Ketoprofeenin biologinen käytettävyys ja farmakokinetiikka sioilla eri antotavoilla ja ketoprofeeniyliannoksen farmakokinetiikka ja vaikutus munuaisiin lampailla

Ketoprofeeni on yleisesti käytetty ei-steroidinen tulehduskipulääke (NSAID) lampaiden ja sikojen kivunlievityksessä. Tietoa ketoprofeenin oikeista annosmääristä eri eläinlajeilla on saatavilla rajallisesti. Oikeaa lääkeainemäärää ei voida luotettavasti ekstrapoloida toisten eläinlajien tai ihmisten perusteella. Epäillyissä tulehduskipulääkemyrkytyksissä ongelmana on tietää, oliko eläimen saama lääkeannos toksinen. Lampailla tehdyn tutkimuksen tavoitteena oli selvittää, muuttuuko ketoprofeenin kinetiikka kymmenkertaisella yliannoksella, tutkia yliannoksen vaikutusta munuaisiin ja löytää yksinkertainen tapa diagnosoida yliannos virtsasta. Sioilla tehdyn tutkimuksen tavoitteena oli selvittää ketoprofeenin biologista käytettävyyttä ja ketoprofeenin farmakokinetiikkaa sioilla intravaskulaarisella, intramuskulaarisella ja peroraalisella annolla. Keskeiset tutkimuksessa määritettävät muuttujat olivat AUC0-_, Cmax ja tmax. Hyötyosuus laskettiin i.v. -annon perusteella. Kuudelle lampaalle annettiin 30 mg/kg i.v. -ketoprofeenia. Ketoprofeenin pitoisuuksia seurattiin 24 tunnin ajan plasmanäytteillä, joiden perusteella määritettiin farmakokineettiset parametrit. Veri- ja virtsanäytteistä tutkittiin muun muassa mahdollisesta munuaisvauriosta kertovia entsyymejä. 24 tunnin kuluttua lääkkeenannosta lampaat lopetettiin ja munuaiset tutkittiin histologisesti. Tutkittaville kahdeksalle sialle annosteltiin 3 mg/kg intravaskulaarista, intramuskulaarista ja oraalista ketoprofeenia sekä 6 mg/kg oraalista ketoprofeenia. Tutkimus suoritettiin satunnaistettuna vaihtovuorotutkimuksena. Ketoprofeenin pitoisuuksia seurattiin plasmanäytteillä 48 tunnin ajan lääkkeenannosta ja kaikille antotavoille laskettiin farmakokineettiset parametrit. Lisäksi tutkittiin valmisteiden biologinen samanarvoisuus. Molempien tutkimusten in vivo -kokeet suoritettiin Eläinlääketieteellisessä tiedekunnassa. Samoin munuaisten histologinen tutkimus ja virtsasta ja verestä tehdyt määritykset, lukuun ottamatta ketoprofeeninpitoisuuden analysointia. Plasman ketoprofeenipitoisuus analysoitiin korkean erotuskyvyn nestekromatografialla (HPLC). Ketoprofeenimääritykset ja farmakokineettinen analyysi suoritettiin Farmasian tiedekunnassa. Lampaiden kymmenkertainen ketoprofeeniyliannos oli toksinen. Seerumin urea- ja kreatiniinipitoisuus nousivat ja histologisissa näytteissä näkyi akuutti munuaistiehyen vaurio. Useiden entsyymien pitoisuus nousi virtsassa. Selvimmin ja nopeimmin nousi virtsan laktaattidehydrogenaasipitoisuus, jonka määrittäminen vaikuttaa potentiaaliselta tavalta diagnosoida ketoprofeenin toksinen annos. Ketoprofeenin eliminaation puoliintumisaika toksisella annoksella oli samaa suuruusluokkaa kuin aiemmissa tutkimuksissa terapeuttisella annoksella, joten yliannos ei muuttanut ketoprofeenin kinetiikkaa. AUC- ja Cmax -arvot olivat suhteessa suurempia kuin terapeuttisella annoksella, joten tutkimuksen perusteella kyseiset arvot eivät nousseet lineaarisesti annoksen noustessa toksiseksi. Sioille annetut ketoprofeenivalmisteet eivät olleet biologisesti samanarvoisia keskenään. Hyötyosuus oli erittäin hyvä kaikilla antotavoilla. tmax oli kaikilla antotavoilla hieman yli tunnin kuluttua lääkkeenannosta. Oraalisen 3 mg/kg -annoksen Cmax oli 5,1 mg/l ja AUC 32 mg l-1 h ja intramuskulaarisen vastaavat arvot olivat 7,6 mg/l ja 37 mg l-1 h. Oraalisen ketoprofeenin annostasojen AUC- ja Cmax -arvot korreloivat keskenään, joten ketoprofeenin kinetiikka oli lineaarista. Intravaskulaarisen ja oraalisen annon puoliintumisajoissa oli tilastollisesti merkitsevä ero. Ketoprofeenin jakautumistilavuudessa ja puhdistumassa ei ollut tilastollisesti merkitsevää eroa eri antotapojen välillä.

