Browsing by Subject "PHARMACOKINETICS"

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  • Adam, Magdy; Salla, Kati; Aho, Riikka; Hänninen, Laura; Taponen, Suvi; Norring, Marianna; Raekallio, Marja; Hokkanen, Ann-Helena (2021)
    Objective To compare the sedative effects of intramuscular xylazine alone or combined with levomethadone or ketamine in calves before cautery disbudding. Study design Randomized, blinded, clinical trial. Animals A total of 28 dairy calves, aged 21 +/- 5 days and weighing 61.0 +/- 9.3 kg (mean +/- standard deviation). Methods Calves were randomly allocated to three groups: xylazine (0.1 mg kg(-1)) and levomethadone (0.05 mg kg(-1); group XL), xylazine (0.1 mg kg(-1)) and ketamine (1 mg kg(-1); group XK) and xylazine alone (0.2 mg kg(-1); group X). Local anaesthesia (procaine hydrochloride) and meloxicam were administered subcutaneously 15 minutes after sedation and 15 minutes before disbudding. The calves' responses to the administration of local anaesthesia and disbudding were recorded. Sedation was assessed at baseline and at intervals up to 240 minutes postsedation. Times of recumbency, first head lift and first standing were recorded. Drug plasma concentrations were measured. Results Data were obtained from 27 animals. All protocols resulted in sedation sufficient to administer local anaesthesia and to perform disbudding. Sedation scores significantly correlated with drug plasma concentrations (p Conclusions and clinical relevance Levomethadone or ketamine with a low dose of xylazine produced short but sufficient sedation for local anaesthesia and disbudding with minimum resistance.
  • Hirschfield, Gideon M.; Beuers, Ulrich; Kupcinskas, Limas; Ott, Peter; Bergquist, Annika; Färkkilä, Martti; Manns, Michael P.; Pares, Albert; Spengler, Ulrich; Stiess, Michael; Greinwald, Roland; Prols, Markus; Wendum, Dominique; Drebber, Uta; Poupon, Raoul (2021)
    Background & Aims: In patients with primary biliary cholangitis (PBC), the efficacy of budesonide, a synthetic corticosteroid displaying high first-pass metabolism, is unresolved. In a placebo-controlled, double-blind trial, we evaluated the added-value of budesonide in those with PBC and ongoing risk of progressive disease despite ursodeoxycholic acid (UDCA) treatment. Methods: We evaluated 62 patients with PBC who had histologically confirmed hepatic inflammatory activity, according to the Ishak score, and an alkaline phosphatase (ALP) >1.5x upper limit of normal (ULN), after at least 6 months of UDCA therapy. Participants were randomly assigned 2:1 to receive budesonide (9 mg/day) or placebo once daily, for 36 months, with UDCA treatment (12-16 mg/kg body weight/day) maintained. Primary efficacy was defined as improvement of liver histology with respect to inflammation and no progression of fibrosis. Secondary outcomes included changes in biochemical markers of liver injury. Results: Recruitment challenges resulted in a study that was underpowered for the primary efficacy analysis. Comparing patients with paired biopsies only (n = 43), the primary histologic endpoint was not met (p>0.05). The proportion of patients with ALP = 15% decrease in ALP and normal bilirubin was higher in the budesonide group than in the placebo group at 12, 24, and 36 months (p Conclusion: Budesonide add-on therapy was not associated with improved liver histology in patients with PBC and insufficient response to UDCA; however, improvements in biochemical markers of disease activity were demonstrated in secondary analyses. Lay summary: Around one-third of patients with primary biliary cholangitis (PBC) needs additional medical therapy alongside ursodeoxycholic acid (UDCA) treatment. In this clinical trial, the addition of the corticosteroid budesonide did not improve liver histology; there were however relevant improvements in liver blood tests. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V.
