scholarly journals Disposition of Phytocannabinoids, Their Acidic Precursors and Their Metabolites in Biological Matrices of Healthy Individuals Treated with Vaporized Medical Cannabis

2021 ◽  
Vol 14 (1) ◽  
pp. 59
Author(s):  
Francesco Paolo Busardò ◽  
Ana Pilar Pérez-Acevedo ◽  
Roberta Pacifici ◽  
Giulio Mannocchi ◽  
Massimo Gottardi ◽  
...  
Keyword(s):  
Time Course ◽  
Oral Fluid ◽  
Biological Fluids ◽  
Subjective Effects ◽  
Area Under The Curve ◽  
Healthy Individuals ◽  
Medical Cannabis ◽  
Biological Matrices ◽  
Similar Time ◽  
High Interindividual Variability

Inhalation by vaporization is a useful application mode for medical cannabis. In this study, we present the disposition of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors, and their metabolites in serum, oral fluid, and urine together with the acute pharmacological effects in 14 healthy individuals treated with vaporized medical cannabis. THC and CBD peaked firstly in serum and then in oral fluid, with higher concentrations in the first biological matrices and consequent higher area under the curve AUCs. Acidic precursors Δ-9-tetrahydrocannabinolic acid A (THCA) and cannabidiolic acid (CBDA) showed a similar time course profile but lower concentrations due to the fact that vaporization partly decarboxylated these compounds. All THC and CBD metabolites showed a later onset with respect to the parent compounds in the absorption phase and a slower decrease to baseline. In agreement with serum kinetics, THC-COOH-GLUC and 7-COOH-CBD were the significantly most excreted THC and CBD metabolites. The administration of vaporized medical cannabis induced prototypical effects associated with the administration of cannabis or THC in humans, with a kinetic trend overlapping that of parent compounds and metabolites in serum. The pharmacokinetics of cannabinoids, their precursors, and their metabolites in biological fluids of individuals treated with vaporized medical cannabis preparations showed a high interindividual variability as in the case of oral medical cannabis decoction and oil. Inhaled medical cannabis was absorbed into the organism earlier than decoction and oil. Cannabinoids reached higher systemic concentrations, also due to the fact that the acid precursors decarboxylated to parent cannabinoids at high temperatures, and consequently, the physiological and subjective effects occurred earlier and resulted with higher intensity. No serious adverse effects were observed.

scholarly journals Comparative analysis of ceruloplasmin level in biological fluids at herpes infection

2013 ◽  
Vol 94 (5) ◽  
pp. 752-754
Author(s):  
N A Terekhina ◽  
S E Reuk ◽  
T I Atamanova
Keyword(s):  
Blood Serum ◽  
Oral Fluid ◽  
Biological Fluids ◽  
Adult Patients ◽  
Control Group ◽  
Healthy Individuals ◽  
Herpes Infection ◽  
Oral Fluids ◽  
Ceruloplasmin Level ◽  
Severity Of The Disease

Aim. To compare the levels of ceruloplasmin in tears, saliva and blood serum of patients with herpetic stomatitis and eye herpes to evaluate the effectiveness of treatment. Methods. Ceruloplasmin levels were determined in tears, saliva and blood serum of 30 children, 22 adult patients with herpetic keratitis and 27 children with acute herpetic stomatitis. Biological fluids of 62 healthy individuals were used as the control group. Results. In patients with eye herpes infection, сeruloplasmin levels increased in oral fluid and blood serum and markedly decreased in tears of both affected and intact eye. Ceruloplasmin levels in biological fluids normalized only among children with light forms of eye herpes at discharge. In the case of acute herpetic stomatitis, ceruloplasmin levels increased in oral fluid and blood serum, depending on the severity of the disease. After the treatment, ceruloplasmin levels in tears, oral fluid and blood plasma normalized only in children with dendritic ulcer (herpes epithelial keratitis), while in adult patients with chronic relapsing eye herpes and in children with highly invasive eye herpes ceruloplasmin levels did not normalize. Conclusion. In the case of infection detected multidirectional ceruloplasmin levels in tears, oral fluids and blood serum changes were found in patients with herpes. Ceruloplasmin level decreased in tears, and increased in blood serum and oral fluid.