In vitro protection of umbilical cord blood-derived primitive hematopoietic stem progenitor cell pool by mannose-specific lectins via antioxidant mechanisms.

BACKGROUND: Earlier we reported that an oral administration of two mannose-specific dietary lectins, banana lectin (BL) and garlic lectin (GL), led to an enhancement of hematopoietic stem and progenitor cell (HSPC) pool in mice. STUDY DESIGN AND METHODS: Cord blood derived CD34+ HSPCs were incubated with BL, GL, Dolichos lectin (DL), or artocarpin lectin (AL) for various time periods in a serum- and growth factor free medium and were subjected to various functional assays. Reactive oxygen species (ROS) levels were detected by using DCHFDA method. Cell fractionation was carried out using lectin-coupled paramagnetic beads. RESULTS: CD34+ cells incubated with the lectins for 10 days gave rise to a significantly higher number of colonies compared to the controls, indicating that all four lectins possessed the capacity to protect HSPCs in vitro. Comparative analyses showed that the protective ability of BL and GL was better than AL and DL and, therefore, further experiments were carried out with them. The output of long-term culture-initiating cell (LTC-IC) and extended LTC-IC assays indicated that both BL and GL protected primitive stem cells up to 30 days. The cells incubated with BL or GL showed a substantial reduction in the ROS levels, indicating that these lectins protect the HSPCs via antioxidant mechanisms. The mononuclear cell fraction isolated by lectin-coupled beads got enriched for primitive HSPCs, as reflected in the output of phenotypic and functional assays.CONCLUSION: The data show that both BL and GL protect the primitive HSPCs in vitro and may also serve as cost-effective HSPC enrichment tools.

Substance misuse problems during pregnancy with special emphasis on buprenorphine

Maternal drug abuse during pregnancy endangers the future health and wellbeing of the infant and growing child. On the other hand, via maternal abstinence, these problems would never occur; so the problems would be totally preventable. Buprenorphine is widely used in opioid maintenance treatment as a substitute medication. In Finland, during 2000 s buprenorphine misuse has steadily increased. In 2009 almost one third of clientele of substance treatment units were in treatment because of buprenorphine dependence. At Helsinki Women s Clinic the first child with prenatal buprenorphine exposure was born in 2001. During 1992-2001 in the three capital area maternity hospitals (Women s clinic, Maternity hospital, Jorvi hospital) 524 women were followed at special antenatal clinics due to substance abuse problems. Three control women were drawn from birth register to each case woman and matched for parity and same place and date of the index birth. According to register data mortality rate was 38-fold higher among cases than controls within 6-15 years after index birth. Especially, the risk for violent or accidental death was increased. The women with substance misuse problems had also elevated risk for viral hepatitis and psychiatric morbidity. They were more often reimbursed for psychopharmaceuticals. Disability pensions and rehabilitation allowances were more often granted to cases than controls. In total 626 children were born from these pregnancies. According to register data 38% of these children were placed in out-of-home care as part of child protection services by the age of two years, and half of them by the age of 12 years, the median follow-up time was 5.8 years. The risk for out-of-home care was associated with factors identifiable during the pre- and perinatal period. In 2002-2005 67 pregnant women with buprenorphine dependence were followed up at the Helsinki University Hospital, Department of Obstetrics and Gynecology. Their pregnancies were uneventful. The prematurity rate was similar and there were no more major anomalies compared to the national statistics. The neonates were lighter compared to the national statistics. They were also born in good condition, with no perinatal hypoxia as defined by standard clinical parameters or certain biochemical markers in the cord blood: erythropoietin, S100 and cardiac troponin-t. Almost 80% of newborns developed neonatal abstinence syndrome (NAS) and two third of them needed morphine medication for it. Maternal smoking over ten cigarettes per day aggravated and benzodiazepine use attenuated NAS. An infant s highest urinary norbuprenorphine concentration during their first 3 days of life correlated with the duration of morphine treatment. The average length of infant s hospital stay was 25 days.