  • Tammela, Teuvo L.; Häggman, Michael; Ladjevardi, Sam; Taari, Kimmo; Isotalo, Taina; Lennernäs, Hans; Weis, Jan; von Below, Catrin; Wassberg, Cecilia; Lennernäs, Bo; Tolf, Anna; Axén, Niklas; Gölander, Carl-Gustaf; Ahlström, Håkan (2017)
    Purpose: We investigated the tolerability, safety and antitumor effects of a novel intraprostatic depot formulation of antiandrogen 2-hydroxyflutamide (in Nano-Zolid (R)) in men with localized prostate cancer. Materials and Methods: Two clinical trials, LPC-002 and LPC-003, were performed in a total of 47 men. The formulation was injected transrectally into the prostate under ultrasound guidance. In LPC-002 the effects on prostate specific antigen and prostate volume were measured for 6 months in 24 patients. In LPC-003 antitumor effects were evaluated by histopathology and magnetic resonance imaging including spectroscopy during 6 or 8 weeks in 23 patients. In each study testosterone and 2-hydroxyflutamide in plasma were measured as well as quality of life parameters. Results: In LPC-002 (mean dose 690 mg) a reduction was observed in prostate specific antigen and prostate volume. Average nadir prostate specific antigen and prostate volume were 24.9% and 14.0% below baseline, respectively. When increasing the dose in LPC-003 to 920 and 1,740 mg, average prostate specific antigen decreased 16% and 23% after 6 and 8 weeks, respectively. Magnetic resonance imaging and magnetic resonance spectroscopy showed morphological changes and a global reduction in metabolite concentrations following treatment, indicating an antitumor response. Injections did not result in hormone related side effects. Three serious adverse events were reported and all resolved with oral antibiotic treatment. Conclusions: Intraprostatic injections of 2-hydroxyflutamide depot formulations showed antitumor effects, and proved to be safe and tolerable. However, for better anticancer effects higher doses and better dose distribution are suggested.
  • Cajanus, Kristiina; Neuvonen, Mikko; Koskela, Outi; Kaunisto, Mari A.; Neuvonen, Pertti J.; Niemi, Mikko; Kalso, Eija (2018)
    We investigated factors affecting analgesic oxycodone concentrations after breast cancer surgery in 1,000 women. Preoperatively, we studied heat and cold pain sensitivities and anxiety scores. Postoperatively, rest and motion pain intensities were measured and intravenous oxycodone was administered until satisfactory analgesia. At this point, the mean oxycodone concentration (variation coefficient) was 33.3 ng/mL (66%) and it was 21.7 ng/mL (69%) when the patient requested oxycodone again. At both time points, the concentrations varied >100-fold between individuals. The analgesic oxycodone concentration was increased by 21.3% per motion pain intensity score on a 0-10 scale and by 22.3% if axillary clearance was performed instead of sentinel node biopsy (P <0.001). Forty-seven women who were older and less anxious than others (P <0.01) required no oxycodone. Anxiety, age, chronic pain, or preoperative pain sensitivity were not independently associated with the analgesic oxycodone concentration. CYP2D6 and CYP3A genotypes did not affect analgesic concentration or duration of analgesia.
  • Kolehmainen, Sara; Ylisaukko-Oja, Tero; Jokelainen, Jari; Koivusalo, Mirkka; Jokiranta, T. Sakari; Sipponen, Taina (2021)
    Objectives We set out to determine the reasons for serum vedolizumab (VDZ) trough concentration (TC) measurements in inflammatory bowel disease (IBD) patients and to evaluate treatment modifications after therapeutic drug measurement (TDM). We also evaluated the effect of increased dosing on patients' response to VDZ therapy. Methods We performed a retrospective cohort study of IBD patients who received VDZ therapy at Helsinki University Hospital and whose VDZ levels were measured between June 2014 and December 2018. Results Altogether, 90 patients (32 Crohn's disease and 58 ulcerative colitis) and 141 VDZ TC measurements were included. 24.1% of measurements took place during induction and 75.9% during the maintenance phase. During induction, 64.7% reached the target TC >20 mu g/ml. During maintenance therapy, 82.2% of VDZ TCs were within or exceeded the suggested target range of 5-15 mu g/ml. Reasons for TDM were: secondary nonresponse (44.0%), assessment of adequate VDZ TC (25.5%), primary nonresponse (12.8%), adverse events (6.4%), and other (11.3%). No treatment changes occurred after 60.3% of VDZ measurements. Increased dose frequency was used after 25.5% of VDZ measurements and 33.3% of these patients experienced improvement. Altogether, 31 (34.4%) patients discontinued the therapy due to inadequate treatment response. No anti-vedolizumab antibodies were detected. Conclusions During the maintenance of VDZ therapy, the majority of VDZ TCs were within the suggested range. Measurement of VDZ TC did not lead to any treatment changes in two-thirds of patients. Dose optimization occurred in a quarter of patients and a third of them benefited from it.
