- Inhibitory effects of Mas-related gene (Mrg) C receptor on chronic morphine-induced spinal glial activation. [Journal Article]
- JPJ Pharmacol Exp Ther 2018 Nov 28
- Glial activation plays a pivotal role in morphine tolerance. This study investigated effect of Mas-related gene (Mrg) C receptor on morphine-induced activation of microglia and astrocytes in the spin...
Glial activation plays a pivotal role in morphine tolerance. This study investigated effect of Mas-related gene (Mrg) C receptor on morphine-induced activation of microglia and astrocytes in the spinal cord and its underlying mechanisms. Intrathecal (i.t.) administration of morphine (20 µg, daily) for 6 days induced a great decline of morphine antinociception and increased expression of GFAP and OX-42 in the spinal dorsal horn. These changes were greatly attenuated by the intermittent co-injection of bovine adrenal medulla 8-22 (BAM8-22, 1 nmol), a specific agonist of MrgC receptor. These modulatory effects were accompanied by the reduction of P2X4 and interleukin-1β (IL-1β) expressions in the spinal dorsal horn. Chronic morphine increased the expression of fractalkine in medium- and small-sized neurons of dorsal root ganglia (DRG). The treatment of BAM8-22 inhibited these changes as well as the increase of TLR4 protein in DRG. Chronic treatment of DRG explant cultures with morphine (3.3 µM, 5 days) increased the levels of fractalkine mRNA. Application of BAM8-22 (10 nM) for 60 min completely blocked the increase of fractalkine mRNA induced by morphine. Our findings indicate that the inhibition of morphine tolerance by MrgC receptor was associated with the modulation of astrocytes and microglia in the spinal dorsal horn and fractalkine and TLR4 expressions in DRG. As MrgC receptor is exclusively located in DRG, intermittent combination of MrgC receptor agonist could be a promising adjunct for chronic use of opiates with limited side effects.
- Development of human target validation classification that predicts future clinical efficacy. [Journal Article]
- JPJ Pharmacol Exp Ther 2018 Nov 27
- Fewer new medicines have become available to patients during the last decades. Clinical efficacy failures in late phase development have been identified as a common cause of this decline. Improved wa...
Fewer new medicines have become available to patients during the last decades. Clinical efficacy failures in late phase development have been identified as a common cause of this decline. Improved ways to ensure early selection of the right drug targets when it comes to efficacy is therefore a highly desirable goal. The aim of this work was to develop a strategy to facilitate selection of novel targets already in the discovery phase which later on in clinical development would demonstrate efficacy. A cross-functional team at AstraZeneca with extensive experience of drug discovery and development participated in several workshops to identify the critical elements that contribute to building human target validation (HTV; the relevance of the target from a human perspective). The elements were consolidated into a ten-point HTV classification system that was ranked from lowest to highest in terms of perceived impact on future clinical efficacy. Using fifty years of legacy research and development (R&D) data the ability of the ten-point HTV classification to predict future clinical efficacy was evaluated. Drug targets were classified as having low, medium or high HTV at the time of candidate drug (CD) selection. Comparing this HTV classification with later clinical development efficacy data showed that HTV classification was highly predictive of future clinical efficacy success. This new strategy for HTV assessment provides a novel approach to early prediction of clinical efficacy and a better understanding of portfolio risk.
- Reversal and prevention of the respiratory-depressant effects of heroin by the novel µ opioid receptor antagonist methocinnamox in rhesus monkeys. [Journal Article]
- JPJ Pharmacol Exp Ther 2018 Nov 21
- One consequence of the ongoing opioid epidemic is a large number of overdose deaths. Naloxone reverses opioid-induced respiratory depression; however, its short duration of action limits the protecti...
One consequence of the ongoing opioid epidemic is a large number of overdose deaths. Naloxone reverses opioid-induced respiratory depression; however, its short duration of action limits the protection it can provide. Methocinnamox (MCAM) is a novel opioid receptor antagonist with a long duration of action. This study examined the ability of MCAM to prevent and reverse the respiratory-depressant effects (minute volume [VE]) of heroin in 5 monkeys. MCAM (0.32 mg/kg) was given before heroin to determine whether it prevents respiratory depression; heroin dose-effect curves were generated 1, 2, 4, and 8 days later, and these effects were compared to those of naltrexone (0.032 mg/kg). Heroin dose dependently decreased VE. MCAM and naltrexone prevented respiratory depression, shifting the heroin dose-effect curve at least 10-fold rightward. MCAM, but not naltrexone, attenuated these effects of heroin for 4 days. MCAM (0.1-0.32 mg/kg) was given 30 min after heroin to determine whether it reverses respiratory depression; heroin dose-effect curves were generated 1, 2, 4, 8, and 16 days later, and these effects were compared to those of naloxone (0.0032-0.1 mg/kg). MCAM and naloxone reversed respiratory depression within 30 min, although only MCAM antagonized heroin on subsequent days. Thus, MCAM prevents and reverses respiratory depression, the potentially lethal effect of heroin, longer than currently used opioid receptor antagonists. Because of its sustained effects, MCAM might provide more effective rescue from and protection against the fatal respiratory-depressant effects of opioids, thereby improving treatment of opioid overdose.