Relation between Tc and hole concentration in superconducting cuprates

The superconducting transition temperature, Tc, of several series of cuprates shows a nonlinear dependence on the hole concentration, nh, determined by chemical titrations. The tc becomes maximum when nh is in the 0.12-0.15 range in cuprates containing a single Cu-O layer and around 0.2 in cuprates containing two Cu-O layers.

Structure and superconducting properties of Tl1?yPbyY1?xCaxSr2Cu2O7star, open: Dependence of Tc on hole concentration

Structure and superconducting properties of Tl1?yPbyY1?xCaxSr2Cu2O7 (y=0.0, 0.1, 0.25 and 0.5) , derived from the parent insulator TlYSr2Cu2O7, have been investigated for different values of x. XANES studies show Pb to be in the 4+ state while Tl is in the 3+ state, suggesting thereby that in this series, (x?y) approximately corresponds to the hole concentration. The in-plane Cu---O distance decreases with increase in x for all values of y. The apical Cu---O distance as well as the Tl(Pb)---O(2) distance show anomalies at x=0.5 in the series with y=0.25; at this composition, Tc also reaches a maximum. In general, the composition (value of x) at which the Tc of Tl1?yPbyY1?xCaxSr2Cu2O7 reaches a maximum depends on the Pb content and the maximum Tc itself increases with increase in y, reaching a value of 105 K at y=0.5. More interestingly, a maximum Tc occurs at an (x?y) value of not, vert, similar0.25, which is close to the hole concentration at maximum Tc in other cuprate superconductors containing two CuO2 layers.

Temperature and concentration dependence of adsorption properties of methane in NaY: a molecular dynamics study

Molecular dynamics calculations on methane sorbed in NaY (Si/Al = 3.0) employing realistic methane-methane and methane-zeolite intermolecular potential functions at different temperatures (50, 150, 220, and 300 K) and concentrations (2, 4, 6, and 8 molecules/cage) are reported. The thermodynamic results are in agreement with the available experimental data. Guest-guest and guest-host radial distribution functions (rdfs), energy distribution functions, distribution of cage occupancy, center-of-cage-center-of-mass (coc-com) rdfs, velocity autocorrelation functions for com and angular motion and the Fourier transformed power spectra, and diffusion coefficients are presented as a function of temperature and concentration. At 50 K, methane is localized near the adsorption site. Site-site migration and essentially free rotational motion are observed at 150 K. Molecules preferentially occupy the region near the inner surface of the alpha-cage. The vibrational frequencies for the com of methane shift toward higher values with decreasing temperature and increasing adsorbate concentration. The observed frequencies for com motion are 36, 53, and 85 cm-1 and for rotational motion at 50 K, 95 and 150 cm-1 in agreement with neutron scattering data. The diffusion coefficients show a type I behavior as a function of loading in agreement with NMR measurements. Cage-to-cage diffusion is found to be always mediated by the surface.

Genetic polymorphisms and laboratory variables as predictors of blood pressure response to antihypertensive drugs