  • Hakomaki, Henriikka; Eskola, Sophia; Kokki, Hannu; Lehtonen, Marko; Räsänen, Juha; Laaksonen, Sakari; Voipio, Hanna-Marja; Ranta, Veli-Pekka; Kokki, Merja (2022)
    Buprenorphine is used during pregnancy for the treatment of opioid use disorder. Limited data exist on the central nervous system (CNS) permeation and distribution, and on the fetal exposure to buprenorphine. The aim of our study was to determine the extent of buprenorphine distribution to CNS in the pregnant sheep, and their fetus at steady-state, and their newborn lambs postdelivery, using three different dosing regimens. Twenty-eight pregnant ewes in late gestation received buprenorphine via 7-day transdermal patch releasing buprenorphine 20 mu g/h (n=9) or 40 mu g/h (n=11), or an extended-release 8 mg/week subcutaneous injection (n=8). Plasma, cerebrospinal fluid, and CNS tissue samples were collected at steady-state from ewes and fetuses, and from lambs 0.33 - 45 hours after delivery. High accumulation of buprenorphine was observed in all CNS tissues. The median CNS/plasma concentration-ratios of buprenorphine in different CNS areas ranged between 13 and 50 in the ewes, and between 26 and 198 in the fetuses. In the ewes the CNS/plasma-ratios were similar after the three dosing regimens, but higher in the fetuses in the 40 mu g/h dosing group, medians 65 - 122, than in the 20 mu g/h group, medians 26 - 54. The subcutaneous injection (theoretical release rate 47.6 mu g/h) produced higher concentrations than observed after 40 mu g/h transdermal patch dosing. The median fetal/maternal concentration-ratios in different dosing groups ranged between 0.21 and 0.54 in plasma, and between 0.38 and 1.3 in CNS tissues, respectively, with the highest ratios observed in the spinal cord. Buprenorphine concentrations in the cerebrospinal fluid were 8 - 13 % of the concurrent plasma concentration in the ewes and 28 % in the fetuses. Buprenorphine was quantifiable in the newborn lambs' plasma and CNS tissues two days postdelivery. Norbu-prenorphine was analyzed from all plasma, cerebrospinal fluid, and CNS tissue samples but was nondetectable or below the LLOQ in most. The current study demonstrates that buprenorphine accumulates into CNS tissues at much higher concentrations than in plasma in pregnant sheep, fetuses, and their newborn lambs even 45 hours after delivery.
  • Itkonen, Matti K.; Tornio, Aleksi; Neuvonen, Mikko; Neuvonen, Pertti J.; Niemi, Mikko; Backman, Janne T. (2019)
    A recent in vitro study suggested that CYP2C8 is essential in the metabolism of desloratadine, an H1 receptor antagonist. If the proposed biotransformation mechanism takes place in vivo in humans, desloratadine could serve as a selective CYP2C8 probe substrate in drug-drug interaction studies. Glucuronide metabo-lites of clopidogrel and gemfibrozil act as time-dependent inhibitors of CYP2C8, but they have not been compared clinically. We conducted a randomized crossover study in 11 healthy subjects to characterize the involvement of CYP2C8 in desloratadine metabolism and to compare the CYP2C8 inhibitory strength of clopidogrel (300 and 75 mg on two following days) with that of gemfibrozil (600 mg BID for 5 days). Compared with placebo (control), clopidogrel increased the area under the plasma concentration-time curve (AUC(0-infinity)) and peak plasma concentration (C-max) of desloratadine to 280% (P = 3 x 10(-7)) and 165% (P = 0.0006), respectively. The corresponding increases by gemfibrozil were to 462% (P = 4 x 10(-7)) and 174% (P = 0.0006). Compared with placebo, clopidogrel and gemfibrozil decreased 3-hydroxyloratadine AUC(0-71h) to 52% (P = 5 x 10(-5)) and 6%(P = 2 X 10(-8)), respectively. Moreover, the 3-hydroxydesloratadine: desloratadine AUC(0-71h) ratios were 21% (P = 7 x 10(-10)) and 1.7% (P = 8 x 10(-11)) of control during the clopidogrel and gemfibrozil phases. Our results confirm that CYP2C8 plays a critical role in the formation of 3-hydroxydesloratadine in humans, making desloratadine a potential CYP2C8 probe substrate. Furthermore, the findings corroborate the previous estimates that clinically relevant doses of clopidogrel cause strong CYP2C8 inhibition, whereas those of gemfibrozil almost completely inactivate the enzyme in humans.
