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Pain Research & Management 2018Methanolic extract of Lindau leaves (MECN) has been proven to possess antinociceptive activity that works via the opioid and NO-dependent/cGMP-independent pathways. In...
Methanolic extract of Lindau leaves (MECN) has been proven to possess antinociceptive activity that works via the opioid and NO-dependent/cGMP-independent pathways. In the present study, we aimed to further determine the possible mechanisms of antinociception of MECN using various nociceptive assays. The antinociceptive activity of MECN was (i) tested against capsaicin-, glutamate-, phorbol 12-myristate 13-acetate-, bradykinin-induced nociception model; (ii) prechallenged against selective antagonist of opioid receptor subtypes (-funaltrexamine, naltrindole, and nor-binaltorphimine); (iii) prechallenged against antagonist of nonopioid systems, namely, -noradrenergic (yohimbine), -adrenergic (pindolol), adenosinergic (caffeine), dopaminergic (haloperidol), and cholinergic (atropine) receptors; (iv) prechallenged with inhibitors of various potassium channels (glibenclamide, apamin, charybdotoxin, and tetraethylammonium chloride). The results demonstrated that the orally administered MECN (100, 250, and 500 mg/kg) significantly ( < 0.05) reversed the nociceptive effect of all models in a dose-dependent manner. Moreover, the antinociceptive activity of 500 mg/kg MECN was significantly ( < 0.05) inhibited by (i) antagonists of μ-, -, and -opioid receptors; (ii) antagonists of -noradrenergic, β-adrenergic, adenosinergic, dopaminergic, and cholinergic receptors; and (iii) blockers of different K channels (voltage-activated-, Ca-activated, and ATP-sensitive-K channels, resp.). In conclusion, MECN-induced antinociception involves modulation of protein kinase C-, bradykinin-, TRVP1 receptors-, and glutamatergic-signaling pathways; opioidergic, -noradrenergic, adrenergic, adenosinergic, dopaminergic, and cholinergic receptors; and nonopioidergic receptors as well as the opening of various K channels. The antinociceptive activity could be associated with the presence of several flavonoid-based bioactive compounds and their synergistic action with nonvolatile bioactive compounds.
Topics: Acanthaceae; Analgesics; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred ICR; Neurotransmitter Agents; Nociception; Pain; Physical Stimulation; Plant Extracts; Plant Leaves; Potassium Channel Blockers; Potassium Channels; Sensory System Agents
PubMed: 29686743
DOI: 10.1155/2018/9536406 -
Journal of Pharmacokinetics and... Aug 2018In this paper we present a framework for the reduction and linking of physiologically based pharmacokinetic (PBPK) models with models of systems biology to describe the...
In this paper we present a framework for the reduction and linking of physiologically based pharmacokinetic (PBPK) models with models of systems biology to describe the effects of drug administration across multiple scales. To address the issue of model complexity, we propose the reduction of each type of model separately prior to being linked. We highlight the use of balanced truncation in reducing the linear components of PBPK models, whilst proper lumping is shown to be efficient in reducing typically nonlinear systems biology type models. The overall methodology is demonstrated via two example systems; a model of bacterial chemotactic signalling in Escherichia coli and a model of extracellular regulatory kinase activation mediated via the extracellular growth factor and nerve growth factor receptor pathways. Each system is tested under the simulated administration of three hypothetical compounds; a strong base, a weak base, and an acid, mirroring the parameterisation of pindolol, midazolam, and thiopental, respectively. Our method can produce up to an 80% decrease in simulation time, allowing substantial speed-up for computationally intensive applications including parameter fitting or agent based modelling. The approach provides a straightforward means to construct simplified Quantitative Systems Pharmacology models that still provide significant insight into the mechanisms of drug action. Such a framework can potentially bridge pre-clinical and clinical modelling - providing an intermediate level of model granularity between classical, empirical approaches and mechanistic systems describing the molecular scale.