Hypertension is one of the major risk factors for cardiovascular morbidity. The advantages of antihypertensive therapy have been clearly demonstrated, but only about 30% of hypertensive patients have their blood pressure (BP) controlled by such treatment. One of the reasons for this poor BP control may lie in the difficulty in predicting BP response to antihypertensive treatment. The average BP reduction achieved is similar for each drug in the main classes of antihypertensive agents, but there is a marked individual variation in BP responses to any given drug. The purpose of the present study was to examine BP response to four different antihypertensive monotherapies with regard to demographic characteristics, laboratory test results and common genetic polymorphisms. The subjects of the present study are participants in the pharmacogenetic GENRES Study. A total of 208 subjects completed the whole study protocol including four drug treatment periods of four weeks, separated by four-week placebo periods. The study drugs were amlodipine, bisoprolol, hydrochlorothiazide and losartan. Both office (OBP) and 24-hour ambulatory blood pressure (ABP) measurements were carried out. BP response to study drugs were related to basic clinical characteristics, pretreatment laboratory test results and common polymorphisms in genes coding for components of the renin-angiotensin system, alpha-adducin (ADD1), beta1-adrenergic receptor (ADRB1) and beta2-adrenergic receptor (ADRB2). Age was positively correlated with BP responses to amlodipine and with OBP and systolic ABP responses to hydrochlorothiazide, while body mass index was negatively correlated with ABP responses to amlodipine. Of the laboratory test results, plasma renin activity (PRA) correlated positively with BP responses to losartan, with ABP responses to bisoprolol, and negatively with ABP responses to hydrochlorothiazide. Uniquely to this study, it was found that serum total calcium level was negatively correlated with BP responses to amlodipine, whilst serum total cholesterol level was negatively correlated with ABP responses to amlodipine. There were no significant associations of angiotensin II type I receptor 1166A/C, angiotensin converting enzyme I/D, angiotensinogen Met235Thr, ADD1 Gly460Trp, ADRB1 Ser49Gly and Gly389Arg and ADRB2 Arg16Gly and Gln27Glu polymorphisms with BP responses to the study drugs. In conclusion, this study confirmed the relationship between pretreatment PRA levels and response to three classes of antihypertensive drugs. This study is the first to note a significant inverse relation between serum calcium level and responsiveness to a calcium channel blocker. However, this study could not replicate the observations that common polymorphisms in angiotensin II type I receptor, angiotensin converting enzyme, angiotensinogen, ADD1, ADRB1, or ADRB2 genes can predict BP response to antihypertensive drugs.

Oral health and kidney disease with emphasis on diabetic nephropathy

Chronic kidney disease (CKD) is a worldwide health problem, with adverse outcomes of cardiovascular disease and premature death. The ageing of populations along with the growing prevalence of chronic diseases such as diabetes and hypertension is leading to worldwide increase in the number of CKD patients. It has become evident that inflammation plays an important role in the pathogenesis of atherosclerosis complications. CKD patients also have an increased risk of atherosclerosis complications (including myocardial infarction, sudden death to cardiac arrhythmia, cerebrovascular accidents, and peripheral vascular disease). In line with this, oral and dental problems can be an important source of systemic inflammation. A decline in oral health may potentially act as an early marker of systemic disease progression. This series of studies examined oral health of CKD patients from predialysis, to dialysis and kidney transplantation in a 10-year follow-up study and in a cross-sectional study of predialysis CKD patients. Patients had clinical and radiographic oral and dental examination, resting and stimulated saliva flow rates were measured, whilst the biochemical and microbiological composition of saliva was analyzed. Lifestyle and oral symptoms were recorded using a questionnaire, and blood parameters were collected from the hospital records. The hypothesis was that the oral health status, symptoms, sensations, salivary flow rates and salivary composition vary in different renal failure stages and depend on the etiology of the kidney disease. No statistically significant difference were seen in the longitudinal study in the clinical parameters. However, some saliva parameters after renal transplantation were significantly improved compared to levels at the predialysis stage. The urea concentration of saliva was high in all stages. The salivary and plasma urea concentrations followed a similar trend, showing the lowest values in kidney transplant patients. Levels of immunoglobulin (Ig) A, G and M all decreased significantly after kidney transplantation. Increased concentrations of IgA, IgG and IgM may reflect disintegration of the oral epithelium and are usually markers of poor general oral condition. In the cross-sectional investigation of predialysis CKD patients we compared oral health findings of diabetic nephropathy patients to those with other kidney disease than diabetes. The results showed eg. more dental caries and lower stimulated salivary flow rates in the diabetic patients. HbA1C values of the diabetic patients were significantly higher than those in the other kidney disease group. A statistically significant difference was observed in the number of drugs used daily in the diabetic nephropathy group than in the other kidney disease group. In the logistic regression analyses, age was the principal explanatory factor for high salivary total protein concentration, and for low unstimulated salivary flow. Poor dental health, severity of periodontal disease seemed to be an explanatory factor for high salivary albumin concentrations. Salivary urea levels were significantly linked with diabetic nephropathy and with serum urea concentrations. Contrary to our expectation, however, diabetic nephropathy did not seem to affect periodontal health more severely than the other kidney diseases. Although diabetes is known to associate with xerostomia and other oral symptoms, it did not seem to increase the prevalence of oral discomfort. In summary, this series of studies has provided new information regarding the oral health of CKD patients. As expected, the commencement of renal disease reflects in oral symptoms and signs. Diabetic nephropathy, in particular, appears to impart a requirement for special attention in the oral health care of patients suffering from this disease.