  • Itkonen, Matti K.; Tornio, Aleksi; Filppula, Anne M.; Neuvonen, Mikko; Neuvonen, Pertti J.; Niemi, Mikko; Backman, Janne T. (2018)
    The oxidation of montelukast is mainly mediated by cytochrome P450 (CYP) 2C8, but other mechanisms may contribute to its disposition. In healthy volunteers, we investigated the effects of two widely used P2Y(12) inhibitors on montelukast pharmacokinetics. Clopidogrel (300mg on day 1 and 75mg on day 2) increased the area under the plasma concentration-time curve (AUC) of montelukast 2.0-fold (90% confidence interval (CI) 1.72-2.28, P <0.001) and decreased the M6:montelukast AUC(0-7h) ratio to 45% of control (90% CI 40-50%, P <0.001). Prasugrel (60mg on day 1 and 10mg on day 2) had no clinically meaningful effect on montelukast pharmacokinetics. Our results imply that clopidogrel is at least a moderate inhibitor of CYP2C8, but prasugrel is not a clinically relevant CYP2C8 inhibitor. The different interaction potentials of clopidogrel and prasugrel are important to consider when antiplatelet therapy is planned for patients at risk for polypharmacy with CYP2C8 substrates.
  • Itkonen, Matti K.; Tornio, Aleksi; Lapatto-Reiniluoto, Outi; Neuvonen, Mikko; Neuvonen, Pertti J.; Niemi, Mikko; Backman, Janne T. (2019)
    Dasabuvir is mainly metabolized by cytochrome P450 (CYP) 2C8 and is predominantly used in a regimen containing ritonavir. Ritonavir and clopidogrel are inhibitors of CYP3A4 and CYP2C8, respectively. In a randomized, crossover study in 12 healthy subjects, we examined the impact of clinical doses of ritonavir (for 5 days), clopidogrel (for 3 days), and their combination on dasabuvir pharmacokinetics, and the effect of ritonavir on clopidogrel. Clopidogrel, but not ritonavir, increased the geometric mean AUC(0-infinity) of dasabuvir 4.7-fold; range 2.0-10.1-fold (P = 8 center dot 10(-7)), compared with placebo. Clopidogrel and ritonavir combination increased dasabuvir AUC(0-infinity) 3.9-fold; range 2.1-7.9-fold (P = 2 center dot 10(-6)), compared with ritonavir alone. Ritonavir decreased the AUC(0-4h) of clopidogrel active metabolite by 51% (P = 0.0001), and average platelet inhibition from 51% without ritonavir to 31% with ritonavir (P = 0.0007). In conclusion, clopidogrel markedly elevates dasabuvir concentrations, and patients receiving ritonavir are at risk for diminished clopidogrel response.
  • Deng, Feng; Tuomi, Suvi-Kukka; Neuvonen, Mikko; Hirvensalo, Päivi; Kulju, Sami; Wenzel, Christoph; Oswald, Stefan; Filppula, Anne M.; Niemi, Mikko (2021)
    Previous studies have shown that lipid-lowering statins are transported by various ATP-binding cassette (ABC) transporters. However, because of varying methods, it is difficult to compare the transport profiles of statins. Therefore, we investigated the transport of 10 statins or statin metabolites by six ABC transporters using human embryonic kidney cell-derived membrane vesicles. The transporter protein expression levels in the vesicles were quantified with liquid chromatography-tandem mass spectrometry and used to scale the measured clearances to tissue levels. In our study, apically expressed breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) transported atorvastatin, fluvastatin, pitavastatin, and rosuvastatin. Multidrug resistance-associated protein 3 (MRP3) transported atorvastatin, fluvastatin, pitavastatin, and, to a smaller extent, pravastatin. MRP4 transported fluvastatin and rosuvastatin. The scaled clearances suggest that BCRP contributes to 87%-91% and 84% of the total active efflux of rosuvastatin in the small intestine and the liver, respectively. For atorvastatin, the corresponding values for P-gp-mediated efflux were 43%-79% and 66%, respectively. MRP3, on the other hand, may contribute to 23%-26% and 25%-37% of total active efflux of atorvastatin, fluvastatin, and pitavastatin in jejunal enterocytes and liver hepatocytes, respectively. These data indicate that BCRP may play an important role in limiting the intestinal absorption and facilitating the biliary excretion of rosuvastatin and that P-gp may restrict the intestinal absorption and mediate the biliary excretion of atorvastatin. Moreover, the basolateral MRP3 may enhance the intestinal absorption and sinusoidal hepatic efflux of several statins. Taken together, the data show that statins differ considerably in their efflux transport profiles. SIGNIFICANCE STATEMENT This study characterized and compared the transport of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin acid and four atorvastatin metabolites by six ABC transporters (BCRP, MRP2, MRP3, MRP4, MRP8, P-gp). Based on in vitro findings and protein abundance data, the study concludes that BCRP, MRP3, and P-gp have a major impact in the efflux of various statins. Together with in vitro metabolism, uptake transport, and clinical data, our findings are applicable for use in comparative systems pharmacology modeling of statins.
