifically. Studies in animal models have shown that cannabinoids can prevent the effects of stress on emotional function and memory processes, facilitate fear extinction, and have an anti-anxiety-like effect in a variety of tasks. Moreover, cannabinoids administered shortly after exposure to a traumatic event were found to prevent the development of PTSD-like phenotype. In this article, we review the existing literature on the use of cannabinoids for treating and preventing PTSD in humans and animal models. There is a need for large-scale clinical trials examining the potential decrease in PTSD symptomatology with the use of cannabis. In animal models, there is a need for a better understanding of the mechanism of action and efficacy of cannabis. Nevertheless, the end result of the current clinical and preclinical data is that cannabinoid agents may offer therapeutic benefits for PTSD.

  16. Contactless decontamination of hair samples: cannabinoids.

    Science.gov (United States)

    Restolho, José; Barroso, Mário; Saramago, Benilde; Dias, Mário; Afonso, Carlos A M

    2017-02-01

    Room temperature ionic liquids (ILs) have already been shown to provide efficient extraction media for several systems, and to capture volatile compounds, namely opiates. In this work, a novel, contactless, artefact-free extraction procedure for the removal of Δ 9 -tetrahrydrocannabinol (THC) from the surface of human hair is presented. To prepare in vitro cannabinoids-contaminated hair, samples were flushed with hashish smoke for 7 h. The decontamination experiments were carried at 100 °C for 24 h, according to the procedure previously described. Fifty-three ILs were screened and presented decontamination efficiencies ranging from 0 to 96 %. Although the majority of the ILs presented efficiencies above 90%, the 1-ethanol-3-methyl tetrafluoroborate (96%) was chosen for further process optimization. The Design of Experiments results demonstrated that all studied variables were significant for the process and the obtained optimum conditions were: 100 °C, 13 h and 175 mg of IL. In the work of Perrotin-Brunel et al. (J. Mol. Struct. 2011, 987, 67), it is demonstrated that, at 100 °C, full conversion of tetrahydrocannabinolic acid (THCA) into THC is obtained after 60 min. Since our decontamination takes place over 13 h at 100 °C, full conversion of THCA into THC is expected. Additionally, our method was compared with the method proposed by Cairns et al. (Forensic Sci. Int. 2004, 145, 97), through the analysis of 15 in vitro contaminated hair samples. The results demonstrated that with our method a mean extraction efficiency of 11 % higher was obtained. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  17. Unravelling bisphenol A pharmacokinetics using physiologically based pharmacokinetic modeling

    Directory of Open Access Journals (Sweden)

    Xiaoxia eYang

    2015-01-01

    Full Text Available Physiologically based pharmacokinetic (PBPK models integrate both chemical- and system-specific information into a mathematical framework, offering a mechanistic approach to predict the internal dose metrics of a chemical and an ability to perform species and dose extrapolations. Bisphenol A (BPA, because of its ubiquitous presence in a variety of consumer products, has received a considerable amount of attention from the public and regulatory bodies. PBPK models using deuterated BPA were developed for immature and adult rats and non-human primates and for adult humans to understand better the dosimetry of BPA. The focus of the present paper is to provide a rationale for interpreting species- and age-related pharmacokinetics of BPA. Gastrointestinal tract metabolism was an important consideration to predict unconjugated BPA serum kinetic profiles in adult and immature rats and monkeys. Biliary excretion and enterohepatic recirculation of BPA conjugates accounted for the slowed systemic clearance of BPA conjugates in rats. For monkeys, renal reabsorption was proposed as a mechanism influencing systemic clearance of BPA conjugates. The quantitative understanding of the processes driving the pharmacokinetics of BPA across different species and life stages using a computational modeling approach provides more confidence in the interpretation of human biomonitoring data and the extrapolation of experimental animal findings to humans.

  18. Comparative pharmacokinetics and pharmacodynamics of a PEGylated recombinant human growth hormone and daily recombinant human growth hormone in growth hormone-deficient children

    Directory of Open Access Journals (Sweden)

    Hou L

    2015-12-01

    Full Text Available Ling Hou,1,* Zhi-hang Chen,2,* Dong Liu,3 Yuan-guo Cheng,2 Xiao-ping Luo1 1Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 2Department of Pharmacy, Beijing Institute of Microbiology and Epidemiology, Beijing, 3Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China *These authors contributed equally to this study Objective: Recombinant human growth hormone (rhGH replacement therapy in children generally requires daily subcutaneous (sc injections, which may be inconvenient for patients. Jintrolong® is a PEGylated rhGH with the purpose of weekly sc injections. The aim of the current study was to examine the pharmacokinetics, pharmacodynamics, safety, and tolerability of multiple sc doses of Jintrolong® vs daily doses of rhGH. Design and methods: Twelve children with growth hormone deficiency participated in this single-center, open-label, crossover Phase I trial. All subjects received daily sc injections of rhGH at 0.0286 mg/kg/d for 7 days, followed by a 4-week washout period and six weekly doses of Jintrolong® at 0.2 mg/kg/w. Results: In comparison with rhGH, sc injection of Jintrolong® produced a noticeably higher Cmax, significantly longer half-life (t1/2, and slower plasma clearance, signifying a profile suitable for long-term treatment. The ratio of the area under the concentration vs time curve (AUC after the seventh and first injections (AUC(0–∞7th/AUC(0–∞1st of rhGH was 1.02, while the AUC(0–∞6th/AUC(0–∞1st of Jintrolong® was 1.03, indicating no accumulation of circulating growth hormone. There was no significant difference in the change in insulin-like growth factor-1 expression produced by 7 days of sc rhGH and weekly Jintrolong® injections. There were no severe adverse events during the trial. Conclusion: The elimination rate of Jintrolong® was

  19. Cannabinoid receptor CB2 modulates axon guidance

    DEFF Research Database (Denmark)

    Duff, Gabriel; Argaw, Anteneh; Cecyre, Bruno

    2013-01-01

    Navigation of retinal projections towards their targets is regulated by guidance molecules and growth cone transduction mechanisms. Here, we present in vitro and in vivo evidences that the cannabinoid receptor 2 (CB2R) is expressed along the retino-thalamic pathway and exerts a modulatory action ...

  20. 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.

  1. Quantification of intact carboplatin in human plasma ultrafitrates using hydrophilic interaction liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study.

    Science.gov (United States)

    Ito, Hajime; Yamaguchi, Hiroaki; Fujikawa, Asuka; Shiida, Narumi; Tanaka, Nobuaki; Ogura, Jiro; Kobayashi, Masaki; Yamada, Takehiro; Mano, Nariyasu; Iseki, Ken

    2013-02-15

    Carboplatin is a platinum agent that is used for treatment of non-small-cell lung cancer and ovarian cancer. A sensitive and selective analytical method for the quantification of carboplatin in human plasma ultrafiltrates using liquid chromatography-tandem mass spectrometry was developed. Human plasma ultrafiltrates were precipitated by acetonitrile containing carboplatin-d4 as an internal standard and were further diluted with acetonitrile. Chromatographic separation was performed on a Accucore HILIC (50mm×2.1mm i.d., 2.6μm) column using mobile phase (acetonitrile-water-acetic acid=90:10:0.1, v/v/v) at the flow rate of 0.2mL/min. Detection was performed on electrospray ionization triple quadrupole tandem mass spectrometer using low-energy collision induced dissociation (CID-MS/MS) analysis operating in the selected reaction monitoring (SRM) scan mode. The lower limit of quantification for carboplatin was 0.025μg/mL. This method covered a linearity range of 0.025-50μg/mL. The intra-day precision and inter-day precision (R.S.D.) ranged from 1.5 to 4.3%, and the accuracy (R.E.) was within ±2.9%. The present method was applied to a clinical pharmacokinetic study of carboplatin in a cancer patient. Copyright © 2012 Elsevier B.V. All rights reserved.

  2. Rapid and sensitive determination of levofloxacin in microsamples of human plasma by high-performance liquid chromatography and its application in a pharmacokinetic study.

    Science.gov (United States)

    Aguilar-Carrasco, José Carlos; Hernández-Pineda, Jessica; Jiménez-Andrade, Juan Miguel; Flores-Murrieta, Francisco Javier; Carrasco-Portugal, Miriam Del Carmen; López-Canales, Jorge Skiold

    2015-03-01

    A rapid, sensitive and simple high-performance liquid chromatographic assay with ultraviolet detection was developed for the quantification of levofloxacin in microsamples (100 μL) of human plasma. The extraction procedure included a protein precipitation technique and a short chromatographic running time (4.5 min). Analyses were carried out on a Symmetry C18 column using a mixture of acetonitrile and 0.01 m potassium dihydrogen aqueous solution (pH 3.4; 14:86 v/v) as mobile phase. The method provided specificity and was linear (r ≥ 0.9992) over the concentration range 0.1-12 µg/mL. The average absolute recovery was 93.59%. The intra- and inter-day coefficients of variation were levofloxacin was stable in all evaluations. The usefulness of this method was demonstrated in a pharmacokinetic study of levofloxacin in healthy adult volunteers. The present method offers two main advantages: (a) the use of microsamples reduces the total volume of blood to be collected from patients; and (b) it provides a good cost-effectiveness ratio. It is concluded that the method is rapid, simple, sensitive, economical and suitable for the determination of levofloxacin in human plasma using a small volume of sample. Copyright © 2014 John Wiley & Sons, Ltd.

  3. 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

  4. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa.

