Systemic hypertonic saline enhances glymphatic spinal cord delivery of lumbar intrathecal morphine

The blood-brain barrier significantly limits effective drug delivery to central nervous system (CNS) targets. The recently characterized glymphatic system offers a perivascular highway for intrathecally (i.t.) administered drugs to reach deep brain structures. Although periarterial cerebrospinal fluid (CSF) influx and concomitant brain drug delivery can be enhanced by pharmacological or hyperosmotic interventions, their effects on drug delivery to the spinal cord, an important target for many drugs, have not been addressed. Hence, we studied in rats whether enhancement of periarterial flow by systemic hypertonic solution might be utilized to enhance spinal delivery and efficacy of i.t. morphine. We also studied whether the hyperosmolar intervention affects brain or cerebrospinal fluid drug concentrations after systemic administration. Periarterial CSF influx was enhanced by intraperitoneal injection of hypertonic saline (HTS, 5.8%, 20 ml/kg, 40 mOsm/kg). The antinociceptive effects of morphine were characterized, using tail flick, hot plate and paw pressure tests. Drug concentrations in serum, tissue and microdialysis samples were determined by liquid chromatography-tandem mass spectrometry. Compared with isotonic solution, HTS increased concentrations of spinal i.t. administered morphine by 240% at the administration level (T13-L1) at 60 min and increased the antinociceptive effect of morphine in tail flick, hot plate, and paw pressure tests. HTS also independently increased hot plate and paw pressure latencies but had no effect in the tail flick test. HTS transiently increased the penetration of intravenous morphine into the lateral ventricle, but not into the hippocampus. In conclusion, acute systemic hyperosmolality is a promising intervention for enhanced spinal delivery of i.t. administered morphine. The relevance of this intervention should be expanded to other i.t. drugs and brought to clinical trials.Peer reviewe

A comprehensive pharmacogenomic study indicates roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics

AimsThe aim was to comprehensively investigate the effects of genetic variability on the pharmacokinetics of rosuvastatin.MethodsWe conducted a genome-wide association study and candidate gene analyses of single dose rosuvastatin pharmacokinetics in a prospective study (n = 159) and a cohort of previously published studies (n = 88).ResultsIn a genome-wide association meta-analysis of the prospective study and the cohort of previously published studies, the SLCO1B1 c.521 T > C (rs4149056) single nucleotide variation (SNV) associated with increased area under the plasma concentration–time curve (AUC) and peak plasma concentration of rosuvastatin (P = 1.8 × 10−12 and P = 3.2 × 10−15). The candidate gene analysis suggested that the ABCG2 c.421C > A (rs2231142) SNV associates with increased rosuvastatin AUC (P = .0079), while the SLCO1B1 c.388A > G (rs2306283) and SLCO2B1 c.1457C > T (rs2306168) SNVs associate with decreased rosuvastatin AUC (P = .0041 and P = .0076). Based on SLCO1B1 genotypes, we stratified the participants into poor, decreased, normal, increased and highly increased organic anion transporting polypeptide (OATP) 1B1 function groups. The OATP1B1 poor function phenotype associated with 2.1-fold (90% confidence interval 1.6–2.8, P = 4.69 × 10−5) increased AUC of rosuvastatin, whereas the OATP1B1 highly increased function phenotype associated with a 44% (16–62%; P = .019) decreased rosuvastatin AUC. The ABCG2 c.421A/A genotype associated with 2.2-fold (1.5–3.0; P = 2.6 × 10−4) increased AUC of rosuvastatin. The SLCO2B1 c.1457C/T genotype associated with 28% decreased rosuvastatin AUC (11–42%; P = .01).ConclusionThese data suggest roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics. Poor SLCO1B1 or ABCG2 function genotypes may increase the risk of rosuvastatin-induced myotoxicity. Reduced doses of rosuvastatin are advisable for patients with these genotypes.</p

Dexmedetomidine enhances glymphatic brain delivery of intrathecally administered drugs