  • Salminen, Jarno; van Gils, Mark; Paloheimo, Markku; Yli-Hankala, Arvi (2016)
    Neuromuscular blockade is usually monitored using train-of-four (TOF) stimulation pattern. A TOF ratio of higher than 90 % is recommended to reduce the risk of adverse effects after anaesthesia. TOF ratio 90 % is used in clinical practice with all different neuromuscular monitors. Kinemyography (KMG) is one commercialized method to obtain numerical TOF values. We compared the KMG data obtained with Datex M-NMT MechanoSensor (TM) module, to the EMG data collected with Datex ElectroSensor (TM), during clinical anaesthesia. Ipsilateral comparisons of the sensors were performed in 20 female patients during clinical procedures in propofol-remifentanil anaesthesia. After initial bolus dose of rocuronium (0.6 mg/kg), the spontaneous recovery of TOF ratio and T1 % were monitored. KMG gave higher TOF values than EMG. The difference was significant at KMG TOF values of 40 % or higher. After anaesthetic induction, but before administration of rocuronium, both TOF sensor values drifted from the TOF value of 1.0, showing either significant spontaneous fade (T1 > T4) or tendency of reverse fade (T1 <T4). KMG overestimates the recovery from neuromuscular blockade when compared with EMG. KMG and EMG cannot be used interchangeably, and TOF ratio 90 % cannot be considered as adequate level of recovery with all monitoring devices.
  • Honkavaara, Juhana M.; Raekallio, Marja R.; Syrja, Pernilla M.; Pypendop, Bruno H.; Knych, Heather K.; Kallio-Kujala, Ira J.; Vainio, Outi M. (2020)
    Objective To quantify the peripheral selectivity of vatinoxan (L-659,066, MK-467) in dogs by comparing the concentrations of vatinoxan, dexmedetomidine and levo-medetomidine in plasma and central nervous system (CNS) tissue after intravenous (IV) coadministration of vatinoxan and medetomidine. Study design Experimental, observational study. Animals A group of six healthy, purpose-bred Beagle dogs (four females and two males) aged 6.5 +/- 0.1 years (mean +/- standard deviation). Methods All dogs were administered a combination of medetomidine (40 mu g kg(-1)) and vatinoxan (800 mu g kg(-1)) as IV bolus. After 20 minutes, the dogs were euthanized with an IV overdose of pentobarbital (140 mg kg(-1)) and both venous plasma and CNS tissues (brain, cervical and lumbar spinal cord) were harvested. Concentrations of dexmedetomidine, levomedetomidine and vatinoxan in all samples were quantified by liquid chromatography-tandem mass spectrometry and data were analyzed with nonparametric tests with post hoc corrections where appropriate. Results All dogs became deeply sedated after the treatment. The CNS-to-plasma ratio of vatinoxan concentration was approximately 1:50, whereas the concentrations of dexmedetomidine and levomedetomidine in the CNS were three- to seven-fold of those in plasma. Conclusions and clinical relevance With the doses studied, these results confirm the peripheral selectivity of vatinoxan in dogs, when coadministered IV with medetomidine. Thus, it is likely that vatinoxan preferentially antagonizes alpha(2)-adrenoceptors outside the CNS.