Topics: Escherichia coli; Humans; Male; Models, Biological; Receptors, Nerve Growth Factor; Signal Transduction; Systems Biology
PubMed: 29582349
DOI: 10.1007/s10928-018-9584-y -
European Neuropsychopharmacology : the... Apr 2018Major depressive disorder (MDD) is a severe psychiatric syndrome with high prevalence and socioeconomic impact. Current antidepressant treatments are based on the... (Review)
Review
Major depressive disorder (MDD) is a severe psychiatric syndrome with high prevalence and socioeconomic impact. Current antidepressant treatments are based on the blockade of serotonin (5-hydroxytryptamine, 5-HT) and/or noradrenaline transporters. These drugs show slow onset of clinical action and limited efficacy, partly due to the activation of physiological negative feed-back mechanisms operating through autoreceptors (5-HT, 5-HT, α-adrenoceptors) and postsynaptic receptors (e.g., 5-HT). As a result, clinically-relevant doses of reuptake inhibitors increase extracellular (active) 5-HT concentrations in the midbrain raphe nuclei but not in forebrain, as indicated by rodent microdialysis studies and by PET-scan studies in primate/human brain. The prevention of these self-inhibitory mechanisms by antagonists of the above receptors augments preclinical and clinical antidepressant effects. Hence, the mixed ß-adrenoceptor/5-HT antagonist pindolol accelerated, and in some cases enhanced, the clinical action of selective serotonin reuptake inhibitors (SSRI). This strategy has been incorporated into two new multi-target antidepressant drugs, vilazodone and vortioxetine, which combine 5-HT reuptake inhibition and partial agonism at 5-HT receptors. Vortioxetine shows also high affinity for other 5-HT receptors, including excitatory 5-HT receptors located in cortical and hippocampal GABA interneurons. 5-HT receptor blockade by vortioxetine enhances pyramidal neuron activity in prefrontal cortex as well as cortical and hippocampal 5-HT release. It is still too soon to know whether these new antidepressants will represent a real advance over existing drugs in the real world. However, their development opened the way to future antidepressant drugs based on the prevention of local and distal self-inhibitory mechanisms attenuating monoamine activity.
Topics: Animals; Antidepressive Agents; Biogenic Monoamines; Depressive Disorder, Major; Humans; Neurotransmitter Agents
PubMed: 29174531
DOI: 10.1016/j.euroneuro.2017.10.032 -
British Journal of Pharmacology Jan 2018Whole body physiologically based pharmacokinetic (PBPK) models have been increasingly applied in drug development to describe kinetic events of therapeutic agents in...
BACKGROUND AND PURPOSE
Whole body physiologically based pharmacokinetic (PBPK) models have been increasingly applied in drug development to describe kinetic events of therapeutic agents in animals and humans. The advantage of such modelling is the ability to incorporate vast amounts of physiological information, such as organ blood flow and volume, to ensure that the model is as close to reality as possible.
EXPERIMENTAL APPROACH
Previous PBPK model development of enantiomers of a series of seven racemic β-blockers, namely, acebutolol, betaxolol, bisoprolol, metoprolol, oxprenolol, pindolol and propranolol, together with S-timolol in rat was based on tissue and blood concentration data at steady state. Compounds were administered in several cassettes with the composition mix and blood and tissue sampling times determined using a D-optimal design.
KEY RESULTS
Closed-loop PBPK models were developed initially based on the application of open loop forcing function models to individual tissues and compounds. For the majority of compounds and tissues, distribution kinetics was adequately characterized by perfusion rate-limited models. For some compounds in the testes and gut, a permeability rate-limited distribution model was required to best fit the data. Parameter estimates of the tissue-to-blood partition coefficient through fitting of individual enantiomers and of racemic pair were generally in agreement and also concur with those from previous steady-state experiments.
CONCLUSIONS AND IMPLICATIONS
PBPK modelling is a very powerful tool to aid drug discovery and development of therapeutic agents in animals and humans. However, careful consideration of the assumptions made during the modelling exercise is essential.