Drug delivery to the central nervous system remains a major problem due to biological barriers. The blood-brainbarrier can be bypassed by administering drugs intrathecally directly to the cerebrospinal fluid (CSF). The glymphatic system, a network of perivascular spaces promoting fluid exchange between CSF and interstitial space, could be utilized to enhance convective drug delivery from the CSF to the parenchyma. Glymphatic flow is highest during sleep and anesthesia regimens that induce a slow-wave sleep-like state. Here, using mass spectrometry and fluorescent imaging techniques, we show that the clinically used alpha(2)-adrenergic agonist dexme-detomidine that enhances EEG slow-wave activity, increases brain and spinal cord drug exposure of intrathecally administered drugs in mice and rats. Using oxycodone, naloxone, and an IgG-sized antibody as relevant model drugs we demonstrate that modulation of glymphatic flow has a distinct impact on the distribution of intrathecally administered therapeutics. These findings can be exploited in the clinic to improve the efficacy and safety of intrathecally administered therapeutics.Peer reviewe

Effect of the first wave of COVID-19 on Poison Control Centre activities in 21 European countries : an EAPCCT initiative

Peer reviewe

Glymfaattinen järjestelmä avaa aivojen padot

Tiivistelmä Glymfaattinen (glia-lymfaattinen) järjestelmä eli glianestekierto on aivojen perivaskulaarinen puhdistusjärjestelmä, joka toimii syvän unen ja anestesian aikana ja mahdollistaa aivo-selkäydinnesteen virtauksen aivokudokseen huuhtomaan valveen aikana kertyneitä aineenvaihduntatuotteita. Aivo-selkäydinneste sukeltaa aivoihin valtimoita ympäröivissä perivaskulaaritiloissa ja pääsee aivokudokseen perivaskulaaritiloja ympäröivien astrosyyttien akvaporiini 4 (AQP4) -vesikanavien avustamana. Aivokudoksessa solunulkoinen neste ja sen sisältämät aineenvaihduntatuotteet, kuten beeta-amyloidi, sekoittuvat aivo-selkäydinnesteeseen. Tämä neste poistuu aivojen soluvälitilasta laskimoiden perivaskulaaritilojen kautta käyttämällä useita ulosvirtausreittejä, muun muassa aivokalvojen imusuonia. Glymfaattisen järjestelmän puutteellisen toiminnan arvellaan altistavan aivojen rappeumasairauksille sekä heikentävän toipumista aivoverenkiertohäiriöstä tai aivovammasta. Järjestelmän toimintaa tehostamalla voitaisiin puolestaan ehkäistä aivojen rappeumasairauksia tai edesauttaa esimerkiksi lääkkeiden pääsyä keskushermostoon. Glymfaattinen järjestelmä kuvattiin ensin koe-eläintutkimuksissa, ja ihmisen vastaavasta järjestelmästä tarvitaan vielä lisää tutkimusnäyttöä.Abstract The glymphatic (glial-lymphatic) system is mainly active during deep sleep and anesthesia, and allows the passage of cerebrospinal fluid into the brain parenchyma to wash the brain of harmful endogenous metabolic waste. Cerebrospinal fluid flows from the subarachnoid space to the periarterial spaces, and enters the brain parenchyma facilitated by astrocytic aquaporin 4 (AQP4) water channels. In the brain parenchyma, metabolic waste products in the interstitial fluid mix with the cerebrospinal fluid. This solute-containing fluid then flows to the perivenous spaces and is drained from the brain through several efflux routes, including the meningeal lymphatic vessels. Impaired glymphatic flow may contribute to the pathogenesis of several chronic neurodegenerative diseases and poor recovery from traumatic brain injury and ischemic stroke. On the other hand, enhancing glymphatic flow might help to prevent neurodegenerative diseases or facilitate drug delivery to the central nervous system. Although the glymphatic system was first described in rodents, recent studies suggest that a similar system functions in the human brain

Introduction of an electrochemical point-of-care assay for quantitative determination of paracetamol in finger-prick capillary whole blood samples