  • Adam, Magdy; Linden, Jere; Raekallio, Marja; Abu-Shahba, Ahmed; Mannerström, Bettina; Seppänen-Kaijansinkko, Riitta; Meller, Anna; Salla, Kati (2021)
    Objectives To investigate the extent of vatinoxan distribution into sheep brain, and whether vatinoxan influences brain concentrations of xylazine; and to examine the utility of cerebrospinal fluid (CSF) as a surrogate of brain tissue concentrations for vatinoxan and xylazine. Study design Randomised, blinded, experimental study. Animals A total of 14 adult female sheep. Methods Sheep were randomly allocated into two equal groups and premeditated with either intravenous (IV) vatinoxan (750 mu g kg(-1), VX) or saline (SX) administered 10 minutes before IV xylazine (500 mu g kg(-1)). Sedation was subjectively assessed at selected intervals before and after treatments. At 10 minutes after xylazine administration, a venous blood sample was collected and the sheep were immediately euthanised with IV pentobarbital (100 mg kg(-1)). Plasma, CSF and brain tissues were harvested, and concentrations of vatinoxan and xylazine were quantified using liquid chromatography-tandem mass spectrometry. Drug ratios were then calculated and the data were analysed as appropriate. Results The brain-to-plasma and CSF-to-plasma ratios of vatinoxan were 0.06 +/- 0.013 and 0.05 +/- 0.01 (mean +/- standard deviation), respectively. Xylazine brain concentrations were not significantly different (835 +/- 262 versus 1029 +/- 297 ng g(-1) in groups VX and SX, respectively) and were approximately 15-fold higher than those in plasma. The CSF-to-brain ratio of vatinoxan was 0.8 +/- 0.2, whereas xylazine concentrations in the brain were approximately 17-fold greater than those in CSF, with and without vatinoxan. Conclusions and clinical relevance Vatinoxan did not significantly affect sedation with xylazine or the concentrations of xylazine in the brain. CSF is not a good predictor of xylazine concentrations in the brain, whereas vatinoxan concentrations were concordant between the brain and CSF, using the dosages in this study.
  • Kasparyan, Gari; Poojari, Chetan; Rog, Tomasz; Hub, Jochen S. (2020)
    Itraconazole is a triazole drug widely used in the treatment of fungal infections, and it is in clinical trials for treatment of several cancers. However, the drug suffers from poor solubility, while experiments have shown that itraconazole delivery in liposome nanocarriers improves both circulation half-life and tissue distribution. The drug release mechanism from the nanocarrier is still unknown, and it depends on several factors including membrane stability against defect formation. In this work, we used molecular dynamics simulations and potential of mean force (PMF) calculations to quantify the influence of itraconazole on pore formation over lipid membranes, and we compared the effect by itraconazole with a pore-stabilizing effect by the organic solvent dimethyl sulfoxide (DMSO). According to the PMFs, both itraconazole and DMSO greatly reduce the free energy of pore formation, by up to similar to 20 kJ mol(-1). However, whereas large concentrations of itraconazole of 8 mol % (relative to lipid) were required, only small concentrations of a few mole % DMSO (relative to water) were sufficient to stabilize pores. In addition, itraconazole and DMSO facilitate pore formation by different mechanisms. Whereas itraconazole predominantly aids the formation of a partial defect with a locally thinned membrane, DMSO mainly stabilizes a transmembrane water needle by shielding it from the hydrophobic core. Notably, the two distinct mechanisms act cooperatively upon adding both itraconazole and DMSO to the membrane, as revealed by an additional reduction of the pore free energy. Overall, our simulations reveal molecular mechanisms and free energies of membrane pore formation by small molecules. We suggest that the stabilization of a locally thinned membrane as well as the shielding of a transmembrane water needle from the hydrophobic membrane core may be a general mechanism by which amphiphilic molecules facilitate pore formation over lipid membranes at sufficient concentrations.
  • Schloer, Sebastian; Brunotte, Linda; Mecate-Zambrano, Angeles; Zheng, Shuyu; Tang, Jing; Ludwig, Stephan; Rescher, Ursula (2021)
    Background and Purpose The SARS-COV-2 pandemic and the global spread of coronavirus disease 2019 (COVID-19) urgently call for efficient and safe antiviral treatment strategies. A straightforward approach to speed up drug development at lower costs is drug repurposing. Here, we investigated the therapeutic potential of targeting the interface of SARS CoV-2 with the host via repurposing of clinically licensed drugs and evaluated their use in combinatory treatments with virus- and host-directed drugs in vitro. Experimental Approach We tested the antiviral potential of the antifungal itraconazole and the antidepressant fluoxetine on the production of infectious SARS-CoV-2 particles in the polarized Calu-3 cell culture model and evaluated the added benefit of a combinatory use of these host-directed drugs with the direct acting antiviral remdesivir, an inhibitor of viral RNA polymerase. Key Results Drug treatments were well-tolerated and potently impaired viral replication. Importantly, both itraconazole?remdesivir and fluoxetine?remdesivir combinations inhibited the production of infectious SARS-CoV-2 particles?>?90% and displayed synergistic effects, as determined in commonly used reference models for drug interaction. Conclusion and Implications Itraconazole?remdesivir and fluoxetine?remdesivir combinations are promising starting points for therapeutic options to control SARS-CoV-2 infection and severe progression of COVID-19.