    Science.gov (United States)

    Ruhaak, Lucia Renee; Felth, Jenny; Karlsson, Pernilla Christina; Rafter, Joseph James; Verpoorte, Robert; Bohlin, Lars

    2011-01-01

    Cyclooxygenase enzymes (COX-1 and COX-2) catalyse the production of prostaglandins from arachidonic acid. Prostaglandins are important mediators in the inflammatory process and their production can be reduced by COX-inhibitors. Endocannabinoids, endogenous analogues of the plant derived cannabinoids, occur normally in the human body. The Endocannabinoids are structurally similar to arachidonic acid and have been suggested to interfere with the inflammatory process. They have also been shown to inhibit cancer cell proliferation. Anti-inflammatory effects of cannabinoids and endocannabinoids have been observed, however the mode of action is not yet clarified. Anti-inflammatory activity (i.e., inhibition of COX-2) is proposed to play an important role in the development of colon cancer, which makes this subject interesting to study further. In the present work, the six cannabinoids tetrahydrocannabinol (Δ⁹-THC), tetrahydrocannabinolic acid (Δ⁹-THC-A), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG) and cannabigerolic acid (CBGA), isolated from Cannabis sativa, were evaluated for their effects on prostaglandin production. For this purpose an in vitro enzyme based COX-1/COX-2 inhibition assay and a cell based prostaglandin production radioimmunoassay were used. Cannabinoids inhibited cyclooxygenase enzyme activity with IC₅₀ values ranging from 1.7·10⁻³ to 2.0·10⁻⁴ M.

  5. Cannabinoids for Symptom Management and Cancer Therapy: The Evidence.

    Science.gov (United States)

    Davis, Mellar P

    2016-07-01

    Cannabinoids bind not only to classical receptors (CB1 and CB2) but also to certain orphan receptors (GPR55 and GPR119), ion channels (transient receptor potential vanilloid), and peroxisome proliferator-activated receptors. Cannabinoids are known to modulate a multitude of monoamine receptors. Structurally, there are 3 groups of cannabinoids. Multiple studies, most of which are of moderate to low quality, demonstrate that tetrahydrocannabinol (THC) and oromucosal cannabinoid combinations of THC and cannabidiol (CBD) modestly reduce cancer pain. Dronabinol and nabilone are better antiemetics for chemotherapy-induced nausea and vomiting (CINV) than certain neuroleptics, but are not better than serotonin receptor antagonists in reducing delayed emesis, and cannabinoids have largely been superseded by neurokinin-1 receptor antagonists and olanzapine; both cannabinoids have been recommended for breakthrough nausea and vomiting among other antiemetics. Dronabinol is ineffective in ameliorating cancer anorexia but does improve associated cancer-related dysgeusia. Multiple cancers express cannabinoid receptors directly related to the degree of anaplasia and grade of tumor. Preclinical in vitro and in vivo studies suggest that cannabinoids may have anticancer activity. Paradoxically, cannabinoid receptor antagonists also have antitumor activity. There are few randomized smoked or vaporized cannabis trials in cancer on which to judge the benefits of these forms of cannabinoids on symptoms and the clinical course of cancer. Smoked cannabis has been found to contain Aspergillosis. Immunosuppressed patients should be advised of the risks of using "medical marijuana" in this regard. Copyright © 2016 by the National Comprehensive Cancer Network.

  6. New insights into antimetastatic and antiangiogenic effects of cannabinoids.

    Science.gov (United States)

    Ramer, Robert; Hinz, Burkhard

    2015-01-01

    Cannabinoids exert antitumorigenic effects via multiple mechanisms. Of these, antimetastatic and antiangiogenic actions have attracted considerable interest in the past years. Regarding the underlying antimetastatic mechanism, several studies revealed cannabinoids to alter the gene expression of cancer cells toward a less-aggressive phenotype and to modulate their secretomic profile. Cannabinoids likewise modulate the release of factors from tumor cells that subsequently suppress the chemoattraction of vessel cells thereby conferring antiangiogenesis. Among the diverse mediators of cannabinoids' antitumorigenic action, the tissue inhibitor of matrix metalloproteinases-1, which is released from cancer cells upon cannabinoid treatment, has been implicated as a pivotal factor conferring both anti-invasive properties of cancer cells as well as antiangiogenic capacities of endothelial cells. In addition, cannabinoids have been shown to inhibit angiogenic capacities of endothelial cells directly via suppressing their proliferation, tube formation, and migration. This chapter reviews the cell- and substance-specific antitumorigenic mechanisms of cannabinoids with particular consideration of their antimetastatic/anti-invasive and antiangiogenic actions. In addition, beneficial interactions of cannabinoids with currently used chemotherapeutics as well as the influence of cannabinoids on tumor-immune surveillance are addressed. Collectively, the currently available data suggest cannabinoids as a potential tool in modern cancer pharmacotherapy. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. 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 CB1 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 CB1 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 CB1 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

  8. Control of Inhibition by the Direct Action of Cannabinoids on GABAA Receptors

    NARCIS (Netherlands)

    Golovko, Tatiana; Min, R.; Lozovaya, Natalia; Falconer, Caroline; Yatsenko, Natalia; Tsintsadze, Timur; Tsintsadze, Vera; Ledent, Catherine; Harvey, Robert J; Belelli, Delia; Lambert, Jeremy J; Rozov, Andrei; Burnashev, Nail

    Cannabinoids are known to regulate inhibitory synaptic transmission via activation of presynaptic G protein-coupled cannabinoid CB1 receptors (CB1Rs). Additionally, recent studies suggest that cannabinoids can also directly interact with recombinant GABAA receptors (GABAARs), potentiating currents

  9. The synthetic cannabinoid WIN-55,212 induced-apoptosis in cytotrophoblasts cells by a mechanism dependent on CB1 receptor.

    Science.gov (United States)

    Almada, Marta; Costa, Lia; Fonseca, Bruno Miguel; Amaral, Cristina; Teixeira, Natércia; Correia-da-Silva, Georgina

    2017-06-15

    The endocannabinoid system has evolved as a key regulator in several pathological and physiological processes, including placentation, decidualization and implantation. In addition, it is known that Cannabis and cannabinoids negatively affect female reproduction. Although, the biological action of synthetic cannabinoids, such as WIN-55,212, in human fertility and pregnancy outcome remain to be unveiled. A tight balance between proliferation, differentiation and apoptosis of trophoblast cells is required for placental development and pregnancy outcome. Therefore, in this work, the effects of the synthetic cannabinoid WIN-55,212 in placental cytotrophoblast cells were explored. For that, it was used a human choriocarcinoma cell line, BeWo cells, and primary cultures of human cytotrophoblasts isolated from term placentas. Results demonstrate that this synthetic cannabinoid induces cell cycle arrest. We also observed that cell viability loss was associated with a disruption of mitochondrial membrane potential and activation of caspases -9 and -3/-7 independently of reactive oxygen species (ROS) production or recruitment of the endoplasmic reticulum stress marker CHOP. Moreover, these effects were prevented by pre-incubation with a selective cannabinoid receptor 1 (CBR1) antagonist (AM281). Thus, our results provide strong evidences of the apoptotic process induced by WIN-55,212 through the activation of the CBR1, which may reveal the impact of cannabinoids consumption during placental development. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Determination of colistin A and colistin B in human plasma by UPLC-ESI high resolution tandem MS: application to a pharmacokinetic study.

    Science.gov (United States)

    Gikas, Evangelos; Bazoti, Fotini N; Katsimardou, Marina; Anagnostopoulos, Dimitrios; Papanikolaou, Konstantinos; Inglezos, Ilias; Skoutelis, Athanasios; Daikos, Georgios L; Tsarbopoulos, Anthony

    2013-09-01

    The resistance of gram-negative bacteria to most available antibiotics and the lack of new antimicrobial agents have prompted the re-emergence of colistin (CS) as potent treatment against most gram-negative microorganisms. Optimal dosing with CS suffers from poor pharmacokinetic characterization mainly due to the analytical challenge of assaying CS in biological fluids and the limited information on quantitative analysis of CS in plasma using high resolution mass spectrometry (MS). Hence, a rapid, simple and accurate analytical method based on ultra performance liquid chromatography (UPLC) combined with electrospray ionization (ESI) tandem mass spectrometry (MS/MS) on a hybrid quadrupole time of flight (QTOF) instrument has been developed and fully validated for the quantification of CS in human plasma. After the pretreatment of plasma samples by solid phase extraction (SPE) and the addition of the internal standard (reserpine, RSP) the analytes were chromatographed on an Acquity BEH C8 column (100 mm × 2.1 mm, 1.7 μm) using gradient elution with 0.5% aqueous acetic acid (AcOH) and acetonitrile with 0.5% AcOH (with CSA and CSB eluting at 1.39 and 1.31 min, respectively). Accurate mass measurement correction was performed on line using the leukine-enkephaline standard. The method presented good fit (regression coefficient≥0.998) over the quantitation range of 0.2-300 and 0.03-4.5 μg mL(-1) with the lower limit of quantitation (LLOQ) being 0.02 and 0.03 μg mL(-1) for CSA and CSB in human plasma, respectively. The intra- and inter-day precision, measured as %relative standard deviation, was better than 10%, whereas the accuracy expressed as %relative error was also better than 10%. The short term, freeze-thaw (three cycles) and in process stability showed non-significant degradation of CS under these conditions. The validation results showed that the developed method demonstrated adequate selectivity and sensitivity. The method has been successfully applied to

  11. 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...

  12. Loratadine bioavailability via buccal transferosomal gel: formulation, statistical optimization, in vitro/in vivo characterization, and pharmacokinetics in human volunteers.