Topics: Adrenergic beta-Antagonists; Animals; Injections, Intravenous; Male; Models, Biological; Rats; Rats, Sprague-Dawley; Tissue Distribution
PubMed: 29053169
DOI: 10.1111/bph.14071 -
Danish Medical Journal Apr 2017Hypothesis The hypotheses of all the four included studies share the common idea that it is possible to augment the effect of antidepressant drug treatment by applying... (Review)
Review
Hypothesis The hypotheses of all the four included studies share the common idea that it is possible to augment the effect of antidepressant drug treatment by applying different interventions and with each intervention attain a clinically meaningful better effect compared to a control condition, and with minor side effects, thus improving the short- and medium-term outcome in major depression. Procedures Study design The basic study design has been the double blind randomised controlled trial (RCT). In the light therapy study, all patients were treated with sertraline for the whole of the study duration. In the first five weeks of the study, patients were randomised to treatment with either 60 minutes of bright white or 30 minutes of dim red light (sham condition). In the four weeks follow-up period, patients were treated with sertraline alone. In the Pindolol study, all patients were treated with venlafaxine and randomised to augmentation with either active or placebo matching pindolol tablets. In the PEMF study patients were continued on ongoing medication and randomised to augmentation with active or inactive (sham) 30 minutes daily PEMF treatment on weekdays. In the Chronos study all patients were treated with duloxetine and randomized to either a combination of three wake therapies with daily bright light treatment and sleep time stabilisation (wake group) or to daily exercise of minimum 30 minutes as an active control intervention (exercise group). The Chronos study was divided into: (1) a one-week run-in phase where duloxetine were started (and continued for the whole 29 week study period), (2) a one-week inpatient intervention phase where patient in the wake group did three wake therapies (sleep abstinence for the whole night and the following day until evening) in combination with daily light therapy and guidance on sleep time stabilisation and patients in the exercise group started a daily exercise program, (3) a seven week continuation phase where patient in the wake group continued light therapy and sleep time stabilisation and patients in the exercise group continued an individual exercise program, and (4) a 20 week follow-up phase with the same treatment elements but where duloxetine dosage could be adjusted or changed to other antidepressants. Recruitment Patients recruited for these studies were allocated from general practitioners, psychiatric specialist practices and for the lesser part from open psychiatric wards. Only a few patients were re-cruited through advertisements (in the PEMF and Chronos studies). Inclusion criteria Inclusion criteria were major depression according to the DSM-IV, including a depressive episode as part of a bipolar disorder. For the PEMF study, treatment resistance was a specific inclusion criterion. Duration of studies Study duration was nine weeks for the light therapy study, 19 days for the Pindolol study, five weeks for the PEMF study, and 29 weeks for the Chronos study. Assessments In all studies, assessments were done with clinician rated scales, patient self-assessment scales, including quality of life scales and a side effect scale. As clinician rated scales we used the Hamilton depression rating scale: the HAM-D17 and its 6 item subscale: the HAM-D6, the Bech Rafaelsen Melancholia scale (MES), and the Bech Rafaelsen Mania scale (MAS). As self-assessment scales we used the Major Depression Inventory (MDI), the Symptom Check-list (SCL-92), and the Preskorn scale. For side effects we used the UKU scale. Further scales used are mentioned in the specific study sections. Assessments in the light therapy study were done weekly for the first six weeks and finally after nine weeks; at four time points in the Pindolol study (baseline, days 6, 11 and 19), weekly for five weeks in the PEMF study and weekly for the first nine weeks of the Chronos study and thereafter every four weeks. The clinical setting for evaluation has been the Psychiatric Research Unit at Mental Health Centre North Zealand. For the Bright Light study, Pindolol and PEMF study patients were also seen at a psychiatric specialist practice in Copenhagen. Biochemical measures In the Light therapy study saliva cortisol was collected at baseline before start of light therapy and sertraline and blood