Postnatal growth rate and gonadal development in circadian tau mutant hamsters reared in constant dim red light

Reproduction ◽  
2000 ◽  
pp. 327-330 ◽  
Author(s):  
RJ Lucas ◽  
JA Stirland ◽  
YN Mohammad ◽  
AS Loudon
Keyword(s):  
Time Course ◽  
Red Light ◽  
Somatic Growth ◽  
Postnatal Growth ◽  
Gonadal Development ◽  
Testicular Development ◽  
Wild Type ◽  
Similar Time ◽  
Syrian Hamsters ◽  
Body Weights

The role of the circadian clock in the reproductive development of Syrian hamsters (Mesocricetus auratus was examined in wild type and circadian tau mutant hamsters reared from birth to 26 weeks of age under constant dim red light. Testis diameter and body weights were determined at weekly intervals in male hamsters from 4 weeks of age. In both genotypes, testicular development, subsequent regression and recrudescence exhibited a similar time course. The age at which animals displayed reproductive photosensitivity, as exhibited by testicular regression, was unrelated to circadian genotype (mean +/- SEM: 54 +/- 3 days for wild type and 59 +/- 5 days for tau mutants). In contrast, our studies revealed a significant impact of the mutation on somatic growth, such that tau mutants weighed 18% less than wild types at the end of the experiment. Our study reveals that the juvenile onset of reproductive photoperiodism in Syrian hamsters is not timed by the circadian system.

Time course of serum levels of leukemia inhibitory factor (LIF) and soluble LIF receptor (sLIF-R) in development of stage II essential hypertension

2017 ◽  
pp. 63-69
Author(s):  
О.А. Радаева ◽  
А.С. Симбирцев
Keyword(s):  
Antihypertensive Therapy ◽  
Time Course ◽  
Pulse Wave ◽  
Antihypertensive Drugs ◽  
Peripheral Resistance ◽  
Serum Levels ◽  
Stage Ii ◽  
Healthy Individuals ◽  
Vasoactive Substances ◽  
Essential Arterial Hypertension

Цель - изучение сывороточных уровней LIF, sLIr и их соотношение с гемодинамическими параметрами (ЧСС, САД, ДАД, ПАД, ЦАД, срАД, УО, МОК, ОПСС, СПВ) и содержанием вазоактивных веществ (AT II, ET-1, NO, ADMA, SDMA, eNOS, iNOS, NT-proСNP, NT-proBNP) у пациентов с эссенциальной артериальной гипертензией (ЭАГ) II стадии. Методы: количество LIF, sLIF-R/gp190 и вазоактивные вещества в сыворотке определяли иммуноферментным методом. Результаты: у пациентов с ЭАГ II стадии вне зависимости от проведения гипотензивной терапии была более высокая концентрация LIF (7,54 (2,8) пг/мл, 7,5 (2,1) пг/мл), по сравнению с условно здоровыми - 1,25 (0,5) пг/мл, р<0,001. При этом у пациентов, не получавших гипотензивные препараты, увеличивался уровень sLIr - (5800 (1470 pg/ml)) по сравнению с больными на фоне гипотензивной терапии (4100 (1380) пг/мл, р<0,001) и условно здоровыми (3800 (1100) пг/мл, р<0,001). При уровне sLIF-R выше 4800 пг/мл обнаруживали связь с увеличением содержания в сыворотке iNOS, NT-proBNP, ADMA, SDMA, (r = 0,5-0,8, р<0,05-0,001) и уменьшением уровня eNOS (r = -0,56-0,86, р<0,05-0,001), что соответствует прогрессированию заболевания. Корреляции между LIF и указанными вазоактивными веществами выявлено не было, что дает основание предполагать, что sLIFr вызывает собственные патогенетические эффекты помимо антагонистической активности по отношению к LIF. Aim. To study levels of serum LIF and sLIF-R and their correlations with hemodynamic parameters (heart rate, systolic BP, diastolic BP, pulse pressure, central BP, mean BP, stroke volume, total peripheral resistance, and pulse wave velocity) and vasoactive substances (AT II, ET-1, NO, ADMA, SDMA, eNOS, iNOS, NT-proСNP, and NT-proBNP) in patients with stage II essential arterial hypertension (EAH). Methods. Serum levels of LIF and sLIF-R/gp190 were measured using ELISA in 180 patients with stage II ЕAН. Results: Patients with EAH II (with or without antihypertensive therapy) had higher serum levels of LIF (7.54 (2.8) pg/ml and 7.5 (2.1) pg/ml, respectively) compared to healthy individuals (1.25 (0.5) pg/ml), р<0.001. Patients not receiving a therapy had higher serum levels of sLIF-R (5800 (1470 pg/ml) than patients receiving antihypertensive drugs (4100 (1380) pg/ml, р<0.001) and healthy individual (3800 (1100) pg/ml, р<0.001). In patients with EAH, sLIF-R levels higher than 4800 pg/ml correlated with increases in iNOS, NT-proBNP, ADMA, and SDMA (r = 0.5-0.8, р<0.05-0.001) and decreases in eNOS (r = -0.56-0.86, р<0.05-0.001), which corresponded to disease progression. LIF did not show any significant correlations with these vasoactive substances, which suggested that sLIF-R exerted its own pathogenetic effects besides antagonizing LIF. Generally, this trend was typical for patients with EAH (II stage) without antihypertensive therapy.

scholarly journals Neurofilament Proteolysis after Focal Ischemia; When Do Cells Die after Experimental Stroke?