    Science.gov (United States)

    Elkomy, Mohammed H; El Menshawe, Shahira F; Abou-Taleb, Heba A; Elkarmalawy, Marwa H

    2017-11-01

    Loratadine (LTD) is an antihistaminic drug that suffers limited solubility, poor oral bioavailability (owing to extensive first-pass metabolism), and highly variable oral absorption. This study was undertaken to develop and statistically optimize transfersomal gel for transbuccal delivery of LTD. Transfersomes bearing LTD were prepared by conventional thin film hydration method and optimized using sequential Quality-by-Design approach that involved Placket-Burman design for screening followed by constrained simplex-centroid design for optimization of a Tween-80/Span-60/Span-80 mixture. The transferosomes were characterized for entrapment efficiency, particle size, and shape. Optimized transferosomes were incorporated in a mucoadhesive gel. The gel was characterized for rheology, ex vivo permeation across chicken pouch buccal mucosa, in vitro release, and mucoadhesion. Pharmacokinetic behavior of LTD formulations was investigated in healthy volunteers following administration of a single 10-mg dose. Optimal transferosomes characterized by submicron size (380 nm), spherical shape and adequate loading capacity (60%) were obtained by using quasi-equal ratio surfactant mixture. In terms of amount permeated, percentage released, and mucoadhesion time, the transferosomal gel proved superior to control, transferosome-free gel. Bioavailability of the transferosomal gel was comparable to Claritin® oral tablets. However, inter-individual variability in Cmax and AUC was reduced by 76 and 90%, respectively, when the buccal gel was used. Linear Correlation of in vitro release with in vivo buccal absorption fractions was established with excellent correlation coefficient (R2>0.97). In summary, a novel buccal delivery system for LTD was developed. However, further clinical investigation is warranted to evaluate its therapeutic effectiveness and utility.

  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. 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.

  15. Regulation of noradrenergic and serotonergic systems by cannabinoids: relevance to cannabinoid-induced effects.

    Science.gov (United States)

    Mendiguren, Aitziber; Aostri, Erik; Pineda, Joseba

    2018-01-01

    The cannabinoid system is composed of Gi/o protein-coupled cannabinoid type 1 receptor (CB1) and cannabinoid type 2 (CB2) receptor and endogenous compounds. The CB1 receptor is widely distributed in the central nervous system (CNS) and it is involved in the regulation of common physiological functions. At the neuronal level, the CB1 receptor is mainly placed at GABAergic and glutamatergic axon terminals, where it modulates excitatory and inhibitory synapses. To date, the involvement of CB2 receptor in the regulation of neurotransmission in the CNS has not been clearly shown. The majority of noradrenergic (NA) cells in mammalian tissues are located in the locus coeruleus (LC) while serotonergic (5-HT) cells are mainly distributed in the raphe nuclei including the dorsal raphe nucleus (DRN). In the CNS, NA and 5-HT systems play a crucial role in the control of pain, mood, arousal, sleep-wake cycle, learning/memory, anxiety, and rewarding behaviour. This review summarizes the electrophysiological, neurochemical and behavioural evidences for modulation of the NA/5-HT systems by cannabinoids and the CB1 receptor. Cannabinoids regulate the neuronal activity of NA and 5-HT cells and the release of NA and 5-HT by direct and indirect mechanisms. The interaction between cannabinoid and NA/5-HT systems may underlie several behavioural changes induced by cannabis such as anxiolytic and antidepressant effects or side effects (e.g. disruption of attention). Further research is needed to better understand different aspects of NA and 5-HT systems regulation by cannabinoids, which would be relevant for their use in therapeutics. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. 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.

  17. Effects of cannabinoids and their receptors on viral infections.

    Science.gov (United States)

    Tahamtan, Alireza; Tavakoli-Yaraki, Masoumeh; Rygiel, Tomasz P; Mokhtari-Azad, Talat; Salimi, Vahid

    2016-01-01

    Cannabinoids, the active ingredient in marijuana, and their derivatives have received remarkable attention in the last two decades because they can affect tumor growth and metastasis. There is a large body of evidence from in vivo and in vitro models showing that cannabinoids and their receptors influence the immune system, viral pathogenesis, and viral replication. The present study reviews current insights into the role of cannabinoids and their receptors on viral infections. The results reported here indicate that cannabinoids and their receptors have different sequels for viral infection. Although activation or inhibition of cannabinoid receptors in the majority of viral infections are proper targets for development of safe and effective treatments, caution is required before using pharmaceutical cannabinoids as a treatment agent for patients with viral infections. © 2015 Wiley Periodicals, Inc.

  18. Cannabinoid-induced autophagy: Protective or death role?

    Science.gov (United States)

    Costa, Lia; Amaral, Cristina; Teixeira, Natércia; Correia-da-Silva, Georgina; Fonseca, Bruno M

    2016-01-01

    Autophagy, the "self-digestion" mechanism of the cells, is an evolutionary conserved catabolic process that targets portions of cytoplasm, damaged organelles and proteins for lysosomal degradation, which plays a crucial role in development and disease. Cannabinoids are active compounds of Cannabis sativa and the most prevalent psychoactive substance is Δ(9)-tetrahydrocannabinol (THC). Cannabinoid compounds can be divided in three types: the plant-derived natural products (phytocannabinoids), the cannabinoids produced endogenously (endocannabinoids) and the synthesized compounds (synthetic cannabinoids). Various studies reported a cannabinoid-induced autophagy mechanism in cancer and non-cancer cells. In this review we focus on the recent advances in the cannabinoid-induced autophagy and highlight the molecular mechanisms involved in these processes. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. 75 FR 71635 - Schedules of Controlled Substances: Temporary Placement of Five Synthetic Cannabinoids Into...

    Science.gov (United States)

    2010-11-24

    ... with these synthetic cannabinoids and their related products including agitation, anxiety, vomiting... cannabinoids is geared towards teens and young adults. Despite disclaimers that the products are not intended...

  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. Constitutive activity of the cannabinoid CB1 receptor regulates the function of co-expressed Mu opioid receptors.

    Science.gov (United States)

    Canals, Meritxell; Milligan, Graeme

    2008-04-25

    The human mu opioid receptor was expressed stably in Flp-In T-REx HEK293 cells. Occupancy by the agonist DAMGO (Tyr-d-Ala-Gly-N-methyl-Phe-Gly-ol) resulted in phosphorylation of the ERK1/2 MAP kinases, which was blocked by the opioid antagonist naloxone but not the cannabinoid CB1 receptor inverse agonist SR141716A. Expression of the human cannabinoid CB1 receptor in these cells from the inducible Flp-In T-REx locus did not alter expression levels of the mu opioid receptor. This allowed the cannabinoid CB1 agonist WIN55212-2 to stimulate ERK1/2 phosphorylation but resulted in a large reduction in the capacity of DAMGO to activate these kinases. Although lacking affinity for the mu opioid receptor, co-addition of SR141716A caused recovery of the effectiveness of DAMGO. In contrast co-addition of the CB1 receptor neutral antagonist O-2050 did not. Induction of the CB1 receptor also resulted in an increase of basal [(35)S]guanosine 5'-3-O-(thio)triphosphate (GTPgammaS) binding and thereby a greatly reduced capacity of DAMGO to further stimulate [(35)S]GTPgammaS binding. CB1 inverse agonists attenuated basal [(35)S]GTPgammaS binding and restored the capacity of DAMGO to stimulate. Flp-In T-REx HEK293 cells were generated, which express the human mu opioid receptor constitutively and harbor a modified D163N cannabinoid CB1 receptor that lacks constitutive activity. Induction of expression of the modified cannabinoid CB1 receptor did not limit DAMGO-mediated ERK1/2 MAP kinase phosphorylation and did not allow SR141716A to enhance the function of DAMGO. These data indicate that it is the constitutive activity inherent in the cannabinoid CB1 receptor that reduces the capacity of co-expressed mu opioid receptor to function.

  2. Effects of cannabinoid drugs on aversive or rewarding drug-associated memory extinction and reconsolidation.

    Science.gov (United States)

    Stern, Cristina A J; de Carvalho, Cristiane R; Bertoglio, Leandro J; Takahashi, Reinaldo N

    2017-07-17

    Posttraumatic stress and drug use disorders may stem from aberrant memory formation. As the endocannabinoid (eCB) system has a pivotal role in emotional memory processing and related synaptic plasticity, here we seek to review and discuss accumulating evidence on how and where in the brain interventions targeting the eCB system would attenuate outcomes associated with traumatic events and/or drug addiction through memory extinction facilitation or reconsolidation disruption. Currently available data from mouse, rat, monkey and healthy human studies investigating the effects of cannabinoid drugs on extinction and reconsolidation of aversive memories are more consistent than those related to rewarding drug-associated memories. Interventions able to attenuate aversive memories by extinction facilitation or reconsolidation disruption have boosted the anandamide-induced activation of cannabinoid type-1 (CB1) receptors. A still limited number of studies report that CB1 receptor activation could also be effective in facilitating the extinction or disrupting the reconsolidation of rewarding drug-associated memories. The reinstatement of extinguished drug memories (relapse) is reduced by CB1 receptor antagonism. The cannabidiol has shown to be effective in any of the aforementioned cases, albeit its mechanism of action is not fully understood. Brain areas in which cannabinoid drugs induce these effects include the prefrontal cortex, amygdala, hippocampus, and/or nucleus accumbens. The potential role of 2-arachidonoylglycerol (2-AG) and cannabinoid type-2 (CB2) receptors in emotional memory extinction and reconsolidation is currently under investigation. Overall, preclinical data support a closer look into certain cannabinoid drugs owing to their safety and potential therapeutic value against stress-related and drug use disorders. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  3. 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.

  4. Involvement of central and peripheral cannabinoid receptors on antinociceptive effect of tetrahydrocannabinol in muscle pain.