AimsMeasuring venous plasma paracetamol concentrations is time- and resource-consuming. We aimed to validate a novel electrochemical point-of-care (POC) assay for rapid paracetamol concentration determinations. MethodsTwelve healthy volunteers received 1 g oral paracetamol, and its concentrations were analysed 10 times over 12 h for capillary whole blood (POC), venous plasma (high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS)), and dried capillary blood (HPLC-MS/MS). ResultsAt concentrations >30 mu M, POC showed upward biases of 20% (95% limits of agreement [LOA] -22 to 62) and 7% (95% LOA -23 to 38) compared with venous plasma and capillary blood HPLC-MS/MS, respectively. There were no significant differences between mean concentrations for the paracetamol elimination phase. ConclusionsUpward biases in POC compared with venous plasma HPLC-MS/MS were likely due to higher paracetamol concentrations in capillary blood than in venous plasma and to faulty individual sensors. The novel POC method is a promising tool for paracetamol concentration analysis.Peer reviewe

Genomewide Association Study of Simvastatin Pharmacokinetics

We investigated genetic determinants of single-dose simvastatin pharmacokinetics in a prospective study of 170 subjects and a retrospective cohort of 59 healthy volunteers. In a microarray-based genomewide association study with the prospective data, the SLCO1B1 c.521T>C (p.Val174Ala, rs4149056) single nucleotide variation showed the strongest, genomewide significant association with the area under the plasma simvastatin acid concentration-time curve (AUC; P = 6.0 x 10(-10)). Meta-analysis with the retrospective cohort strengthened the association (P = 1.6 x 10(-17)). In a stepwise linear regression candidate gene analysis among all 229 participants, SLCO1B1 c.521T>C (P = 1.9 x 10(-13)) and CYP3A4 c.664T>C (p.Ser222Pro, rs55785340, CYP3A4*2, P = 0.023) were associated with increased simvastatin acid AUC. Moreover, the SLCO1B1 c.463C>A (p.Pro155Thr, rs11045819, P = 7.2 x 10(-6)) and c.1929A>C (p.Leu643Phe, rs34671512, P = 5.3 x 10(-4)) variants associated with decreased simvastatin acid AUC. Based on these results and the literature, we classified the volunteers into genotype-predicted OATP1B1 and CYP3A4 phenotype groups. Compared with the normal OATP1B1 function group, simvastatin acid AUC was 273% larger in the poor (90% confidence interval (CI), 137%, 488%; P = 3.1 x 10(-6)), 40% larger in the decreased (90% CI, 8%, 83%; P = 0.036), and 67% smaller in the highly increased function group (90% CI, 46%, 80%; P = 2.4 x 10(-4)). Intermediate CYP3A4 metabolizers (i.e., heterozygous carriers of either CYP3A4*2 or CYP3A4*22 (rs35599367)), had 87% (90% CI, 39%, 152%, P = 6.4 x 10(-4)) larger simvastatin acid AUC than normal metabolizers. These data suggest that in addition to no function SLCO1B1 variants, increased function SLCO1B1 variants and reduced function CYP3A4 variants may affect the pharmacokinetics, efficacy, and safety of simvastatin. Care is warranted if simvastatin is prescribed to patients carrying decreased function SLCO1B1 or CYP3A4 alleles.Peer reviewe

The glymphatic system:current understanding and modeling

Abstract We review theoretical and numerical models of the glymphatic system, which circulates cerebrospinal fluid and interstitial fluid around the brain, facilitating solute transport. Models enable hypothesis development and predictions of transport, with clinical applications including drug delivery, stroke, cardiac arrest, and neurodegenerative disorders like Alzheimer’s disease. We sort existing models into broad categories by anatomical function: Perivascular flow, transport in brain parenchyma, interfaces to perivascular spaces, efflux routes, and links to neuronal activity. Needs and opportunities for future work are highlighted wherever possible; new models, expanded models, and novel experiments to inform models could all have tremendous value for advancing the field