Effects of intramuscular vatinoxan (MK-467), co-administered with medetomidine and butorphanol, on cardiopulmonary and anaesthetic effects of intravenous ketamine in dogs

Objective To investigate the impact of intramuscular (IM) co-administration of the peripheral alpha(2)-adrenoceptor agonist vatinoxan (MK-467) with medetomidine and butorphanol prior to intravenous (IV) ketamine on the cardiopulmonary and anaesthetic effects in dogs, followed by atipamezole reversal. Study design Randomized, masked crossover study. Animals A total of eight purpose-bred Beagle dogs aged 3 years. Methods Each dog was instrumented and administered two treatments 2 weeks apart: medetomidine (20 mu g kg(-1)) and butorphanol (100 mu g kg(-1)) premedication with vatinoxan (500 mu g kg(-1); treatment MVB) or without vatinoxan (treatment MB) IM 20 minutes before IV ketamine (4 mg kg(-1)). Atipamezole (100 mu g kg(-1)) was administered IM 60 minutes after ketamine. Heart rate (HR), mean arterial (MAP) and central venous (CVP) pressures and cardiac output (CO) were measured; cardiac (CI) and systemic vascular resistance (SVRI) indices were calculated before and 10 minutes after MVB or MB, and 10, 25, 40, 55, 70 and 100 minutes after ketamine. Data were analysed with repeated measures analysis of covariance models. A p-value Results At most time points, HR and CI were significantly higher, and SVRI and CVP significantly lower with MVB than with MB. With both treatments, SVRI and MAP decreased after ketamine, whereas HR and CI increased. MAP was significantly lower with MVB than with MB; mild hypotension (57-59 mmHg) was recorded in two dogs with MVB prior to atipamezole administration. Sedation, induction, intubation and recovery scores were not different between treatments, but intolerance to the endotracheal tube was observed earlier with MVB. Conclusions and clinical relevance Haemodynamic performance was improved by vatinoxan co-administration with medetomidine-butorphanol, before and after ketamine administration. However, vatinoxan was associated with mild hypotension after ketamine with the dose used in this study. Vatinoxan shortened the duration of anaesthesia.Peer reviewe

Peripheral α2-adrenoceptor antagonism affects the absorption of intramuscularly coadministered drugs

Objective: We determined the possible effects of a peripherally acting alpha2-adrenoceptor antagonist, MK-467, on the absorption of intramuscularly (IM) co-administered medetomidine, butorphanol and midazolam. Study design: Randomized, experimental, blinded cross-over study. Animals: Six healthy Beagle dogs. Methods: Two IM treatments were administered: 1) medetomidine hydrochloride (20 μg kg-1) + butorphanol (100 μg kg-1) + midazolam (200 μg kg-1) (MBM), and; 2) MBM + MK-467 hydrochloride (500 μg kg-1) (MBM-MK), mixed in a syringe. Heart rate was recorded at regular intervals. Sedation was assessed with visual analog scales (0 – 100 mm). Drug concentrations in plasma were analyzed with liquid chromatography - tandem mass spectrometry, with chiral separation of dex- and levomedetomidine. Maximum drug concentrations in plasma (Cmax) and time to Cmax (Tmax) were determined. Paired t-tests, with Bonferroni correction when appropriate, were used for comparisons between the treatments. Results: Data from five dogs were analyzed. Heart rate was significantly higher from 20 until 90 minutes after MBM-MK. The Tmax for midazolam and levomedetomidine (mean ± standard deviation) were approximately halved with co-administration of MK-467, from 23 ± 9 to 11 ± 6 minutes (p = 0.049) for midazolam and from 32 ± 15 to 18 ± 6 minutes for levomedetomidine (p = 0.036), respectively. Conclusions and clinical relevance: MK-467 accelerated the absorption of IM co-administered drugs. This is clinically relevant as it may hasten the onset of peak sedative effects.Peer reviewe

Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2-mediated mechanism

Background and Purpose Many drugs and environmental contaminants induce hypercholesterolemia and promote the risk of atherosclerotic cardiovascular disease. We tested the hypothesis that pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, regulates the level of circulating atherogenic lipids in humans and utilized mouse experiments to identify the mechanisms involved.Experimental Approach We performed serum NMR metabolomics in healthy volunteers administered rifampicin, a prototypical human PXR ligand or placebo in a crossover setting. We used high-fat diet fed wild-type and PXR knockout mice to investigate the mechanisms mediating the PXR-induced alterations in cholesterol homeostasis.Key Results Activation of PXR induced cholesterogenesis both in pre-clinical and clinical settings. In human volunteers, rifampicin increased intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and total cholesterol and lathosterol-cholesterol ratio, a marker of cholesterol synthesis, suggesting increased cholesterol synthesis. Experiments in mice indicated that PXR activation causes widespread induction of the cholesterol synthesis genes including the rate-limiting Hmgcr and upregulates the intermediates in the Kandutsch-Russell cholesterol synthesis pathway in the liver. Additionally, PXR activation induced plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of hepatic LDL uptake, in both mice and humans. We propose that these effects were mediated through increased proteolytic activation of sterol regulatory element-binding protein 2 (SREBP2) in response to PXR activation.Conclusion and Implications PXR activation induces cholesterol synthesis, elevating LDL and total cholesterol in humans. The PXR-SREBP2 pathway is a novel regulator of the cholesterol and PCSK9 synthesis and a molecular mechanism for drug- and chemical-induced hypercholesterolemia

Sosiaalityöntekijöiden kokemuksia päiväkotihoidosta lastensuojelun avohuollon tukitoimena

TIIVISTELMÄ Oulun seudun ammattikorkeakoulu Sosiaalialan koulutusohjelma Tekijät: Heidi Hautajärvi & Susanna Kotilainen Opinnäytetyön nimi: Sosiaalityöntekijöiden kokemuksia päiväkotihoidosta lastensuojelun avohuollon tukitoimena Työn ohjaajat: Päivi Onkalo & Markku Koivisto Työn valmistumislukukausi ja -vuosi: Kevät 2011 Sivumäärä: 52 + 1 liitesivua Tutkimuksemme tarkoituksena on kuvailla sosiaalityöntekijöiden kokemuksia päiväkotihoidosta lastensuojelun avohuollon tukitoimena. Keskiössä ovat kokemukset lapsen kasvun ja kehityksen ja vanhemmuuden tukemisesta päiväkotihoidossa, silloin kun kyseessä on lastensuojelun avohuollon tukitoimi. Tutkimustehtävämme on: Millaisia kokemuksia sosiaalityöntekijöillä on päiväkotihoidosta lastensuojelun avohuollon tukitoimena? Tutkimuksesta saatua kokemuksellista tietoa on mahdollista käyttää päiväkotihoidon kehittämiseen avohuollon tukitoimena. Tekemällä tämän tutkimuksen vahvistamme omaa ammatillisuuttamme tulevina lastentarhanopettajina tai lastensuojelun työntekijöinä. Tutkimuksemme teoreettinen viitekehys rakentuu käsitteille lastensuojelun avohuolto, päiväkotihoito lapsen kasvun ja kehityksen tukena sekä päiväkotihoito vanhemmuuden tukena. Tässä tut-kimuksessa lastensuojelun avohuolto ja päiväkotihoito ovat ne kontekstit, joissa lapsen kasvun ja kehityksen sekä vanhemmuuden tukeminen tapahtuu. Lapsen kasvu ja kehitys käsittävät tutkimuksessamme kokonaisvaltaisesti lapsen fyysisen, tunne-elämän ja sosiaalisen kehityksen. Vanhemmuuden tukemisella tarkoitamme vanhempien tukemista heidän kasvatustehtävässään. Tutkimuksemme on laadullinen eli kvalitatiivinen, ja tutkimus tehdään tapaustutkimuksen näkökulmasta. Aineiston keräsimme syksyllä 2010 haastattelemalla kolmea sosiaalityöntekijää. Haastattelumenetelmänä käytimme teemahaastattelua. Aineiston analysoimme teoriaohjaavan sisällönanalyysin avulla. Tutkimustuloksemme vahvistavat käsitystä siitä, että päiväkotihoito avohuollon tukitoimena tukee lasta parhaiten perustehtävänsä myötä. Se tukee kokonaisvaltaisesti lapsen kasvua ja kehitystä sekä vanhemmuutta. Vanhemmuuden tukemisella on suuri merkitys, mutta toteutuakseen päiväkotihoito vaatii sitoutumista ja sopeutumista