    Science.gov (United States)

    Bagüés, Ana; Martín, M Isabel; Sánchez-Robles, Eva M

    2014-12-15

    Cannabinoid (CB) receptors have emerged as an attractive therapeutic target for pain management in recent years and the interest in the use of cannabinoids is gradually increasing, particularly in patients where conventional treatments fail. Muscle pain is a major clinical problem and new pharmacological approaches are being studied. Recently, we have demonstrated that cannabinoid synthetic agonists are useful to reduce muscular pain in two animal models, where the local administration is effective. Now, we want to know if tetrahydrocannabinol (THC), a cannabinoid natural derivative with therapeutic use in humans, is also effective in reducing acute muscle pain. The antinociceptive effect of THC by systemic (i.p.) and local (i.m.) administration was tested in two animal models of acute muscle pain, rat masseter and gastrocnemius, induced by hypertonic saline (HS) injection. The drugs used were the non-selective agonist THC and two selective cannabinoid antagonists, AM251 (CB1) and AM630 (CB2). THC, i.p. and i.m. administered, reduced the nociceptive behaviours induced by HS in both muscular pain models. The antinociceptive effect induced by the systemic administration of THC was mediated by CB1 receptors in the masseter muscle whereas in gastrocnemius both CB1 and CB2 receptors participated. When THC was administered locally, only CB2 receptors were involved in the antinociceptive effect in both muscles. This study suggests that THC could be a future pharmacological option in the treatment of muscle pain. The local administration of THC could be an interesting option to treat this type of pain avoiding the central adverse effects. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Chronic psychoemotional stress impairs cannabinoid-receptor-mediated control of GABA transmission in the striatum.

    Science.gov (United States)

    Rossi, Silvia; De Chiara, Valentina; Musella, Alessandra; Kusayanagi, Hajime; Mataluni, Giorgia; Bernardi, Giorgio; Usiello, Alessandro; Centonze, Diego

    2008-07-16

    Exposure to stressful events has a myriad of consequences in animals and in humans, and triggers synaptic adaptations in many brain areas. Stress might also alter cannabinoid-receptor-mediated transmission in the brain, but no physiological study has addressed this issue so far. In the present study, we found that social defeat stress, induced in mice by exposure to aggression, altered cannabinoid CB(1)-receptor-mediated control of synaptic transmission in the striatum. In fact, the presynaptic inhibition of GABAergic IPSCs induced by the cannabinoid CB(1) receptor agonist HU210 [(6aR)-trans-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol] was reduced after a single stressful episode and fully abolished after 3 and 7 d of stress exposure. Repeated psychoemotional stress also impaired the sensitivity of GABA synapses to endocannabinoids mobilized by group I metabotropic glutamate receptor stimulation, whereas the cannabinoid CB(1)-mediated control of glutamate transmission was unaffected by repeated exposure to an aggressor. Corticosteroids released in response to the activation of the hypothalamic-pituitary-adrenal axis played a major role in the synaptic defects observed in stressed animals, because these alterations were fully prevented by pharmacological blockade of glucocorticoid receptors and were mimicked by corticosterone injections. The recovery of stress-induced synaptic defects was favored when stressed mice were given access to a running wheel or to sucrose consumption, which function as potent natural rewards. A similar rescuing effect was obtained by a single injection of cocaine, a psychostimulant with strong rewarding properties. Targeting cannabinoid CB(1) receptors or endocannabinoid metabolism might be a valuable option to treat stress-associated neuropsychiatric conditions.

  6. Simultaneous determination of blonanserin and its metabolite in human plasma and urine by liquid chromatography-tandem mass spectrometry: application to a pharmacokinetic study.

    Science.gov (United States)

    Wen, Yu-Guan; Ni, Xiao-Jia; Zhang, Ming; Liu, Xia; Shang, De-Wei

    2012-08-15

    Blonanserin is a novel atypical antipsychotic with highly selective receptor antagonist activity to dopamine D₂ and 5-HT(2A). N-desethyl blonanserin (blonanserin C) is its major active metabolite in human plasma. Herein we report a new highly sensitive, selective, and rapid liquid chromatography-tandem mass spectrometry method to determine blonanserin and blonanserin C simultaneously in human plasma and urine, with N-desethyl-chlor-blonanserin (blonanserin D) as internal standard (IS). Blonanserin and blonanserin C were extracted from aliquots of plasma and urine with ethyl acetate and dichloromethane (4:1) as the solvent and chromatographic separation was performed using an Agilent Eclipse Plus C₁₈ column. The mobile phase was composed of: acetonitrile and ammonium formate-formic acid buffer containing 5mM ammonium formate and 0.1% formic acid (87:13, v/v). To quantify blonanserin, blonanserin C, and blonanserin D, respectively, multiple reaction monitoring (MRM) transition of m/z 368.2→297.2, m/z 340.2→297.1, and m/z 356.2→313.3 was performed in positive mode. The analysis time was about 5.5 min. The calibration curve was linear in the concentration range of 0.01-2 ng/ml. The lower limit of quantification reached 0.01 ng/ml. The intra and inter-day precision and relative errors were less than 8.0% and 6.6% for three QC levels in plasma and urine. The current LC-MS/MS method was validated as simple, sensitive, and accurate and has been successfully applied to investigate the pharmacokinetics of blonanserin and blonanserin C in humans. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. Use of bile correction factors for allometric prediction of human pharmacokinetic parameters of torcetrapib, a facile cholesteryl ester transfer protein inhibitor.

    Science.gov (United States)

    Mullangi, Ramesh; Ahlawat, Preeti; Trivedi, Ravi K; Srinivas, Nuggehally R

    2009-01-01

    Torcetrapib was the lead candidate belonging to the class of cholesteryl ester transfer protein (CETP) inhibitor which was being developed for the management of cardiovascular risk factors by raising HDL. The availability of pharmacokinetic parameters (clearance: CL/F, volume of distribution: Vd/F, elimination rate constant: K(el) and elimination half-life: t(l/2)) in mice, rats and monkeys, enabled the prediction of human parameter values using the well accepted tool of allometry. Although allometry work has been largely restricted to intravenous drugs, the present case of torcetrapib showed that allometry may be equally applicable to oral route. Simple allometry appeared to markedly inflate the human parameters for CL/F, Vd/F, K(el), and t(1/2). However, the application of bile correction factors provided allometric equations of 0.2486W(0.877) (R2 = 0.9416), 1.4723W(1.8263) (R2 = 0.8873), 0.1685W(-095) (R2 = 0.828) and 4.1044W(0.493) (R2 = 0.9337) for CL/F, Vd/F, K(el) and t(1/2), rendering a closer prediction of human parameter values. Accordingly, the predicted (observed) values of torcetrapib were 10.3 L/h (15.8 L/h), 3449 L (4810 L), 0.00298 h(-1) (0.00328 h(-1)) and 211 h (231 h) for CL/F, Vd/F, K(el) and t(1/2), respectively. In summary, the data suggested that allometry tool with appropriate bile correction factors could be effectively used in a prospective manner for other orally administered CETP inhibitors.

  8. Cannabinoider i behandling av kroniske smertetilstander : En systematisk litteraturgjennomgang

    OpenAIRE

    Viken, Erlend; Osnes, John Erik

    2006-01-01

    Objective: To establish whether cannabis is an effective and safe analgesic in chronic painful conditions. Background: The medical applications of Cannabis have long been a focus of public and scientific interest. Cannabinoids are the active compounds extracted from the Cannabis Sativa plant. Recently there has been renewed interest in cannabinoids for medicinal purposes. The discovery of cannabinoid CB1/CB2 receptors and endogenous ligands, has shed new light on the therapeutic potential...

  9. The effect of the once-daily human glucagon-like peptide 1 analog liraglutide on the pharmacokinetics of acetaminophen.

    Science.gov (United States)

    Kapitza, Christoph; Zdravkovic, Milan; Hindsberger, Charlotte; Flint, Anne

    2011-08-01

    Acetaminophen is a commonly used analgesic and antipyretic drug, and is frequently used to study gastric emptying. Due to its high permeability and high solubility, acetaminophen can be used as a pharmacologic model for medications with similar characteristics. The objective of this study was to assess the effect of liraglutide on the pharmacokinetics (PK) of acetaminophen in patients with type 2 diabetes. This was a randomized, placebo-controlled, two-period crossover trial in which subjects with type 2 diabetes received placebo or liraglutide. After steady state PK of liraglutide 1.8 mg/ placebo were established, a single dose of acetaminophen 1 g was administered at the time of liraglutide C(max) (maximum concentration). The PK profile of acetaminophen was assessed at 18 time points during the 8-hour post-dosing period. Placebo and liraglutide were considered equivalent with respect to area under the curve (AUC)(0-∞) and AUC(0-480) min of acetaminophen if the 90% CI for the ratio was fully contained within the limits of 0.80 to 1.25. All subjects (n=18; mean [SD] age 59 [7] years, body mass index [BMI] 29.7 [4.2] kg/m(2), and glycated hemoglobin [HbA(1c)] 7.8% [0.6%]) completed the study. Equivalence was demonstrated between liraglutide 1.8 mg at steady state and placebo, with respect to acetaminophen AUC(0-∞) (estimated ratio 1.04; 90% CI: 0.97, 1.10) and acetaminophen AUC(0-480) min (estimated ratio 0.95; 90% CI: 0.89, 1.01). During liraglutide, a lower C(max) was observed (estimated ratio 0.69; 90% CI: 0.56, 0.85) and the median acetaminophen t(max) occurred 15 minutes later compared with placebo. The overall exposure of acetaminophen following a 1 g dose was comparable for subjects taking liraglutide or placebo, and the clinical impact of the lower C(max) and delay in absorption of acetaminophen was considered to be transient and small, and without clinical relevance. No adjustment for acetaminophen is recommended when used concomitantly with liraglutide.