1999 ◽  
Vol 19 (6) ◽  
pp. 652-660 ◽  
Author(s):  
Jaroslaw Aronowski ◽  
Ki-Hyun Cho ◽  
Roger Strong ◽  
James C. Grotta
Keyword(s):  
Time Course ◽  
Infarct Volume ◽  
Focal Ischemia ◽  
Cellular Damage ◽  
Experimental Stroke ◽  
Infarct Core ◽  
Similar Time ◽  
The Core ◽  
Tetrazolium Staining ◽  
Previous Demonstration

To determine the occurrence and time-course of presumably irreversible subcellular damage after moderate focal ischemia, rats were subjected to 1, 3, 6, 9, or 24 hours of permanent unilateral middle cerebral and common carotid occlusion or 3 hours of reversible occlusion followed by 3, 6, or 21 hours of reperfusion. The topography and the extent of damage were analyzed with tetrazolium staining and immunoblot using an antibody capable of detecting breakdown of neurofilament. Neurofilament proteolysis began after 3 hours in the infarct core but was still incomplete in penumbral regions up to 9 hours. Similarly, tetrazolium-staining abnormalities were observed in the core of 50% of animals after 3 hours of ischemia. At 6 hours of permanent ischemia, infarct volume was maximal, and further prolongation of occlusion to 9 or 24 hours did not increase abnormal tetrazolium staining. In contrast to permanent ischemia and in agreement with the authors' previous demonstration of “reperfusion injury” in this model, prolongation of reperfusion from 3 hours to 6 and 21 hours after 3 hours of reversible occlusion gradually augmented infarct volume by 203% and 324%, respectively. Neurofilament proteolysis initiated approximately 3 hours after ischemia was quantitatively greatest in the core and extended during reperfusion to incorporate penumbra with a similar time course to that of tetrazolium abnormalities. These data demonstrate that, at least as measured by neurofilament breakdown and mitochondrial failure, extensive cellular damage is not present in penumbral regions for up to 9 hours, suggesting the potential for rescuing these regions by appropriate and timely neuroprotective strategies.

scholarly journals 5-HT1A Serotonergic, α-Adrenergic and Opioidergic Receptors Mediate the Analgesic Efficacy of Vortioxetine in Mice

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3242
Author(s):  
Nazlı Turan Yücel ◽  
Ümmühan Kandemir ◽  
Ümide Demir Özkay ◽  
Özgür Devrim Can
Keyword(s):  
Analgesic Activity ◽  
Time Course ◽  
Motor Coordination ◽  
Antidepressant Drug ◽  
Area Under The Curve ◽  
Analgesic Efficacy ◽  
Synthesis Inhibitor ◽  
Tail Immersion ◽  
Adrenoceptor Blocker ◽  
The Central Nervous System

Vortioxetine is a multimodal antidepressant drug that affects several brain neurochemicals and has the potential to induce various pharmacological effects on the central nervous system. Therefore, we investigated the centrally mediated analgesic efficacy of this drug and the mechanisms underlying this effect. Analgesic activity of vortioxetine (5, 10 and 20 mg/kg, p.o.) was examined by tail-clip, tail-immersion and hot-plate tests. Motor performance of animals was evaluated using Rota-rod device. Time course measurements (30–180 min) showed that vortioxetine (10 and 20 mg/kg) administrations significantly increased the response latency, percent maximum possible effect and area under the curve values in all of the nociceptive tests. These data pointed out the analgesic effect of vortioxetine on central pathways carrying acute thermal and mechanical nociceptive stimuli. Vortioxetine did not alter the motor coordination of mice indicating that the analgesic activity of this drug was specific. In mechanistic studies, pre-treatments with p-chlorophenylalanine (serotonin-synthesis inhibitor), NAN-190 (serotonin 5-HT1A receptor antagonist), α-methyl-para-tyrosine (catecholamine-synthesis inhibitor), phentolamine (non-selective α-adrenoceptor blocker), and naloxone (non-selective opioid receptor blocker) antagonised the vortioxetine-induced analgesia. Obtained findings indicated that vortioxetine-induced analgesia is mediated by 5-HT1A serotonergic, α-adrenergic and opioidergic receptors, and contributions of central serotonergic and catecholaminergic neurotransmissions are critical for this effect.