  • Hälli, Outi; Haimi, Minna; Laurila, Tapio; Oliviero, Claudio; Viitasaari, Elina Anna Maria; Orro, Toomas; Peltoniemi, Olli Aarno Tapio; Scheinin, Mika; Siren, Saija; Valros, Anna Elisabet; Heinonen, Mari Leena (2018)
    Background: Infection with respiratory pathogens can influence production as well as animal welfare. There is an economical and ethical need to treat pigs that suffer from respiratory diseases. Our aim was the evaluation of the possible effects of oral NSAID medication given in feed in acute outbreaks of respiratory disease in finishing pigs. The short-and long-term impact of NSAID dosing on clinical signs, daily weight gain, blood parameters and behaviour of growing pigs in herds with acute respiratory infections were evaluated. Four finishing pig farms suffering from acute outbreaks of respiratory disease were visited thrice after outbreak onset (DAY 0, DAY 3 and DAY 30). Pigs with the most severe clinical signs (N = 160) were selected as representative pigs for the herd condition. These pigs were blood sampled, weighed, evaluated clinically and their behaviour was observed. After the first visit, half of the pens (five pigs per pen in four pens totalling 20 representative pigs per herd, altogether 80 pigs in four herds) were treated with oral ketoprofen (target dose 3 mg/kg) mixed in feed for three days and the other half (80 pigs) with a placebo. In three of the herds, some pigs were treated also with antimicrobials, and in one herd the only pharmaceutical treatment was ketoprofen or placebo. Results: Compared to the placebo treatment, dosing of ketoprofen reduced sickness behaviour and lowered the rectal temperature of the pigs. Clinical signs, feed intake or blood parameters were not different between the treatment groups. Ketoprofen treatment was associated with somewhat reduced weight gain over the 30-day follow-up period. Concentration analysis of the S-and R-enantiomers of ketoprofen in serum samples collected on DAY 3 indicated successful oral drug administration. Conclusions: Ketoprofen mainly influenced the behaviour of the pigs, while it had no effect on recovery from respiratory clinical signs. However, the medication may have been started after the most severe clinical phase of the respiratory disease was over, and this delay might complicate the evaluation of treatment effects. Possible negative impact of ketoprofen on production parameters requires further evaluation.
  • Kallio-Kujala, I. J.; Bennett, R. C.; Raekallio, M. R.; Yatkin, E.; Meierjohann, A.; Savontaus, E.; Scheinin, M.; Spillmann, T.; Vainio, O. M. (2018)
    The commonly used sedative alpha(2)-adrenoceptor agonist dexmedetomidine has adverse cardiovascular effects in dogs that can be prevented by concomitant administration of the peripherally acting alpha(2)-adrenoceptor antagonist MK-467. An ancillary effect of dexmedetomidine is to decrease insulin release from the pancreas, whereas MK-467 stimulates insulin release. This study assessed the effects of co-administered dexmedetomidine and MK-467 in a canine glibenclamide-induced hypoglycaemia model. In a randomised, cross-over experiment, eight beagle dogs received five intravenous treatments, comprising two administrations of saline, with dexmedetomidine or dexmedetomidine and MK-467, and three administrations of glibenclamide, with saline, dexmedetomidine or dexmedetomidine and MK-467. Plasma concentrations of glucose, lactate, insulin, glucagon and the test drugs were monitored. Administration of glibenclamide significantly increased insulin secretion and decreased blood glucose concentrations. Dexmedetomidine counteracted glibenclamide-evoked hypoglycaemia. This was opposed by the alpha(2)-adrenoceptor antagonist MK-467, but the glibenclamide-evoked hypoglycaemia was not potentiated by co-administration of dexmedetomidine and MK-467. None of the dogs developed uncontrolled hypoglycaemia. Thus, the combination of dexmedetomidine and MK-467 appeared to be safe in this canine hypoglycaemia model. Nevertheless, when MK-467 is used to alleviate the undesired cardiovascular effects of alpha(2)-adrenoceptor agonists in dogs, it should be used with caution in animals at risk for hypoglycaemia because of its insulin-releasing and hypoglycaemic effects. (C) 2018 The Author(s). Published by Elsevier Ltd.