  10. Development, validation of liquid chromatography-tandem mass spectrometry method for simultaneous determination of rosuvastatin and metformin in human plasma and its application to a pharmacokinetic study

    Directory of Open Access Journals (Sweden)

    P Pavan Kumar

    2015-01-01

    Full Text Available A new, simple and accurate liquid chromatography-tandem mass spectrometry (LC-MS/MS method for simultaneous determination of rosuvastatin (ROS and metformin (MET in human plasma was developed. The assay procedure involved simple protein precipitation with acetonitrile. Following precipitation, fraction of supernatant was decanted and evaporated under gentle stream of nitrogen at 40΀C. The residue was reconstituted in mobile phase and injected. The chromatographic separation was achieved with Thermo Hypurity C18 column (50 mm Χ 4.6 mm, 5 μ using a mobile phase composition containing 0.1% v/v formic acid in water and acetonitrile (30:70, v/v at a flow rate of 0.4 mL/min. The total run time was 3.5 min. The method showed good linearity in the range 0.5-200 ng/mL for ROS and 2-2000 ng/mL for MET with correlation coefficient (r >0.9994 for both the analytes. The intra and inter-day precision values for ROS and MET met the acceptance criteria as per regulatory guidelines. The battery of stability studies viz., bench-top, freeze-thaw and long term stability were performed. The developed method was applied to a pharmacokinetic study.

  11. Safety and pharmacokinetics of the anti-orthopoxvirus compound ST-246 following a single daily oral dose for 14 days in human volunteers.

    Science.gov (United States)

    Chinsangaram, Jarasvech; Honeychurch, Kady M; Tyavanagimatt, Shanthakumar R; Leeds, Janet M; Bolken, Tove' C; Jones, Kevin F; Jordan, Robert; Marbury, Thomas; Ruckle, Jon; Mee-Lee, Denis; Ross, Eric; Lichtenstein, Israel; Pickens, Margaret; Corrado, Michael; Clarke, Jean M; Frimm, Annie M; Hruby, Dennis E

    2012-09-01

    ST-246 is being evaluated as a treatment for pathogenic orthopoxvirus infections in humans. To this end, a phase 2, double-blind, randomized, placebo-controlled, multicenter trial was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of ST-246 when administered as a single daily oral dose (400 mg or 600 mg) for 14 days in fed adult volunteers. ST-246 was safe and well tolerated, with no deaths or serious adverse events reported during the study. There was a low incidence of treatment-emergent adverse events (TEAEs), the most common of which were mild nausea and headache. There were no clinically significant results from laboratory assessments, vital sign measurements, physical examinations, or electrocardiograms. The PK and dose proportionality of ST-246 were determined. The PK analysis showed that steady state was achieved by day 5 for the ST-246 400-mg treatment group and by day 6 for the 600-mg group. The dose proportionality analysis showed that the 400- and 600-mg ratio of dose-normalized peak drug concentration in plasma (C(max)) and relative exposure for each dosing interval (AUC(τ)) ranged from 80% to 85%. However, the 90% confidence intervals did not include 1.0, so dose proportionality could not be concluded. Overall, ST-246 was shown to be safe, and the PK was predictable. These results support further testing of ST-246 in a multicenter pivotal clinical safety study for licensure application.

  12. Comparison of LC-UV and LC-MS methods for simultaneous determination of teriflunomide, dimethyl fumarate and fampridine in human plasma: application to rat pharmacokinetic study.

    Science.gov (United States)

    Suneetha, A; Raja, Rajeswari K

    2016-09-01

    This study describes a comparison between LC-UV and LC-MS method for the simultaneous analyses of a few disease-modifying agents of multiple sclerosis. Quantitative determination of fampridine (FAM), teriflunomide (TFM) and dimethyl fumarate (DMF) was performed in human plasma with the recovery values in the range of 85-115%. A reversed-phase high-performance liquid chromatography (HPLC) with UV as well as MS detection is used. The method utilizes an XBridge C18 silica column and a gradient elution with mobile phase consisting of ammonium formate and acetonitrile at a flow rate of 0.5 mL min(-1) . The method adequately resolves FAM, TFM and DMF within a run time of 15 min. Owing to low molecular weights, the estimation of DMF and FAM is more versatile in UV than MS detection. With LC-UV, the detection limits of FAM, TFM and DMF were 0.1, 0.05, 0.05 μg and the quantification limit for all the analytes was 1 μg. With LC-MS, the detection and quantification limits for all of the analytes were 1 and 5 ng, respectively. The two techniques were completely validated and shown to be reproducible and sensitive. They were applied to a pharmacokinetic study in rats by a single oral dose. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  13. Simultaneous determination of ambroxol and salbutamol in human plasma by ultra-performance liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study.

    Science.gov (United States)

    Guo, Zhening; Chen, Yangsheng; Ding, Xiaoliang; Huang, Chenrong; Miao, Liyan

    2016-11-01

    A rapid, selective and sensitive liquid chromatography-tandem mass spectrometry assay method was developed for simultaneous determination of ambroxol and salbutamol in human plasma using citalopram hydrobromide as internal standard (IS). The sample was alkalinized with ammonia water (33:67, v/v) and extracted by single liquid-liquid extraction with ethyl acetate. Separation was achieved on Waters Acquity UPLC BEH C18 column using a gradient program at a flow rate of 0.2 mL/min. Detection was performed using electrospray ionization in positive ion multiple reaction monitoring mode by monitoring the ion transitions m/z 378.9 → 263.6 (ambroxol), m/z 240.2 → 147.7 (salbutamol) and m/z 325.0 → 261.7 (IS). The total analytical run time was relatively short (3 min). Calibration curves were linear in the concentration range of 0.5-100.0 ng/mL for ambroxol and 0.2-20.0 ng/mL for salbutamol, with intra- and inter-run precision (relative standard deviation) ambroxol and from 94.5 to 104.1% for salbutamol. The method was successfully applied in a clinical pharmacokinetic study of the compound ambroxol and salbutamol tablets. Copyright © 2016 John Wiley & Sons, Ltd.

  14. HPLC-MS/MS method for the simultaneous quantification of desmethylmebeverine acid, mebeverine acid and mebeverine alcohol in human plasma along with its application to a pharmacokinetics study.

    Science.gov (United States)

    Moskaleva, Natalia E; Baranov, Pavel A; Mesonzhnik, Natalia V; Appolonova, Svetlana A

    2017-05-10

    A new simple, rapid and sensitive high pressure liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed and validated for simultaneous analysis of mebeverine metabolites as: mebeverine alcohol (MAL), mebeverine acid (MAC) and desmethylmebeverine acid (DMAC) in human plasma. Sample preparation was performed by protein precipitation following the separation of analytes using an Acquity UPLC BEN C8 column 1.7 mm 2.1×50mm (Waters, USA). 2H5-desmethylmebeverine acid (2H5-DMAC) was used as the internal standard (IS). The proposed method was validated with linear ranges of 0.1-10ng/mL; 1-100ng/mL and 5-1000ng/mL for MAL, MAC and DMAC, respectively. Accuracy for all analytes (%RE), given as deviation between nominal and measured concentration and assay variability (CV) ranged from -4.04% to 4.60% and from 0.31% to 6.43% respectively both for within- and between-run. The overall recoveries for all metabolites were above 85%. The proposed method was used successfully for analysis of real samples from a pharmacokinetics study. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Cannabinoid-induced alterations in brain disposition of drugs of abuse.

    Science.gov (United States)

    Reid, M J; Bornheim, L M

    2001-06-01

    Marijuana contains a complex mixture of compounds including tetrahydrocannabinol (THC), the major psychoactive constituent, and cannabidiol (CBD), a nonpsychoactive constituent. We have shown previously that CBD pretreatment of mice increases brain levels of THC and have now further characterized this effect and determined whether the brain pharmacokinetics of other drugs are also affected. CBD pretreatment of mice (30-60 min) increased brain levels of THC nearly 3-fold, whereas CBD co-administration did not. Because marijuana is often consumed with other drugs, the influence of cannabinoids on the brain levels of several other drugs of abuse was also determined. CBD pretreatment of mice increased brain levels (2- to 4-fold) of subsequently administered cocaine as well as phencyclidine (PCP). Although CBD pretreatment increased blood and brain levels of cocaine comparably, blood levels of PCP were only modestly elevated (up to 50%). Behavioral tests indicated that the CBD-mediated increases in the brain levels of THC, cocaine, and PCP correlated with increased pharmacological responses. Pretreatment with THC instead of CBD could similarly increase brain levels of cocaine, PCP, and CBD, although with a lower potency than CBD. On the other hand, pretreatment of mice with CBD had no effect on the brain levels of several other drugs of abuse including morphine, methadone, or methylenedioxyphenyl-methamphetamine. These findings demonstrate that cannabinoids can increase the brain concentrations and pharmacological actions of several other drugs of abuse, thereby providing a biochemical basis for the common practice of using marijuana concurrently with such drugs.

  16. Influence of 22-day treatment on the anticonvulsant properties of cannabinoids.

    Science.gov (United States)

    Karler, R; Borys, H K; Turkanis, S A

    1982-08-01

    Mice were given delta-9-tetrahydrocannabinol (delta-9-THC) cannabidiol (CBD) or phenytoin (PHT) daily for 22 days. Drug activity was measured weekly in three different anticonvulsant tests: the maximal electroshock threshold, the 60-Hz-electroshock threshold and the 6-Hz-electroshock threshold. In order to correlate potential pharmacodynamic and pharmacokinetic changes resulting from repeated treatment, brain-drug concentrations were determined at each test time. The results from the delta-9-THC study indicate that, although tolerance developed in all three tests, there were no changes in the brain-drug concentration. For CBD the pharmacodynamics were strikingly different: an increase in sensitivity to the drug developed in two of the tests, tolerance in only one test. Here again, there were no changes in brain-drug concentrations. The results of the PHT study differed from both the cannabinoids, for tolerance developed in one test, an increase in sensitivity in one test, and the activity was unchanged in the third test. Again, the brain concentrations remained constant throughout. The results demonstrate that both tolerance and increased sensitivity can develop concomitantly with anticonvulsant effects of the cannabinoids and PHT, and that these modifications in drug activity appear to result from cellular or functional rather than dispositional changes.