scholarly journals TGF-β1 increases permeability of ciliated airway epithelia via redistribution of claudin 3 from tight junction into cell nuclei

2021 ◽  
Author(s):  
Carolin Schilpp ◽  
Robin Lochbaum ◽  
Peter Braubach ◽  
Danny Jonigk ◽  
Manfred Frick ◽  
...  
Keyword(s):  
Time Course ◽  
Atopic Asthma ◽  
Ciliated Cells ◽  
Cell Nuclei ◽  
Tissue Remodelling ◽  
Similar Time ◽  
Airway Epithelia ◽  
Epithelial Integrity ◽  
Motile Cilia ◽  
Tgf Β1

AbstractTGF-β1 is a major mediator of airway tissue remodelling during atopic asthma and affects tight junctions (TJs) of airway epithelia. However, its impact on TJs of ciliated epithelia is sparsely investigated. Herein we elaborated effects of TGF-β1 on TJs of primary human bronchial epithelial cells. We demonstrate that TGF-β1 activates TGF-β1 receptors TGFBR1 and TGFBR2 resulting in ALK5-mediated phosphorylation of SMAD2. We observed that TGFBR1 and -R2 localize specifically on motile cilia. TGF-β1 activated accumulation of phosphorylated SMAD2 (pSMAD2-C) at centrioles of motile cilia and at cell nuclei. This triggered an increase in paracellular permeability via cellular redistribution of claudin 3 (CLDN3) from TJs into cell nuclei followed by disruption of epithelial integrity and formation of epithelial lesions. Only ciliated cells express TGF-β1 receptors; however, nuclear accumulations of pSMAD2-C and CLDN3 redistribution were observed with similar time course in ciliated and non-ciliated cells. In summary, we demonstrate a role of motile cilia in TGF-β1 sensing and showed that TGF-β1 disturbs TJ permeability of conductive airway epithelia by redistributing CLDN3 from TJs into cell nuclei. We conclude that the observed effects contribute to loss of epithelial integrity during atopic asthma.

scholarly journals Pseudo-streaming potentials in Necturus gallbladder epithelium. II. The mechanism is a junctional diffusion potential.

1992 ◽  
Vol 99 (3) ◽  
pp. 317-338 ◽  
Author(s):  
L Reuss ◽  
B Simon ◽  
C U Cotton
Keyword(s):  
Time Course ◽  
Bathing Solution ◽  
Intercellular Spaces ◽  
Similar Time ◽  
Streaming Potentials ◽  
Osmotic Water ◽  
Lateral Intercellular Spaces ◽  
Transepithelial Voltage ◽  
Time Courses ◽  
Good Agreement

The mechanisms of apparent streaming potentials elicited across Necturus gallbladder epithelium by addition or removal of sucrose from the apical bathing solution were studied by assessing the time courses of: (a) the change in transepithelial voltage (Vms). (b) the change in osmolality at the cell surface (estimated with a tetrabutylammonium [TBA+]-selective microelectrode, using TBA+ as a tracer for sucrose), and (c) the change in cell impermeant solute concentration ([TMA+]i, measured with an intracellular double-barrel TMA(+)-selective microelectrode after loading the cells with TMA+ by transient permeabilization with nystatin). For both sucrose addition and removal, the time courses of Vms were the same as the time courses of the voltage signals produced by [TMA+]i, while the time courses of the voltage signals produced by [TBA+]o were much faster. These results suggest that the apparent streaming potentials are caused by changes of [NaCl] in the lateral intercellular spaces, whose time course reflects the changes in cell water volume (and osmolality) elicited by the alterations in apical solution osmolality. Changes in cell osmolality are slow relative to those of the apical solution osmolality, whereas lateral space osmolality follows cell osmolality rapidly, due to the large surface area of lateral membranes and the small volume of the spaces. Analysis of a simple mathematical model of the epithelium yields an apical membrane Lp in good agreement with previous measurements and suggests that elevations of the apical solution osmolality elicit rapid reductions in junctional ionic selectivity, also in good agreement with experimental determinations. Elevations in apical solution [NaCl] cause biphasic transepithelial voltage changes: a rapid negative Vms change of similar time course to that of a Na+/TBA+ bi-ionic potential and a slow positive Vms change of similar time course to that of the sucrose-induced apparent streaming potential. We conclude that the Vms changes elicited by addition of impermeant solute to the apical bathing solution are pseudo-streaming potentials, i.e., junctional diffusion potentials caused by salt concentration changes in the lateral intercellular spaces secondary to osmotic water flow from the cells to the apical bathing solution and from the lateral intercellular spaces to the cells. Our results do not support the notion of junctional solute-solvent coupling during transepithelial osmotic water flow.