was drawn for thyroid analysis. In the Chronos study saliva and 24 hour urine cortisol was collected in the patients randomised to the exercise group. Main results The main results from the Bright Light study covering the first five weeks of the study are given in the PhD thesis "Adjunctive bright light in nonseasonal major depression" defended and awarded on the 18 November 2004 at the University of Copenhagen. Results from the cortisol measurement and for the four weeks extension period were published in separate papers after the PhD thesis and are included in this thesis. Results from the Bright Light study Analysis of the saliva cortisol measurements taken at baseline of the study as cortisol awakening profiles (CAR) showed that patients responded differentially to light treatment according to their CAR levels (dichotomized to high or low about the mean). Thus, in the bright light group HAM-D17 scores were reduced by 15.7 (4.2) points for patients with a low CAR (below mean), and 11.4 (4.8) points for patients with a high CAR (above mean). In the dim light group the corresponding values were 11.1 (5.2) for patients with a low CAR and 11.3 (5.3) for patients with a high CAR. This interaction between CAR and treatment group was statistically significant (p = 0.006). Survival analysis, for the first five weeks of the study period, showed a statistically significant higher response rate (χ2= 9.6, p =0.002) and higher remission rate (χ2 = 12.5, p = 0.0004) for the bright light treated group versus the dim light treated group. At end of the five weeks of light treatment response rates were 66.7% versus 40.7 % and remission rates were 41.7 % versus 14.8 % for the bright versus dim light treated group. In the subsequent publication that covered the four weeks extension period where light treatment was discontinued, data showed that the attained differences in response and remission rates between groups were not sustained. The offset of effect was nearly complete after four weeks of continued treatment on sertraline only. Thus, at end-point, response rates were 79.2 % versus 75.9 % and remission rates were 60 .4 % versus 55.6% in the bright versus dim light groups. The conclusion reached was that bright light in non-seasonal depression should be used to achieve an earlier antidepressant response and that light therapy probably should be of longer duration. Results from the Pindolol study The results from the Pindolol study showed that pindolol did not augment the effect of venlafaxine for the whole sample. However, for those patients classified as slow metabolizers, based on their O-desmethylvenlafaxine/venlafaxine ratio (ODV/V), pindolol did augment the antidepressant effect. For patients classified as fast metabolizers, pindolol worsened the outcome. This interaction between ODV/V ratio and treatment group was statistically significant (p = 0.01). Results from the PEMF study The results from the PEMF Study showed that treatment with active versus sham PEMF augmented the effect of the ongoing anti-depressant medication treatment. Thus, patients in the active PEMF group attained a statistically significant greater score reduction from week one and at all subsequent assessments compared to the sham treated group (p < 0.01). Response and remission rates in the active PEMF group were also larger than in the sham treated group with response rates at endpoint of 61.0 % versus 12.9 % (p < 0.01) and remission rates of 33.9 % versus 4.1 % (p < 0.05). Results from the Chronos study The Chronos study, published in three papers, covers a one-week intervention phase, a seven weeks continuation phase, and a 20 weeks follow-up phase. Results from the intervention week showed that patient treated in the wake group, from the day after the first wake therapy, had en clinically and statistically significant better antidepressant effect compared to the exercise group. On the HAM-D6 scale (which does not contains sleep items), patients in the wake group had a response rate after the first wake therapy of 58.7% versus 13.7% i the exercise group (p <0.0001) and a remission rate of 38.6% versus 2.9% (p <0.0001). After the second recovery sleep (the night after the second wake therapy = dag 5) patients in the wake group had a response rate of 75.0% versus 25.1% in the exercise group (p <0.0001) and remission rates of 58.6% versus 6.0% (p <0.0001). Results from the continuation phase showed, on the HAM-D17 scale which was used at all the following assessments, at week two response rates of 41.4% in the wake group and 12.8% in the exercise group (p = 0.003) and remission rates of 23.9% versus 5.4% (p = 0,004). This clinically relevant