Quantitative analysis of 4β- and 4α‑hydroxycholesterol in human plasma and serum by UHPLC/ESI-HR-MS

Abstract Cholesterol oxidation product 4β‑hydroxycholesterol (4β‑OHC) may possibly be used as an endogenous biomarker of CYP3A enzyme activity and as CYP3A4 is involved in the metabolism of approximately 50% of the drugs in clinical use, the monitoring of CYP3A activity by 4β‑OHC plasma or serum levels, may be of clinical significance. The plasma and serum concentrations of 4α‑hydroxycholesterol (4α‑OHC), an isomer of 4β‑OHC, increase during uncontrolled storage conditions and therefore serve as an indicator of proper handling of samples. A sensitive and simple high-throughput method for the simultaneous quantification of both 4α‑OHC and 4β‑OHC in human plasma and serum was developed utilizing ultrahigh performance liquid chromatography coupled with high resolution mass spectrometry (UHPLC/ESI-HR-MS). The chromatographic analysis was carried out on a Waters HSS T3 C18 reversed phase column with a mobile phase composed of 0,1% formic acid with 200 mg/l sodium acetate, and methanol. 4β‑OHC and 4α‑OHC and also internal standard d7‑4β‑OHC were monitored using HR-MS as sodium adducts, which could not be used as a precursor ions in conventional tandem mass spectrometry methods due to their extensive stability in collision for MS/MS. The use of HR-MS detection enabled avoiding laborious sample derivatization, which is required with triple quadrupole mass spectrometer-based methods to achieve adequate analytical sensitivity for 4β‑OHC, as the underivatized molecule is otherwise poorly ionized to other molecular ions than sodium adduct. Chromatographic separation of 4α‑OHC and 4β‑OHC was obtained and confirmed with standard samples prepared in blank surrogate matrix. The lower limits of quantitation in the assay were 0.5 ng/ml for 4β‑OHC, and 2 ng/ml for 4α‑OHC. Endogenous levels of 4β‑OHC can vary between 10 and 100 ng/ml depending on the possible induction or inhibition of CYP3A4, whereas the levels of 4α‑OHC can vary between 5 and 100 ng/ml, depending on the storage conditions of the samples. Thus, the sensitivity of the assay developed allows for the simultaneous measurement of endogenous levels of 4α‑OHC and 4β‑OHC cost-effectively and with high throughput. The method was successfully used for the determination of 4β‑OHC and 4α‑OHC concentrations in clinical plasma and serum samples collected before and after treatment with a known CYP3A4 inducer rifampicin. The endogenous levels in clinical human samples before treatment varied between 13.4 and 31.9 ng/ml for 4β‑OHC, and between 3.53 and 5.65 ng/ml for 4α‑OHC, and a three-fold increase in 4β‑OHC plasma levels was observed after the rifampicin treatment, while 4α‑OHC levels remained unaffected

Den cirkulära bilen (förstudie)