  17. Drug Distribution to Human Tissues: Prediction and Examination of the Basic Assumption in In Vivo Pharmacokinetics-Pharmacodynamics (PK/PD) Research.

    Science.gov (United States)

    Poulin, Patrick

    2015-06-01

    The tissue:plasma partition coefficients (Kp ) are good indicators of the extent of tissue distribution. Therefore, advanced tissue composition-based models were used to predict the Kp values of drugs under in vivo conditions on the basis of in vitro and physiological input data. These models, however, focus on animal tissues and do not challenge the predictions with human tissues for drugs. The first objective of this study was to predict the experimentally determined Kp values of seven human tissues for 26 drugs. In all, 95% of the predicted Kp values are within 2.5-fold error of the observed values in humans. Accordingly, these results suggest that the tissue composition-based model used in this study is able to provide accurate estimates of drug partitioning in the studied human tissues. Furthermore, as the Kp equals to the ratio of total concentration between tissue and plasma, or the ratio of unbound fraction between plasma (fup ) and tissue (fut ), this parameter Kp would deviate from the unity. Therefore, the second objective was to examine the corresponding relationships between fup and fut values experimentally determined in humans for several drugs. The results also indicate that fup may significantly deviate to fut ; the discrepancies are governed by the dissimilarities in the binding and ionization on both sides of the membrane, which were captured by the tissue composition-based model. Hence, this violated the basic assumption in in vivo pharmacokinetics-pharmacodynamics (PK/PD) research, since the free drug concentration in tissue and plasma was not equal particularly for the ionizable drugs due to the pH gradient effect on the fraction of unionized drug in plasma (fuip ) and tissue (fuit ) (i.e., fup × fuip × total plasma concentration = fut × fuit × total tissue concentration, and, hence, the free drug concentration in plasma and tissue differed by fuip/fuit). Therefore, this assumption should be adjusted for the ionized drugs, and, hence, a

  18. 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

  19. A Gut Gone to Pot: A Case of Cannabinoid Hyperemesis Syndrome due to K2, a Synthetic Cannabinoid

    OpenAIRE

    Anene Ukaigwe; Paras Karmacharya; Anthony Donato

    2014-01-01

    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...

  20. 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.

  1. Implication of cannabinoids in neurological diseases.

    Science.gov (United States)

    Alsasua del Valle, Angela

    2006-01-01

    1. Preparations from Cannabis sativa (marijuana) have been used for many centuries both medicinally and recreationally. 2. Recent advances in the knowledge of its pharmacological and chemical properties in the organism, mainly due to Delta(9)-tetrahydrocannabinol, and the physiological roles played by the endocannabinoids have opened up new strategies in the treatment of neurological and psychiatric diseases. 3. Potential therapeutic uses of cannabinoid receptor agonists include the management of spasticity and tremor in multiple sclerosis/spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, cancer, and vasodilation that accompanies advanced cirrhosis. CB(1) receptor antagonists have therapeutic potential in Parkinson's disease. 4. Dr. Julius Axelrod also contributed in studies on the neuroprotective actions of cannabinoids.

  2. 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.

  3. Pharmacokinetics of anthocyanins and antioxidant effects after the consumption of anthocyanin-rich acai juice and pulp (Euterpe oleracea Mart.) in human healthy volunteers.

    Science.gov (United States)

    Mertens-Talcott, Susanne U; Rios, Jolian; Jilma-Stohlawetz, Petra; Pacheco-Palencia, Lisbeth A; Meibohm, Bernd; Talcott, Stephen T; Derendorf, Hartmut

    2008-09-10

    The acai berry is the fruit of the acai palm and is traditionally consumed in Brazil but has gained popularity abroad as a food and functional ingredient, yet little information exists on its health effect in humans. This study was performed as an acute four-way crossover clinical trial with acai pulp and clarified acai juice compared to applesauce and a non-antioxidant beverage as controls. Healthy volunteers (12) were dosed at 7 mL/kg of body weight after a washout phase and overnight fast, and plasma was repeatedly sampled over 12 h and urine over 24 h after consumption. Noncompartmental pharmacokinetic analysis of total anthocyanins quantified as cyanidin-3-O-glucoside showed Cmax values of 2321 and 1138 ng/L at t max times of 2.2 and 2.0 h, and AUC last values of 8568 and 3314 ng h L(-1) for pulp and juice, respectively. Nonlinear mixed effect modeling identified dose volume as a significant predictor of relative oral bioavailability in a negative nonlinear relationship for acai pulp and juice. Plasma antioxidant capacity was significantly increased by the acai pulp and applesauce. Individual increases in plasma antioxidant capacity of up to 2.3- and 3-fold for acai juice and pulp, respectively were observed. The antioxidant capacity in urine, generation of reactive oxygen species, and uric acid concentrations in plasma were not significantly altered by the treatments. Results demonstrate the absorption and antioxidant effects of anthocyanins in acai in plasma in an acute human consumption trial.

  4. 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.

  5. 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.

  6. [Therapeutical use of the cannabinoids in psychiatry].

    Science.gov (United States)

    Crippa, José Alexandre S; Zuardi, Antonio Waldo; Hallak, Jaime E C

    2010-05-01

    To review the main advances related to the potential therapeutic use of cannabinoid compounds in psychiatry. A search was performed in the online databases PubMed, ScieELO, and Lilacs for studies and literature reviews concerning therapeutic applications of cannabinoids in psychiatry, especially cannabidiol, rimonabant, Delta(9)-tetrahydrocannabinol, and their analogues. Cannabidiol was found to have therapeutic potential with antipsychotic, anxiolytic, and antidepressant properties, in addition to being effective in other conditions. Delta(9)-tetrahydrocannabinol and its analogues were shown to have anxiolytic effects in the treatment of cannabis dependence and to function as an adjuvant in the treatment of schizophrenia, although additional studies are necessary to support this finding. Rimonabant was effective in the treatment of the subjective and physiological symptoms of cannabis intoxication and functioned as an adjuvant in the treatment of tobacco addiction. The potential to induce adverse reactions such as depression and anxiety restrained the clinical use of this CB(1) antagonist. Cannabinoids may be of great therapeutic interest to psychiatry; however, further controlled trials are necessary to confirm the existing findings and to establish the safety of such compounds.

  7. The discovery of a cannabinoid receptor

    Energy Technology Data Exchange (ETDEWEB)

    Devane, W.A.

    1989-01-01

    A tritiated form of CP-55,940, a Pfizer cannabinoid analog that is 20- to 100-fold more potent than {Delta}{sup 9}-tetrahydrocannabinol in various in vivo and in vitro models of cannabimimetric activity, was used as the tool with which to probe for a cannabinoid receptor in rat cortical membranes. The bound and free ligand were successfully separated using a centrifugation assay. Specific binding was saturable, rapidly attained, and completely reversible. The K{sub D}'s derived from kinetic analysis of binding agreed well with the K{sub D}'s derived from saturation and displacement analysis. The ({sup 3}H)CP-55,940 binding site exhibited high affinity with a K{sub D} of 68 pM as determined by LIGAND analysis of homologous displacement studies. The ability of other cannabinoid drugs to displace ({sup 3}H)CP-55,940 binding correlated well with the potency of these drugs in in vivo and in vitro models of cannabimimetic activity. The K{sub i} of {Delta}{sup 9}-THC was 1.6 nM. Cannabidiol and cannabigerol, which both lack psychoactivity in man, displaced specific binding by less than 50% at 1 {mu}M.

  8. Preclinical Metabolism and Disposition of SB939 (Pracinostat), an Orally Active Histone Deacetylase Inhibitor, and Prediction of Human Pharmacokinetics

    NARCIS (Netherlands)

    Jayaraman, Ramesh; Reddy, Venkatesh Pilla; Pasha, Mohammed Khalid; Wang, Haishan; Sangthongpitag, Kanda; Yeo, Pauline; Hu, Chang Yong; Wu, Xiaofeng; Xin, Liu; Goh, Evelyn; New, Lee Sun; Ethirajulu, Kantharaj

    2011-01-01

    The preclinical absorption, distribution, metabolism, and excretion (ADME) properties of Pracinostat [(2E)-3-[2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl]-N-hydroxyarylamide hydrochloride; SB939], an orally active histone deacetylase inhibitor, were characterized and its human

  9. Plasma and cerebrospinal fluid pharmacokinetics of the histone deacetylase inhibitor, belinostat (PXD101), in non-human primates

    DEFF Research Database (Denmark)

    Warren, K.E.; McCully, C.; Dvinge, H.

    2008-01-01

    is a novel, potent, pan-HDAC inhibitor with antiproliferative activity on a wide variety of tumor cell lines. We studied the cerebrospinal fluid (CSF) penetration of intravenous (IV) belinostat in a non-human primate model as a surrogate for blood:brain barrier penetration. DESIGN: Five adult rhesus monkeys...

  10. 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.

  11. 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.

  12. Combination Chemistry: Structure-Activity Relationships of Novel Psychoactive Cannabinoids.

    Science.gov (United States)

    Wiley, Jenny L; Marusich, Julie A; Thomas, Brian F

    2017-01-01

    Originally developed as research tools for use in structure-activity relationship studies, synthetic cannabinoids contributed to significant scientific advances in the cannabinoid field. Unfortunately, a subset of these compounds was diverted for recreational use beginning in the early 2000s. As these compounds were banned, they were replaced with additional synthetic cannabinoids with increasingly diverse chemical structures. This chapter focuses on integration of recent results with those covered in previous reviews. Whereas most of the early compounds were derived from the prototypic naphthoylindole JWH-018, currently popular synthetic cannabinoids include tetramethylcyclopropyl ketones and indazole-derived cannabinoids (e.g., AB-PINACA, AB-CHMINACA). Despite their structural differences, psychoactive synthetic cannabinoids bind with high affinity to CB1 receptors in the brain and, when tested, have been shown to activate these receptors and to produce a characteristic profile of effects, including suppression of locomotor activity, antinociception, hypothermia, and catalepsy, as well as Δ9-tetrahydrocannabinol (THC)-like discriminative stimulus effects in mice. When they have been tested, synthetic cannabinoids are often found to be more efficacious at activation of the CB1 receptor and more potent in vivo. Further, their chemical alteration by thermolysis during use and their uncertain stability and purity may result in exposure to degradants that differ from the parent compound contained in the original product. Consequently, while their intoxicant effects may be similar to those of THC, use of synthetic cannabinoids may be accompanied by unpredicted, and sometimes harmful, effects.