and statistically significant difference between the wake and exercise groups was maintained at all the subsequent assessments with response rates of 71.4% versus 47.3% (p = 0.04) and remission rates of 45.6% versus 23.1% (p = 0.04), at week nine. Results from the 20 weeks follow-up phase showed a continued better effect in the wake group at all visits with HAM-D17 depression scored at week 29 of 7.5 (SE = 0.9) in the wake group versus 10.1 (SE = 0.9), (p = 0.02) in the exercise group. Remission rates were higher in the wake group with endpoint rates of 61.9% versus 37.9% (p = 0.01) in the exercise group. Response rates was only numerically, but not statistically, higher in the wake group with 74.6% versus 64.4% in the exercise group (p = 0.22). The sleep diary data showed a statistically smaller day-to-day variation in sleep onset, sleep midpoint, sleep offset and sleep duration in the wake group compared to the exercise group as a sign of better day-to-day sleep-wake cycle control in the wake group (p < 0.01). In the first nine weeks of the study patients in the wake group had a moderate sleep phase advance that diminished during the follow-up period. The hypothesised predictors for response to wake therapy were confirmed. Thus, in the wake group, a positive diurnal variation (morning worst, evening best) was associated with a better out-come, after the wake therapies, compared to a negative diurnal variation (morning best, evening worst). In the exercise group, the reverse was found, as a positive diurnal variation was associated with worse outcome, compared to a negative diurnal variation. This interaction between group and diurnal variation was statistically significant (p = 0.0004). The positive predictive value of response to the first wake therapy (i.e. maintaining response also at week two) was 56.3 % and the negative predictive value of non-response to the first wake therapy (i.e. maintaining no response also at week two) was 75.0 %. The impact of naps on depression severity was examined. In the wake group, patients who napped on the days after wake therapy compared to those patients not napping, had a more severe deterioration at the following assessment at week two (p = 0.02). Patients in the exercise group were able to perform exercise with a mean of 63.0 minutes/day (55.3) for the first eight weeks.
Topics: Antidepressive Agents; Depressive Disorder, Major; Double-Blind Method; Exercise Therapy; Female; Humans; Male; Phototherapy; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Severity of Illness Index; Transcranial Magnetic Stimulation; Treatment Outcome
PubMed: 28385173
DOI: No ID Found -
Scientific Reports Jan 2017Mechanisms underlying β-adrenoreceptor (βAR) inverse agonist mediated bronchoprotectiveness remain unknown. We incubated ICI118,551, formoterol, budesonide, and...
Mechanisms underlying β-adrenoreceptor (βAR) inverse agonist mediated bronchoprotectiveness remain unknown. We incubated ICI118,551, formoterol, budesonide, and formoterol plus budesonide, as well as ICI118,551 or pindolol plus formoterol, ICI118,551 plus forskolin, SQ22,536 or H89 plus formoterol in ASMCs to detect expressions of MR, PLCβ and IP. The level of MR in the presence of 10 mmol/L ICI118,551 were significantly decreased at 12 h, 24 h and 48 h (P < 0.05), and at 24 h were significantly reduced in ICI118,551 with concentration of 10mmol/L, 10mmol/L, 10mmol/L, and 10mmol/L (P < 0.05). The level of IP in 10mmol/L ICI118,551 was significantly diminished at 24 h (P < 0.01), except for that at 1 h, neither was in the level of PLCβ. A concentration of 10mmol/L ICI118,551 at 24 h showed a significant reduction of MR level compared to formoterol (P < 0.01), budesonide (P < 0.01), and formoterol + budesonide (P < 0.05), but significant reduction of PLCβ and IP was only found between 10mmol/L ICI118,551 and formoterol at 24 h, but not in the comparison of budesonide or formoterol + budesonide. Pindolol and H89 could not inhibit the formoterol-induced expression of MR (P > 0.05), but SQ22,536 significantly antagonized the formoterol-induced MR expression (P < 0.05). In conclusions, βAR inverse agonist, ICI118,551, exerts similar bronchoprotective effects to corticosteroids via decreasing the expression of MR and inhibiting the production of IP.
Topics: Adrenergic beta-2 Receptor Agonists; Animals; Bronchodilator Agents; Cells, Cultured; Colforsin; Down-Regulation; Drug Inverse Agonism; Formoterol Fumarate; Inositol 1,4,5-Trisphosphate; Male; Myocytes, Smooth Muscle; Phospholipase C beta; Pindolol; Rats; Rats, Wistar; Receptor, Muscarinic M3; Receptors, Adrenergic, beta-2
PubMed: 28051147
DOI: 10.1038/srep39905