Syftet med förstudien Den cirkulära bilen var att börja bygga konkreta visioner som möjliggör att Sverige har en cirkulärt anpassad bilflotta med fossilfria och klimatneutrala transporter år 2045 och att bygga en solid bas för ett steg 2-projekt, som i sin tur kommer att ge stöd och kapacitet för aktörer att accelerera den cirkulära bilvärdekedjan. Projektet har samlat 13 parter från hela värdekedjan och gemensamt lagt grunden till vidare arbete i ett fortsättningsprojekt – en ansökan som genererat intresse från ett stort antal parter både befintliga och nytillkommande. Inom studien har startmöten och workshops genomförts där parter samlats digitalt och frågeställningar sonderats. Intervjuer har genomförts med parter där möjligheter och utmaningar med omställningen diskuterats. Studiebesök har genomförts där kunskapsdelning skett och samverkan möjliggjorts. Fysisk workshop har genomförts med samtliga parter. Här tittade man gemensamt på trender och möjliga framtidsscenarios genom hela systemet. Detta gav en bra grund för det vidare arbetet med steg 2. Förstudien har genererat stort intresse från aktörer i hela värdekedjan, skapat nya kontakter och möjligheter till samverkan och blivit uppstarten på en gemensam kunskapsresa för verklig förändring. Studien har initierat arbete brett i värdekedjan kopplat till gemensamma frågeställningar samt framtidsspaningar, vilket möjliggör gemensamt arbete för bred omställning och tydliggjort behovet av åtgärder som förflyttar hela systemet. Detta ses som en god grund för ett steg 2 projekt med förutsättningar för att förverkliga den cirkulära bilvärdekedjan

Pregnane X receptor activator rifampin increases blood pressure and stimulates plasma renin activity

Abstract We conducted a clinical trial with 22 healthy volunteers to investigate the effects of pregnane X receptor (PXR) agonist rifampin on blood pressure (BP). The study was randomized, crossover, single‐blind, and placebo‐controlled. Rifampin 600 mg or placebo once daily was administered for a week and the 24‐hour ambulatory BP was monitored at the end of each arm on the eighth day. Rifampin elevated the mean systolic and diastolic 24‐hour BP (4.7 mmHg, P < 0.0001, and 3.0 mmHg, P < 0.001, respectively) as well as the mean heart rate (3.5 bpm, P = 0.038). The serum renin concentration and the plasma renin activity were increased. Although rifampin increased circulating 4β‐hydroxycholesterol (4βHC) as expected, the plasma 4βHC concentration strongly negatively correlated with 24‐hour BP, especially systolic, in both rifampin and placebo arms (rifampin systolic BP, r = −0.69, P < 0.001; placebo systolic BP, r = −0.70, P < 0.001). The 4βHC, an agonist for liver X receptor (LXR), induced renin expression modestly in LXR‐α expressing Calu‐6 cells but only at unphysiologically high 4βHC concentrations. In conclusion, rifampin stimulates renin activity and has a hypertensive effect. This finding should be considered when designing interaction studies involving rifampin or other PXR agonists. Furthermore, PXR may represent a putative therapeutic target for the treatment of hypertension

Den cirkulära bilen (förstudie)

Syftet med förstudien Den cirkulära bilen var att börja bygga konkreta visioner som möjliggör att Sverige har en cirkulärt anpassad bilflotta med fossilfria och klimatneutrala transporter år 2045 och att bygga en solid bas för ett steg 2-projekt, som i sin tur kommer att ge stöd och kapacitet för aktörer att accelerera den cirkulära bilvärdekedjan. Projektet har samlat 13 parter från hela värdekedjan och gemensamt lagt grunden till vidare arbete i ett fortsättningsprojekt – en ansökan som genererat intresse från ett stort antal parter både befintliga och nytillkommande. Inom studien har startmöten och workshops genomförts där parter samlats digitalt och frågeställningar sonderats. Intervjuer har genomförts med parter där möjligheter och utmaningar med omställningen diskuterats. Studiebesök har genomförts där kunskapsdelning skett och samverkan möjliggjorts. Fysisk workshop har genomförts med samtliga parter. Här tittade man gemensamt på trender och möjliga framtidsscenarios genom hela systemet. Detta gav en bra grund för det vidare arbetet med steg 2. Förstudien har genererat stort intresse från aktörer i hela värdekedjan, skapat nya kontakter och möjligheter till samverkan och blivit uppstarten på en gemensam kunskapsresa för verklig förändring. Studien har initierat arbete brett i värdekedjan kopplat till gemensamma frågeställningar samt framtidsspaningar, vilket möjliggör gemensamt arbete för bred omställning och tydliggjort behovet av åtgärder som förflyttar hela systemet. Detta ses som en god grund för ett steg 2 projekt med förutsättningar för att förverkliga den cirkulära bilvärdekedjan