scholarly journals Correlation between Charge Movement and Ionic Current during Slow Inactivation in Shaker K+ Channels

1997 ◽  
Vol 110 (5) ◽  
pp. 579-589 ◽  
Author(s):  
Riccardo Olcese ◽  
Ramón Latorre ◽  
Ligia Toro ◽  
Francisco Bezanilla ◽  
Enrico Stefani
Keyword(s):  
Time Course ◽  
Voltage Dependence ◽  
Ionic Current ◽  
K Channel ◽  
Charge Movement ◽  
Slow Inactivation ◽  
Gating Currents ◽  
Similar Time ◽  
K Channels ◽  
Recovery From Inactivation

Prolonged depolarization induces a slow inactivation process in some K+ channels. We have studied ionic and gating currents during long depolarizations in the mutant Shaker H4-Δ(6–46) K+ channel and in the nonconducting mutant (Shaker H4-Δ(6–46)-W434F). These channels lack the amino terminus that confers the fast (N-type) inactivation (Hoshi, T., W.N. Zagotta, and R.W. Aldrich. 1991. Neuron. 7:547–556). Channels were expressed in oocytes and currents were measured with the cut-open-oocyte and patch-clamp techniques. In both clones, the curves describing the voltage dependence of the charge movement were shifted toward more negative potentials when the holding potential was maintained at depolarized potentials. The evidences that this new voltage dependence of the charge movement in the depolarized condition is associated with the process of slow inactivation are the following: (a) the installation of both the slow inactivation of the ionic current and the inactivation of the charge in response to a sustained 1-min depolarization to 0 mV followed the same time course; and (b) the recovery from inactivation of both ionic and gating currents (induced by repolarizations to −90 mV after a 1-min inactivating pulse at 0 mV) also followed a similar time course. Although prolonged depolarizations induce inactivation of the majority of the channels, a small fraction remains non–slow inactivated. The voltage dependence of this fraction of channels remained unaltered, suggesting that their activation pathway was unmodified by prolonged depolarization. The data could be fitted to a sequential model for Shaker K+ channels (Bezanilla, F., E. Perozo, and E. Stefani. 1994. Biophys. J. 66:1011–1021), with the addition of a series of parallel nonconducting (inactivated) states that become populated during prolonged depolarization. The data suggest that prolonged depolarization modifies the conformation of the voltage sensor and that this change can be associated with the process of slow inactivation.

scholarly journals Calcium metabolism in rat hepatocytes

1978 ◽  
Vol 170 (3) ◽  
pp. 615-625 ◽  
Author(s):  
S Foden ◽  
P J Randle
Keyword(s):  
Cyclic Amp ◽  
Time Course ◽  
Rat Hepatocytes ◽  
Ionophore A23187 ◽  
Total Calcium ◽  
Free Medium ◽  
Adrenergic Agonists ◽  
Calcium Efflux ◽  
Similar Time ◽  
Carbonyl Cyanide

1. The total calcium concentration in rat hepatocytes was 7.9 microgram-atoms/g dry wt.; 77% of this was mitochondrial. Approx. 20% of cell calcium exchanged with 45Ca within 2 min. Thereafter incorporation proceeded at a low rate to reach 28% of total calcium after 60 min. Incorporation into mitochondria showed a similar time course and accounted for 20% of mitochondrial total calcium after 60 min. 2. The alpha-adrenergic agonists phenylephrine and adrenaline + propranolol stimulated incorporation of 45Ca into hepatocytes. Phenylephrine was shown to increase total calcium in hepatocytes. Phenylephrine inhibited efflux fo 45Ca from hepatocytes perifused with calcium-free medium. 3. Glucagon, dibutryl cyclic AMP and beta-adrenergic agonists adrenaline and 3-isobutyl-1-methyl-xanthine stimulated calcium efflux from hepatocytes perifused with calcium-free medium. The effect of glucagon was blocked by insulin. Insulin itself had no effect on calcium efflux and it did not affect the response to dibutyryl cyclic AMP. 4. Incorporation of 45Ca into mitochondria in hepatocytes was stimulated by phenylephrine and inhibited by glucagon and by carbonyl cyanide p-trifluoromethoxyphenylhydrazone. The effect of glucagon was blocked by insulin. 5. Ionophore A23187 stimulated hepatocyte uptake of 45Ca, uptake of 45Ca into mitochondria in hepatocytes and efflux of 45Ca into a calcium-free medium.

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