Risk to heroin users of poly-drug use of pregabalin or gabapentin

The fluorescent Ca2+ sensitive dyes Fura Red (ratiometric) and Fluo-4 (non-ratiometric) are widely utilized for the optical assessment of Ca2+ fluctuations in vitro as well as in situ. The fluorescent behavior of these dyes is strongly depends on temperature, pH, ionic strength and pressure. It is crucial to understand the response of these dyes to pressure when applying calcium imaging technologies in the field of high pressure bioscience. Therefore, we use an optically accessible pressure vessel to pressurize physiological Ca2+-buffered solutions at different fixed concentrations of free Ca2+ (1 nM to 25.6 μM) and a specified dye concentration (12 μM) to pressures of 200 MPa, and record dye fluorescence intensity. Our results show that Fluo-4 fluorescence intensity is reduced by 31% per 100 MPa, the intensity of Fura Red is reduced by 10% per 100 MPa. The mean reaction volume for the dissociation of calcium from the dye molecules [Formula: see text] is determined to -17.8 ml mol-1 for Fluo-4 and -21.3 ml mol-1 for Fura Red. Additionally, a model is presented that is used to correct for pressure-dependent changes in pH and binding affinity of Ca2+ to EGTA, as well as to determine the influence of these changes on dye fluorescence

Risk to heroin users of poly-drug use of pregabalin or gabapentin

AIM: To examine the risk to heroin users of also using gabapentin or pregabalin (gabapentoids). DESIGN: Multi-disciplinary study: we (a) examined trends in drug-related deaths and gabapentoid prescription data in England and Wales to test for evidence that any increase in deaths mentioning gabapentin or pregabalin is associated with trends in gabapentoid prescribing and is concomitant with opioid use; (b) interviewed people with a history of heroin use about their polydrug use involving gabapentin and pregabalin; and (c) studied the respiratory depressant effects of pregabalin in the absence and presence of morphine in mice to determine whether concomitant exposure increased the degree of respiratory depression observed. SETTING: England and Wales. Interviews were conducted with 30 participants (19 males, 11 female). MEASUREMENTS: (a) Office of National Statistics drug-related deaths from 1 January 2004 to 31 December 2015 that mention both an opioid and pregabalin or gabapentin; (b) subjective views on the availability, use, interactions and effects of polydrug use involving pregabalin and gabapentin; and (c) rate and depth of respiration. RESULTS: Pregabalin and gabapentin prescriptions increased approximately 24% per year from 1 million in 2004 to 10.5 million in 2015. The number of deaths involving gabapentoids increased from fewer than one per year prior to 2009 to 137 in 2015; 79% of these deaths also involved opioids. The increase in deaths was correlated highly with the increase in prescribing (correlation coefficient 0.94; 5% increase in deaths per 100 000 increase in prescriptions). Heroin users described pregabalin as easy to obtain. They suggested that the combination of heroin and pregabalin reinforced the effects of heroin but were concerned it induced 'blackouts' and increased the risk of overdose. In mice, a low dose of S-pregabalin (20 mg/kg) that did not itself depress respiration reversed tolerance to morphine depression of respiration (resulting in 35% depression of respiration, P < 0.05), whereas a high dose of S-pregabalin (200 mg/kg) alone depressed respiration and this effect summated with that of morphine. CONCLUSIONS: For heroin users, the combination of opioids with gabapentin or pregabalin potentially increases the risk of acute overdose death through either reversal of tolerance or an additive effect of the drugs to depress respiration

Effect of tamoxifen and brain-penetrant protein kinase c and c-jun n-terminal kinase inhibitors on tolerance to opioid-induced respiratory depression in mice

Respiratory depression is the major cause of death in opioid overdose. We have previously shown that prolonged treatment of mice with morphine induces profound tolerance to the respiratory-depressant effects of the drug (Hill et al., 2016). The aim of the present study was to investigate whether tolerance to opioid-induced respiratory depression is mediated by protein kinase C (PKC) and/or c-Jun N-terminal kinase (JNK). We found that although mice treated for up to 6 days with morphine developed tolerance, as measured by the reduced responsiveness to an acute challenge dose of morphine, administration of the brain-penetrant PKC inhibitors tamoxifen and calphostin C restored the ability of acute morphine to produce respiratory depression in morphine-treated mice. Importantly, reversal of opioid tolerance was dependent on the nature of the opioid ligand used to induce tolerance, as these PKC inhibitors did not reverse tolerance induced by prolonged treatment of mice with methadone nor did they reverse the protection to acute morphine-induced respiratory depression afforded by prolonged treatment with buprenorphine. We found no evidence for the involvement of JNK in morphine-induced tolerance to respiratory depression. These results indicate that PKC represents a major mechanism underlying morphine tolerance, that the mechanism of opioid tolerance to respiratory depression is ligand-dependent, and that coadministration of drugs with PKC-inhibitory activity and morphine (as well as heroin, largely metabolized to morphine in the body) may render individuals more susceptible to overdose death by reversing tolerance to the effects of morphine

A climatological analysis of the southwest monsoon rainfall in the Philippines

The historical behavior of the southwest monsoon (SWM) rainfall in the Philippines is described using observed rainfall during the months of June to September from 1961 to 2010. Data are obtained from meteorological stations situated in the western half of the country where the impact of SWM is well pronounced. Time series analysis indicates significant decreasing trends from 0.026% to 0.075% per decade in the total SWM rainfall in six of the nine stations (Ambulong, Baguio, Coron, Dagupan, Iba and Vigan) in the past 50 years. A rainfall anomaly index is derived to characterize the inter-annual variability and the influence of the El Niño Southern Oscillation on the SWM rainfall. Results show no above normal rainfall events associated with La Niña years and few occurrences of below normal rainfall associated with El Niño events. Years where the SWM rainfall significantly deviates from its climate mean are also identified. Furthermore, an examination of the rainfall extremes indicate an increasing trend in the number of days without rain, which can be detected with statistical confidence in Ambulong (2.9% per decade), Baguio (5.9% per decade) and Dagupan (4.0% per decade), as well as a decreasing trend in the heavy rainfall days. These findings suggest a climatic change towards a prolonged dry period and an overall decreasing trend in rainfall during the SWM season over western Philippines in the recent decades, which can have serious implications on the country\u27s agricultural sector

Fourth Report on Chicken Genes and Chromosomes 2022

International audienc