  • Alanne, Leena; Bhide, Amarnath; Hoffren, Jonna; Lantto, Juulia; Huhta, Heikki; Kokki, Merja; Haapsamo, Mervi; Acharya, Ganesh; Räsänen, Juha (2020)
    Introduction We hypothesized that nifedipine and sildenafil would have no detrimental effects on placental hemodynamics and gas exchange under fetal hypoxemia. Methods In 33 chronically instrumented fetal sheep, placental volume blood flow (QPlac) and umbilical artery (UA) vascular impedance were measured by Doppler ultrasonography. Fetal carotid artery blood pressure and blood gas values were monitored. After baseline data collection, maternal and fetal hypoxemia were induced. Following hypoxemia phase data collection, 12 fetuses received sildenafil and 9 fetuses nifedipine infusion, and 12 fetuses served as controls receiving saline infusion. Data were collected 30 and 120 min after infusion was started. Then maternal oxygenation was normalized and normoxemia phase data were collected, while infusion was continued. Results Hypoxemia significantly decreased fetal pO2 and blood pressure. In the sildenafil group at 30- and 120-min hypoxemia + infusion phases, fetal blood pressure and QPlac were significantly lower and pCO2 higher than at baseline without returning to baseline level at normoxemia + infusion phase. In hypoxemia, nifedipine did not affect fetal blood pressure or placental hemodynamics. Both in the sildenafil and nifedipine groups, fetal pO2 remained significantly lower at normoxemia + infusion phase than in the control group. Umbilical artery vascular impedance did not change during the experiment. Discussion In fetal hypoxemia, sildenafil had detrimental effects on placental hemodynamics that disturbed placental gas exchange. Nifedipine did not alter placental hemodynamics in hypoxemia but disturbed placental gas exchange upon returning to normoxemia. Umbilical artery vascular impedance did not reflect alterations in placental hemodynamics.
  • Tapio, H.; Raekallio, M. R.; Mykkänen, A.; Männikkö, S.; Scheinin, M.; Bennett, R. C.; Vainio, O. (2019)
    Background Medetomidine suppresses cardiovascular function and reduces gastrointestinal motility in horses mainly through peripheral alpha(2)-adrenoceptors. Vatinoxan, a peripheral alpha(2)-antagonist, has been shown experimentally to alleviate the adverse effects of some alpha(2)-agonists in horses. However, vatinoxan has not been investigated during constant-rate infusion (CRI) of medetomidine in standing horses. Objectives To evaluate effects of vatinoxan on cardiovascular function, gastrointestinal motility and on sedation level during CRI of medetomidine. Study design Experimental, randomised, blinded, cross-over study. Methods Six healthy horses were given medetomidine hydrochloride, 7 mu g/kg i.v., without (MED) and with (MED+V) vatinoxan hydrochloride, 140 mu g/kg i.v., followed by CRI of medetomidine at 3.5 mu g/kg/h for 60 min. Cardiorespiratory variables were recorded and borborygmi and sedation levels were scored for 120 min. Plasma drug concentrations were measured. The data were analysed using repeated measures ANCOVA and paired t-tests as appropriate. Results Initially heart rate (HR) was significantly lower and mean arterial blood pressure (MAP) significantly higher with MED compared with MED+V. For example at 10 min HR (mean +/- s.d.) was 26 +/- 2 and 31 +/- 5 beats/minute (P = 0.04) and MAP 129 +/- 15 and 103 +/- 13 mmHg (P
  • Verrinder, Elsi; Wester, Niklas; Leppänen, Elli; Lilius, Tuomas; Kalso, Eija; Mikladal, Bjo̷rn; Varjos, Ilkka; Koskinen, Jari; Laurila, Tomi (2021)
    Disposable single-use electrochemical sensor strips were used for quantitative detection of small concentrations of morphine in untreated capillary whole blood. Single-walled carbon nanotube (SWCNT) networks were fabricated on a polymer substrate to produce flexible, reproducible sensor strips with integrated reference and counter electrodes, compatible with industrial-scale processes. A thin Nafion coating was used on top of the sensors to enable direct electrochemical detection in whole blood. These sensors were shown to detect clinically relevant concentrations of morphine both in buffer and in whole blood samples. Small 38 mu L finger-prick blood samples were spiked with 2 mu L of morphine solution of several concentrations and measured without precipitation of proteins or any other further pretreatment. A linear range of 0.5-10 mu M was achieved in both matrices and a detection limit of 0.48 mu M in buffer. In addition, to demonstrate the applicability of the sensor in a point-of-care device, single-determination measurements were done with capillary samples from three subjects. An average recovery of 60% was found, suggesting that the sensor only measures the free, unbound fraction of the drug. An interference study with other opioids and possible interferents showed the selectivity of the sensor. This study clearly indicates that these Nafion/SWCNT sensor strips show great promise as a point-of-care rapid test for morphine in blood.