  13. 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

  14. Cannabinoids and Pain: Sites and Mechanisms of Action.

    Science.gov (United States)

    Starowicz, Katarzyna; Finn, David P

    2017-01-01

    The endocannabinoid system, consisting of the cannabinoid1 receptor (CB1R) and cannabinoid2 receptor (CB2R), endogenous cannabinoid ligands (endocannabinoids), and metabolizing enzymes, is present throughout the pain pathways. Endocannabinoids, phytocannabinoids, and synthetic cannabinoid receptor agonists have antinociceptive effects in animal models of acute, inflammatory, and neuropathic pain. CB1R and CB2R located at peripheral, spinal, or supraspinal sites are important targets mediating these antinociceptive effects. The mechanisms underlying the analgesic effects of cannabinoids likely include inhibition of presynaptic neurotransmitter and neuropeptide release, modulation of postsynaptic neuronal excitability, activation of the descending inhibitory pain pathway, and reductions in neuroinflammatory signaling. Strategies to dissociate the psychoactive effects of cannabinoids from their analgesic effects have focused on peripherally restricted CB1R agonists, CB2R agonists, inhibitors of endocannabinoid catabolism or uptake, and modulation of other non-CB1R/non-CB2R targets of cannabinoids including TRPV1, GPR55, and PPARs. The large body of preclinical evidence in support of cannabinoids as potential analgesic agents is supported by clinical studies demonstrating their efficacy across a variety of pain disorders. © 2017 Elsevier Inc. All rights reserved.

  15. The effects of synthetic cannabinoids on executive function.

    Science.gov (United States)

    Cohen, K; Kapitány-Fövény, M; Mama, Y; Arieli, M; Rosca, P; Demetrovics, Z; Weinstein, A

    2017-04-01

    There is a growing use of novel psychoactive substances (NPSs) including synthetic cannabinoids. Synthetic cannabinoid products have effects similar to those of natural cannabis but the new synthetic cannabinoids are more potent and dangerous and their use has resulted in various adverse effects. The purpose of the study was to assess whether persistent use of synthetic cannabinoids is associating with impairments of executive function in chronic users. A total of 38 synthetic cannabinoids users, 43 recreational cannabis users, and 41 non-user subjects were studied in two centers in Hungary and Israel. Computerized cognitive function tests, the classical Stroop word-color task, n-back task, and a free-recall memory task were used. Synthetic cannabinoid users performed significantly worse than both recreational and non-cannabis users on the n-back task (less accuracy), the Stroop task (overall slow responses and less accuracy), and the long-term memory task (less word recall). Additionally, they have also shown higher ratings of depression and anxiety compared with both recreational and non-users groups. This study showed impairment of executive function in synthetic cannabinoid users compared with recreational users of cannabis and non-users. This may have major implications for our understanding of the long-term consequences of synthetic cannabinoid based drugs.

  16. Cannabinoids:their role in pain and palliation.

    Science.gov (United States)

    McCarberg, Bill H

    2007-01-01

    Controversy is associated with the issue of cannabis and cannabinoids in clinical care in the United States. Recent research has demonstrated the underlying mechanisms of cannabinoid analgesia via endocannabinoids, an endogenous system of retrograde neuromodulatory messengers that work in tandem with endogenous opioids. Additional receptor and non-receptor mechanisms of cannabinoid drugs have pertinent activity, including anti-carcinogenesis and neuroprotection, that may be of key importance in aging and terminal patient populations. The results of clinical trials with synthetic and plant-based cannabinoids suggest that the role of formulation and delivery system is critical in optimizing the risk-benefit profile of cannabinoid products. Synergy between opioids and cannabinoids may produce opioid-sparing effects, as well as extend the duration of analgesia and reduce opioid tolerance and dependence. This article reviews the mechanism of action of cannabinoids, examines marketed agents and those in clinical trials, and addresses their role in treatment of chronic pain, cancer, neurodegenerative diseases, and HIV/ AIDS. The ability of cannabinoid medicines to treat pain, associated sleep disorders, appetite loss, muscle spasm and a wide variety of other symptoms suggests that such agents may in the future play an important role in palliative care.

  17. Do cannabinoids have a role in cancer pain management?

    Science.gov (United States)

    Farquhar-Smith, W Paul

    2009-03-01

    Historically cannabinoids have been used for both therapy and recreation, yet the elucidation of the endocannabinoid system and their chemistry has been relatively recent. Prohibition of cannabis has meant few clinical trials, especially in cancer pain. This review will consider previous animal and clinical data and assess more recent investigations of clinical effectiveness of cannabinoids in pain and specifically cancer pain. Meta-analyses based on historical studies question the utility of cannabinoids in pain due to modest analgesia and problematic central side effects. However, there has been a resurgence in clinical trials of cannabis extracts and analogues. New data have contributed to the understanding of how cannabinoids work and proposed how to obtain analgesia unfettered by adverse effects. Moreover, recent clinical trials have demonstrated the current role of cannabinoids may be to attain small but significant benefit in refractory chronic and cancer pain. Cannabinoids may be a useful addition to current analgesic treatments. The evidence supports a possible role for cannabinoids in refractory cancer pain. However, to realize the full potential of cannabinoids suggested by preclinical data, it is likely that peripheral CB1 or CB2 receptors or modulation of endocannabinoids will have to be targeted to achieve analgesia without dose limiting side effects.

  18. Functional role of cannabinoid receptors in urinary bladder.

    Science.gov (United States)

    Tyagi, Pradeep; Tyagi, Vikas; Yoshimura, Naoki; Chancellor, Michael

    2010-01-01

    Cannabinoids, the active components of Cannabis sativa (maijuana), 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.

  19. Simultaneous Pharmacokinetic Modeling of Alkylresorcinols and Their Main Metabolites Indicates Dual Absorption Mechanisms and Enterohepatic Elimination in Humans

    DEFF Research Database (Denmark)

    Marklund, Matti; Strömberg, Eric A,; Lærke, Helle Nygaard

    2014-01-01

    a single dose (120 g) of rye bran and validated against fasting plasma concentrations from 8 women and 7 men with controlled rye bran intake (23, 45, or 90 g/d). Alkylresorcinols in the lymph and plasma of a pig fed a single alkylresorcinol dose (1.3 mmol) were quantified to assess absorption. Human...... of absorbed alkylresorcinols was metabolized before reaching the systemic circulation. Plasma concentrations of alkylresorcinols and their metabolites depended on absorption and formation, respectively, and the mean ± SEM terminal elimination half-life of alkylresorcinols (1.9 ± 0.59 h), DHPPA (1.5 ± 0.26 h......% of the alkylresorcinol dose was recovered in the lymph. DHPPA was identified in both human ileostomal effluent and pig bile, indicating availability of DHPPA for absorption and enterohepatic circulation.Conclusion: Intact alkylresorcinols have advantages over DHBA and DHPPA as plasma biomarkers for whole-grain wheat...

  20. 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.

    2012-01-01

    Background 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. Methods 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. Results Maximum whole blood THC occurred 3.0 h after the first oral THC dose and 103.5 h (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 1-5 h after a single oral THC dose and throughout multiple dosing, respectively. Models were only 60% and 12.5% accurate 12.5 and 22.5 h after the last THC dose, respectively. Conclusions 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. PMID:22464363

  1. 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.

  2. A rapid and sensitive HPLC method for the analysis of metronidazole in human plasma: application to single dose pharmacokinetic and bioequivalence studies

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    Jaber Emami

    2006-03-01

    Full Text Available A sensitive, accurate and rapid reverse phase HPLC method was developed to quantitate plasma levels of metronidazole in order to conduct a comparative bioavailability studies. The drug and internal standard were added to plasma samples, vortexed and then zinc sulfate solution was added in order to precipitate the plasma proteins. Samples were centrifuged at 3000 rpm for 10 min. The supernatant layer was separated and analyzed on a phenyl (300 × 4.6mm column, with 5% acetonitrile in 0.1 M KH2PO4 buffer (pH = 4.5 at 324 nm. The standard curve covering 0.15 – 30 μg/ml concentration range, was linear (r2 = 0.9999, relative errors were within 2.48 to 9.15 % and the CV% ranged from 2.999 to 10.796. The method is suitable for bioavailability, pharmacokinetic, and bioequivalent studies in human. The in-vivo study was carried out in 12 healthy volunteers according to a single dose, two-sequence, cross over randomized design. The bioavailability was compared using the total area under the plasma level versus time curve (AUC0-48, AUC0-, peak plasma concentration (Cmax and time to Cmax (Tmax. No statistically significant difference was found between the AUC0- , Cmax and Tmax values of the test and reference, Flagyl® (p > 0.05. The 90% CI for the ratio of the AUC0- (0.94-1.07 and Cmax (0.88-1.03 and the logarithmically transformed AUC0- (0.99-1.01 and Cmax (0.94-1.01 values of the generic product over those of Flagyl® was calculated to be within the acceptable limit of 0.80-1.20 and 0.80-1.25, respectively. It was, therefore, concluded that the generic metronidazole was bioequivalent with the innovator formulation.

  3. Finasteride Quantification in Human Plasma by High-Performance Liquid Chromatography Coupled to Electrospray Ionization Tandem Mass Spectrometry. Application to a Comparative Pharmacokinetics Study.