- Nicotine modulates growth factors and microRNA to promote inflammatory and fibrotic processes. [Journal Article]
- JPJ Pharmacol Exp Ther 2018 Nov 16
- Idiopathic pulmonary fibrosis (IPF) is a fatal disease that destroys the structure and function of the lungs. Risk factors include advanced age and genetic predisposition. However, tobacco use is the...
Idiopathic pulmonary fibrosis (IPF) is a fatal disease that destroys the structure and function of the lungs. Risk factors include advanced age and genetic predisposition. However, tobacco use is the chief modifiable risk factor. The prevalence of tobacco use in IPF reaches up to 80%. Although tobacco smoke contains over 5,000 chemicals, nicotine is a major component. Nicotine is a bioactive molecule that acts upon nicotinic acetylcholine receptors expressed on neuronal and non-neuronal cells including endothelial cells. Accordingly, it has pleiotropic effect including on cell proliferation and angiogenesis. The angiogenic effect is partly mediated by stimulation of growth factors including FGF, PDGF, and VEGF. Nintedanib, FDA-approved drug for IPF, works by inhibiting receptors for these growth factors suggesting pathobiologic role of the growth factors in IPF, and a potential mechanism by which tobacco use may exacerbate the disease process. Additionally, nicotine downregulates anti-inflammatory microRNAs (miRs) in lung cells. Here, we profiled the expression of miRs in lung tissues explanted from lung injury model and examined the effect of nicotine on one of the identified miRs (miR-24) and its downstream targets. Our data shows that miR-24 is downregulated during lung injury and is suppressed by nicotine. We also found that nicotine upregulates the expression of inflammatory cytokines targeted by miR-24. Finally, nicotine stimulated growth factors, fibroblast proliferation, collagen release and expression of myofibroblast markers. Taken together, nicotine, alone or as component of tobacco smoke, may accelerate the disease process in IPF through stimulation of growth factors and downregulation of anti-inflammatory miRs.
- Alpha-tocopherol potentiates the cervical resistance decreasing effects of COX-inhibitors in pregnant rats: the putative role of cyclooxygenase-2 inhibition. [Journal Article]
- JPJ Pharmacol Exp Ther 2018 Nov 15
- Vitamin E and their analogues as antioxidant and lipid soluble compounds can have diverse effects on the physiological processes. By binding to receptors and enzymes, they may modify the action of dr...
Vitamin E and their analogues as antioxidant and lipid soluble compounds can have diverse effects on the physiological processes. By binding to receptors and enzymes, they may modify the action of drugs. It has been proved that alpha-tocopherol succinate modifies the effects of β2 agonist terbutaline and cyclooxygenase (COX) inhibitors on rat trachea and myometrium. Our aim was to investigate how alpha-tocopherol and COX inhibitors may influence cervical resistance in rats. The cervical resistance of non-pregnant and 22-day-pregnant Sprague-Dawley rats was determined in an isolated organ bath in vitro. Alpha-tocopherol-succinate (10-7 M) was used, while the COX non-selective diclofenac (10-6 M), the COX-2 selective rofecoxib (10-6 M) and the COX-1 selective SC-560 (10-6 M) were applied as inhibitors. The COX activities of the cervices were measured by enzyme-immunoassay. The modifying effect of single doses of COX-inhibitors and tocopherol on the onset of labor was investigated in vivo. The cervical resistance of non-pregnant samples was not changed by either alpha-tocopherol or COX inhibitors. On pregnant cervices, tocopherol, diclofenac or rofecoxib pretreatment decreased cervical resistance that was further reduced by COX-inhibitors after pretreatment with tocopherol. Alpha-tocopherol elicited a significant COX-2 enzyme inhibition in pregnant cervical samples. By co-administration of tocopherol and rofecoxib, the parturition was initiated earlier than in the other groups. It is supposed that COXs play a significant role not only in cervical ripening, but also in the contraction of the cervical smooth muscle a few hours before parturition. This latter action may be developed by COX-2 liberated prostaglandins.
- A pragmatic utility function to describe the risk-benefit composite of opioid and non-opioid analgesic medication. [Journal Article]
- JPJ Pharmacol Exp Ther 2018 Nov 15
- It is not straightforward to simultaneously evaluate benefits and harms of pain management, as different drugs may possess different analgesia and adverse effect profiles. Utility functions, derived ...