Pregnane X receptor‒4β‐hydroxycholesterol axis in the regulation of overweight‐ and obesity‐induced hypertension

Abstract Background: Mechanisms mediating hypertensive effects of overweight and obesity have not been fully elucidated. We showed previously that activation of pregnane X receptor (PXR) by rifampicin elevates 24‐hour blood pressure (BP) and plasma 4β‐hydroxycholesterol (4βHC), agonist for liver X receptor (LXR). Methods and Results: In combined “PXR activation data set” (n=62) of 4 clinical trials, 1 week rifampicin dosing increased office systolic BP (SBP) by 3.1 mm Hg, DBP 1.8 mm Hg, and mean arterial pressure 2.2 mm Hg in comparison with placebo (P<0.01). Plasma 4βHC had negative correlation with SBP both in rifampicin (r=−0.46, P=0.0002) and placebo (r=−0.45, P=0.0003) arms, although 4βHC was elevated >3‐fold by rifampicin. In “non‐intervention data set” (n=102) of patients with obesity and healthy volunteers (body mass index, 19.2–55.2 kg/m2), 4βHC had negative correlations (P<0.00001) with office SBP (r=−0.51), diastolic BP (r=−0.50), and mean arterial pressure (r=−0.54). Lean women had higher 4βHC than men, with increasing weight repressing 4βHC (r=−0.62, P<0.00001) in both sexes. In multiple linear regression analysis, the only statistically significant predictor for SBP was 4βHC. Six‐day PXR agonist dosing elevated SBP in rats (n=7–8/group). PXR activation elevated 4βHC and after PXR agonist was withdrawn and elevated 4βHC was left to act alone, SBP was reduced on days 7 to 14 in comparison with control rats. Conclusions: PXR activation elevates SBP. Elevated circulating 4βHC lowers SBP in rats, and higher 4βHC is an independent predictor of lower SBP in humans. PXR‐4βHC‐LXR is novel BP‐regulating pathway deregulated in overweight and obesity by repressed 4βHC, with implications for sex‐specific BP regulation. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00985270, NCT01293422, NCT01690104, NCT02329405, and NCT01330251

Oxycodone concentrations in the central nervous system and cerebrospinal fluid after epidural administration to the pregnant ewe

Abstract The main sites of the analgesic action of oxycodone are the brain and spinal cord. The present study describes the concentrations of oxycodone and its metabolites in the brain and spinal cord after epidural administration to the ewe. Twenty pregnant ewes undergoing laparotomy were randomized into two groups to receive epidural oxycodone: infusion group (n = 10, 0.1 mg·kg−1 bolus followed by continuous infusion of 0.05 mg·kg−1·h−1 for five days) or repeated boluses group (n = 10, 0.2 + 2x0.1 mg·kg−1 bolus followed by a 0.2 mg·kg−1 bolus every 12 hours for five days). After five days of oxycodone administration, arterial blood samples were collected, the sheep were killed, and a CSF sample and tissue samples from the cortex, thalamus, cerebellum and spinal cord were obtained for the quantification of oxycodone and its main metabolites. The median plasma and CSF concentrations of oxycodone were 9.0 and 14.2 ng·mL−1 after infusion and 0.4 and 1.1 ng·mL−1 after repeated boluses. In the infusion group, the cortex, thalamus and cerebellum oxycodone concentrations were 4‐8 times higher and in the spinal cord 1310 times higher than in plasma. In the repeated boluses group, brain tissue concentrations were similar in the three areas, and in the spinal cord were 720 times higher than in plasma. Oxymorphone was the main metabolite detected, which accumulated in the brain and spinal cord tissue. In conclusion, first, accumulation of oxycodone and oxymorphone in the CNS was observed, and second, high spinal cord concentrations suggest that epidural oxycodone may provide segmental analgesia