    Science.gov (United States)

    Moreno, R A; Moreno, P; Borges, N C; Donato, J L; Oliveira, S E; Borges, N C

    2015-09-01

    A specific, fast and sensitive LC-MS/MS assay was developed for the determination of finasteride in human plasma using betamethsone dipropionate as the internal standard (IS). The limit of quantification was 1.0 ng/ml and the method was linear in the range of 1.0-25.0 ng/ml. The retention times were 0.75 min for finasteride and 0.85 min for IS. Method intra-batch precision and accuracy ranged from 3.6 to 7.1%, and 96.6 to 103.9%, respectively. Inter-batch precision ranged from 2.5 to 3.4%, while Inter-batch accuracy ranged from 100.3 to 103.5%. The analytical method was applied to evaluate the pharmacokinetic and relative bioavailability of 2 different pharmaceutical formulations containing 1.0 mg of finasteride. This study evaluated 38 volunteers in a randomized, 2-period crossover study with 7 days washout period between doses. The geometric mean and respective 90% CI of finasteride test/reference percent ratios were 95.68% (91.2 - 104.6%) for Cmax, 97.5% (92.1-103.3%) for AUC0-t and 98.1 (92.67-103.8) for AUC0-inf. Based on the 90% confidence interval of the individual ratios (test formulation/reference formulation) for Cmax and AUC0-inf, it was concluded that the test formulation is bioequivalent to the reference one with respect to the rate and extent of absorption of finasteride. © Georg Thieme Verlag KG Stuttgart · New York.

  4. Predictive value of pharmacokinetics-adjusted phenotypic susceptibility on response to ritonavir-enhanced protease inhibitors (PIs) in human immunodeficiency virus-infected subjects failing prior PI therapy.

    Science.gov (United States)

    Eron, Joseph J; Park, Jeong-Gun; Haubrich, Richard; Aweeka, Francesca; Bastow, Barbara; Pakes, Gary E; Yu, Song; Wu, Hulin; Richman, Douglas D

    2009-06-01

    The activities of protease inhibitors in vivo may depend on plasma concentrations and viral susceptibility. This nonrandomized, open-label study evaluated the relationship of the inhibitory quotient (IQ [the ratio of drug exposure to viral phenotypic susceptibility]) to the human immunodeficiency virus type 1 (HIV-1) viral load (VL) change for ritonavir-enhanced protease inhibitors (PIs). Subjects on PI-based regimens replaced their PIs with ritonavir-enhanced indinavir (IDV/r) 800/200 mg, fosamprenavir (FPV/r) 700/100 mg, or lopinavir (LPV/r) 400/200 mg twice daily. Pharmacokinetics were assessed at day 14; follow-up lasted 24 weeks. Associations between IQ and VL changes were examined. Fifty-three subjects enrolled, 12 on IDV/r, 33 on FPV/r, and 8 on LPV/r. Median changes (n-fold) (FC) of 50% inhibitory concentrations (IC(50)s) to the study PI were high. Median 2-week VL changes were -0.7, -0.1, and -1.0 log(10) for IDV/r, FPV/r, and LPV/r. With FPV/r, correlations between the IQ and the 2-week change in VL were significant (Spearman's r range, -0.39 to -0.50; P PI-experienced subjects with highly resistant HIV-1, short-term VL responses to RTV-enhanced FPV/r correlated best with baseline susceptibility. The IQ improved correlation in analyses of all arms where a greater range of virologic responses was observed.

  5. 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

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    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.

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

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    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

  7. Simultaneous determination of rupatadine and its metabolite desloratadine in human plasma by a sensitive LC-MS/MS method: application to the pharmacokinetic study in healthy Chinese volunteers.

    Science.gov (United States)

    Wen, Jun; Hong, Zhanying; Wu, Yiwen; Wei, Hua; Fan, Guorong; Wu, Yutian

    2009-02-20

    A sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed for simultaneous determination of rupatadine and its metabolite desloratadine in human plasma. After the addition of diphenhydramine, the internal standard (IS), plasma samples were extracted with a mixture of methyl tert-butyl ether and n-hexane (1:1, v/v). The analysis was performed on a Ultimate AQ-C18 (4.6mm x 100mm, 5microm) column using a mobile phase consisting of a 80/20 mixture of methanol/water containing 0.0005% formic acid pumped at 0.3mlmin(-1). The analytes and the IS were detected in positive ionization mode and monitoring their precursor-->product ion combinations of m/z 416-->309, 311-->259, and 256-->167, respectively, in multiple reaction monitoring mode. The linear ranges of the assay were 0.1-50 and 0.1-20ngml(-1) for rupatadine and desloratadine, respectively. The lower limits of reliable quantification for both rupatadine and desloratadine were 0.1ngml(-1), which offered high sensitivity and selectivity. The within- and between-run precision was less than 7.2%. The accuracy ranged from -9.2% to +6.4% and -7.2% to +7.2% for rupatadine and desloratadine in quality control samples at three levels, respectively. The method has been successfully applied to a pharmacokinetic study of rupatadine and its major metabolite after oral administration of 10, 20 and 40mg rupatadine tablets to healthy Chinese volunteers.

  8. Single Ascending Dose Safety and Pharmacokinetics of CDRI-97/78: First-in-Human Study of a Novel Antimalarial Drug

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    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.

  9. 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.

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

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    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.

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

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    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.

  12. Synthetic cannabinoid hyperemesis resulting in rhabdomyolysis and acute renal failure.

    Science.gov (United States)

    Argamany, Jacqueline R; Reveles, Kelly R; Duhon, Bryson

    2016-04-01

    Synthetic cannabinoid usage has increased in the past decade. Concurrently, emergency management of associated adverse effects due to synthetic cannabinoid usage has also risen. Reported toxicities include psychosis, seizures, cardiotoxicity, acute kidney injury, and death. While cannabis was first described as a cause of acute hyperemesis in 2004, a more recent case series also describes the association between cannabinoid hyperemesis and risk of acute renal failure. Synthetic cannabinoids have also been reported to cause acute hyperemesis and acute renal failure; however, the risk of rhabdomyolysis-induced renal failure has yet to be elucidated. In this article, we report the first known case of synthetic cannabinoid hyperemesis leading to rhabdomyolysis and acute renal failure.

  13. The arguments for and against cannabinoids application in glaucomatous retinopathy.

    Science.gov (United States)

    Panahi, Yunes; Manayi, Azadeh; Nikan, Marjan; Vazirian, Mahdi

    2017-02-01

    Glaucoma represents several optic neuropathies leading to irreversible blindness through progressive retinal ganglion cell (RGC) loss. Reduction of intraocular pressure (IOP) is known as the only modifiable factor in the treatment of this disorder. Application of exogenous cannabinoids to lower IOP has attracted attention of scientists as potential agents for the treatment of glaucoma. Accordingly, neuroprotective effect of these agents has been recently described through modulation of endocannabinoid system in the eye. In the present work, pertinent information regarding ocular endocannabinoid system, mechanism of exogenous cannabinoids interaction with the ocular endocannabinoid system to reduce IOP, and neuroprotection property of cannabinoids will be discussed according to current scientific literature. In addition to experimental studies, bioavailability of cannabinoids, clinical surveys, and adverse effects of application of cannabinoids in glaucoma will be reviewed. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  14. Efficacy of Teicoplanin-Gentamicin Given Once a Day on the Basis of Pharmacokinetics in Humans for Treatment of Enterococcal Experimental Endocarditis

    Science.gov (United States)

    López, Pedro; Gavaldà, Joan; Martin, M. Teresa; Almirante, Benito; Gomis, Xavier; Azuaje, Carlos; Borrell, Nuria; Pou, Leonor; Falcó, Vicenç; Pigrau, Carles; Pahissa, Albert

    2001-01-01

    With the aim of investigating home therapy for enterococcal endocarditis, we compared the efficacy of teicoplanin combined with gentamicin given once a day or in three daily doses (t.i.d.) with the standard treatment, ampicillin plus gentamicin administered t.i.d., for treating experimental enterococcal endocarditis. The antibiotics were administered by using “human-like pharmacokinetics” (H-L), i.e, pharmacokinetics like those in humans, that simulated the profiles of these drugs in human serum. Animals with catheter-induced endocarditis were infected intravenously with 108 CFU of Enterococcus faecalis EF91 (MICs and MBCs of ampicillin, gentamicin, and teicoplanin, 0.5 and 32, 16 and 32, and 0.5 and 1 μg/ml, respectively) and were treated for 3 days with ampicillin H-L at 2 g every 4 h plus gentamicin H-L at 1 mg/kg every 8 h, or teicoplanin H-L at 10 mg/kg every 24 h, alone or combined with gentamicin, administered at dose of H-L at 1 mg/kg every 8 h or H-L at 4.5 mg/kg every 24 h. The results of therapy for experimental endocarditis due to EF91 showed that teicoplanin alone was as effective as ampicillin alone in reducing the bacterial load (P > 0.05). The combination of ampicillin or teicoplanin with gentamicin was more effective than the administration of both drugs alone in reducing the log10CFU/gram of aortic vegetation (P Teicoplanin plus gentamicin H-L at 4.5 mg/kg, both administered every 24 h, showed an efficacy equal to the “gold standard,” ampicillin plus gentamicin H-L at 1 mg/kg t.i.d. (P > 0.05). Increasing the interval of administration of gentamicin to a single daily dose combined with teicoplanin resulted in a reduction of bacteria in the vegetations equivalent to that achieved with the recommended regimen of ampicillin plus thrice-daily gentamicin in the treatment of experimental endocarditis due to E. faecalis. Teicoplanin plus gentamicin, both administered once a day, may be useful home therapy for selected cases of enterococcal

  15. Lisdexamfetamine: A pharmacokinetic</