It is not straightforward to simultaneously evaluate benefits and harms of pain management, as different drugs may possess different analgesia and adverse effect profiles. Utility functions, derived from the pharmacokinetics and pharmacodynamics of individual outcome parameters, have been constructed to address this problem. Here we construct "pragmatic" utility functions based on measurements of benefit and harms, but without making assumptions about the underlying pharmacokinetics and pharmacodynamics. Using data from two previous studies, utility functions were designed by estimating the probability of occurrence of benefit and harm and combining these into one function. Study 1 was a clinical trial on the effect of oral pregabalin on pain relief in chronic pancreatitis patients, with end-points analgesia and dizziness monitored for 21 days. Study 2 was an experimental study on the effect of intravenous fentanyl on antinociception and respiratory depression in healthy volunteers. From study 1 the utility function was negative the first week of treatment, indicative of the greater probability of dizziness than analgesia, but positive thereafter. From study 2 the utility function showed a nadir 30 minutes after dosing, after which the probability function slowly increased towards zero. A pragmatic utility function based on the probability of two binary outcomes, analgesia and adverse effect, was successfully constructed using data from two previous studies. Results yielded valuable insights into the utility of treatment and may be highly educative for physicians and may be used in development of potent analgesics with serious side effects.
- Transient Receptor Potential (TRP) Ion Channel - Dependent Toxicity of Silica Nanoparticles and Poly(amido amine) (PAMAM) Dendrimers. [Journal Article]
- JPJ Pharmacol Exp Ther 2018 Nov 15
- Fundamental to the design and development of nanoparticles for applications in nanomedicine is a detailed understanding of their biological fate and potential toxic effects. Transient receptor potent...
Fundamental to the design and development of nanoparticles for applications in nanomedicine is a detailed understanding of their biological fate and potential toxic effects. Transient receptor potential (TRP) ion channels are a large superfamily of cation channels with varied physiological functions. This superfamily is classified into six related subfamilies; TRPC (canonical), V (vanilloid), M (melastatin), A (ankyrin), P (polycystin) and ML (mucolipin). TRPA1, M2 and M8 are nonselective Ca2+-permeable cation channels which regulate calcium pathways under oxidative stress. Some of these channels are highly expressed in immune cells where they can regulate cytokine production and inflammatory responses. Using a series of well characterized silica nanoparticles with variations in size (approximately 50-350 nm in diameter) and porosity, as well as cationic and anionic poly(amido amine) (PAMAM) dendrimers of similar size, we examined the toxicity of these nanoparticles to HEK-293 cells overexpressing different TRP channels. Our data shows that the toxicity of smaller and mesoporous silica nanoparticles was influenced by expression of the TRPM2 and TRPM8 channels, while only mesoporous SiNPs showed TRPA1-related toxicity. Additionally, TRPA1 and TRPM2 played a role in the toxicity of cationic dendrimers, but not for anionic dendrimers. TRPV4 does not seem to play a significant role in silica nanoparticle or PAMAM toxicity.
- Convulsant effects of abused synthetic cannabinoids JWH-018 and 5F-AB-PINACA are mediated by agonist actions at CB1 receptors in mice. [Journal Article]
- JPJ Pharmacol Exp Ther 2018 Nov 12
- Convulsant effects of abused synthetic cannabinoid (SCB) drugs have been reported in humans and laboratory animals, but the mechanism of these effects is not known. We compared convulsant effects of ...
Convulsant effects of abused synthetic cannabinoid (SCB) drugs have been reported in humans and laboratory animals, but the mechanism of these effects is not known. We compared convulsant effects of partial CB1R agonist ∆9-tetrahydrocannabinol (THC), full CB1R agonist SCBs JWH-018 and 5F-AB-PINACA, and classical chemical convulsant pentylenetetrazol (PTZ) using an observational rating scale in mice. THC did not elicit convulsions, but both SCBs did so as effectively and more potently than PTZ. SCB-elicited convulsions were attenuated by the CB1R antagonist rimonabant or by THC, or by dose regimens of THC and JWH-018 which downregulate and desensitize CB1Rs. None of these treatments altered the convulsant effects of PTZ, although diazepam attenuated PTZ-elicited convulsions without altering SCB-induced convulsant effects. Repeated administration of a sub-threshold dose of PTZ kindled convulsant effects, but this was not observed with the SCBs, and no cross-kindling was observed. Repeated administration of the SCBs resulted in tolerance to convulsant effects, but no cross-tolerance to PTZ was observed. Inhibition on Phase I metabolism via non-selective inhibition of CYP450s with 1-aminobenzotriazole (1-ABT) potentiated the hypothermic effects of the SCBs and protected against the convulsant effects of JWH-018, but not those of 5F-AB-PINACA or PTZ. Incubation of human liver microsomes with the SCBs showed that JWH-018 is eliminated via oxidation, while 5F-AB-PINACA is not. These studies suggest that SCB-elicited convulsions are mediated by high intrinsic efficacy at CB1Rs, and that benzodiazepines may not be effective treatments. Finally, drug metabolism may dramatically modulate the convulsant effects of some, but not all, SCBs.
- Experimental evidence for re-secretion of PGE2 across rat alveolar epithelium by OATP2A1/SLCO2A1-mediated transcellular transport. [Journal Article]
- JPJ Pharmacol Exp Ther 2018 Nov 12
- Prostaglandin transporter Oatp2a1/Slco2a1 is expressed at the apical (AP) membranes of type-1 alveolar epithelial (AT1) cells. To investigate the role of OATP2A1 in PGE2 handling by alveolar epitheli...
Prostaglandin transporter Oatp2a1/Slco2a1 is expressed at the apical (AP) membranes of type-1 alveolar epithelial (AT1) cells. To investigate the role of OATP2A1 in PGE2 handling by alveolar epithelium, we studied PGE2 transport across and secretion from monolayers of rat AT1-like (AT1-L) cells obtained by trans-differentiation of type-2 alveolar epithelial cells (AT2) isolated from male Wistar rats. Rat AT1-L cells expressed Oatp2a1/Slco2a1, together with smaller amounts of Mrp4/Abcc4 and Oct1/Slc22a1 PGE2 uptake was saturable with Km 43.9 ± 21.9 nM. Transcellular transport of PGE2 across AT1-L cells grown on permeable filters in the AP-to-basolateral (BL) direction was 5-fold greater than that in the reverse direction, and was saturable with Km 118 ± 26.8 nM; it was significantly inhibited by OATP inhibitors, bromosulfophthalein (BSP) and suramin, and an MRP4 inhibitor, ceefourin-1. The effects of BSP on the distribution of PGE2 produced by bradykinin-treated AT1-L cells and PGE2-d4 externally added on the AP side of the cells were simultaneously monitored. In the presence of BSP, PGE2 increased more rapidly on the AP side, while PGE2-d4 decreased more slowly on the AP side. The decrease in PGE2-d4 from the AP side corresponded well to the increase on the BL side, indicating that intracellular metabolism did not occur. These results suggest that Oatp2a1 and Mrp4 mediate transepithelial transport of PGE2 in the AP-to-BL direction. Therefore, OATP2A1 may be an important regulator of PGE2 in alveolar epithelium by reducing secretion of PGE2 and facilitating "re-secreting" PGE2 present in the alveolar lumen to the interstitial space or blood.
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- Towards Further Verification of Physiologically-Based Kidney Models: Predictability of the Effects of Urine-Flow and Urine-pH on Renal Clearance. [Journal Article]
- JPJ Pharmacol Exp Ther 2018 Nov 09
- In vitro-in vivo extrapolation (IVIVE) of renal excretory clearance (CLR) using the physiologically-based kidney models can provide mechanistic insight into the interplay of multiple processes occurr...
In vitro-in vivo extrapolation (IVIVE) of renal excretory clearance (CLR) using the physiologically-based kidney models can provide mechanistic insight into the interplay of multiple processes occurring in the renal tubule. However, the ability of these models to quantitatively capture the impact of perturbed conditions (e.g., urine flow/ urine pH changes) on CLR has not been fully evaluated. The current work aimed to assess the predictability of the effect of urine flow and urine pH on CLR and tubular drug concentrations (selected examples). Passive diffusion clearance across the nephron tubule membrane was scaled from in vitro Caco-2 permeability data by nephron tubular surface area to predict fraction reabsorbed and CLR of caffeine, chloramphenicol, creatinine, dextroamphetamine, nicotine, sulfamethoxazole and theophylline. CLR values predicted using mechanistic kidney model at urinary pH of 6.2 and 7.4 resulted in prediction bias of 2.87 and 3.62-fold, respectively. Model simulations captured urine flow dependent CLR, albeit with minor under-prediction of the observed magnitude of change. The relationship between drug solubility, urine flow and urine pH, illustrated in simulated intra-tubular concentrations of acyclovir and sulfamethoxazole, was in agreement with clinical data on tubular precipitation and crystal-induced acute kidney injury. This study represents the first systematic evaluation of the ability of the mechanistic kidney model to capture the impact of urine flow and urine pH on CLR and drug tubular concentrations with the aim to facilitate refinement of IVIVE-based mechanistic prediction of renal excretion.