A note on "effects of couple stresses on the blood flow through an artery with mild stenosis"

Some errors have been observed in the analytical expression for the resistance to flow (lambda R), and in the computation of shear stress distribution (tau R) in the analysis of Prawal Sinha and Chandan Singh (1). These errors have been rectified in the present analysis. Also, better values have been suggested for the couple stress parameter alpha for getting better results for lambda R and tau R.

Occurrence of maximum Tc at an optimal carrier concentration in superconducting bismuth and thallium cuprates

The superconducting transition temperatures in Bi2Ca1−xLnxSr2Cu2O8+δ, TlCa1−xLnxSr2Cu2O6+δ, and Tl0.8Ca1−xLnxBa2Cu23O6+δ (Ln=Y or rare earth) vary with composition and show a maximum at a specific value of x or δ. This observation suggests that an optimal carrier concentration is required to attain maximum Tc in such cuprates which seem to be two‐band systems

Do the Hydrolysis Products, Methylamine and N,N'-Dimethylurea, Play any Role in the Methyl Isocyanate-Induced Haematological and Biochemical Changes in Rabbits?

The subcutaneous administration of methyl isocyanate (MIC) to female rabbits, resulted in significant increases in haemoglobin concentration, erythrocyte volume fraction and leucocyte number in blood, as well as plasma total proteins, and urea. The present study was designed to investigate whether the hydrolytic products of MIC, methylamine (MA) and N,N'-dimethylurea (DMU) play any role in eliciting these changes. Both MA and DMU administered subcutaneously in an equimolar dose to that of 1.0 LD50 MIC, 2.2 mmol kg-1, had no influence on these parameters, although there was a marginal increase in the plasma urea level shortly after the administration of DMU. This study establishes that the observed haematological and biochemical changes induced by MIC intoxication in rabbits are mostly due to MIC.

Production of Carcinogenic Acetaldehyde by Oral Microbiome

Oral cancer is the seventh most common cancer worldwide and its incidence is increasing. The most important risk factors for oral cancer are chronic alcohol consumption and tobacco smoking, up to 80 % of oral carcinomas are estimated to be caused by alcohol and tobacco. They both trigger an increased level of salivary acetaldehyde, during and after consumption, which is believed to lead to carcinogenesis. Acetaldehyde has multiple mutagenic features and it has recently been classified as a Group 1 carcinogen for humans by the International Agency for Research on Cancer. Acetaldehyde is metabolized from ethanol by microbes of oral microbiota. Some oral microbes possess alcohol dehydrogenase enzyme (ADH) activity, which is the main enzyme in acetaldehyde production. Many microbes are also capable of acetaldehyde production via alcohol fermentation from glucose. However, metabolism of ethanol into acetaldehyde leads to production of high levels of this carcinogen. Acetaldehyde is found in saliva during and after alcohol consumption. In fact, rather low ethanol concentrations (2-20mM) derived from blood to saliva are enough for microbial acetaldehyde production. The high acetaldehyde levels in saliva after alcohol challenge are explained by the lack of oral microbiota and mucosa to detoxify acetaldehyde by metabolizing it into acetate and acetyl coenzymeA. The aim of this thesis project was to specify the role of oral microbes in the in vitro production of acetaldehyde in the presence of ethanol. In addition, it was sought to establish whether microbial metabolism could also produce acetaldehyde from glucose. Furthermore, the potential of xylitol to inhibit ethanol metabolism and acetaldehyde production was explored. Isolates of oral microbes were used in the first three studies. Acetaldehyde production was analyzed after ethanol, glucose and fructose incubation with gas chromatography measurement. In studies I and III, the ADH enzyme activity of some microbes was measured by fluorescence. The effect of xylitol was analyzed by incubating microbes with ethanol and xylitol. The fourth study was made ex vivo and microbial samples obtained from different patient groups were analyzed. This work has demonstrated that isolates of oral microbiota are able to produce acetaldehyde in the presence of clinically relevant ethanol and glucose concentrations. Significant differences were found between microbial species and isolates from different patient groups. In particular, the ability of candidal isolates from APECED patients to produce significantly more acetaldehyde in glucose incubation compared to healthy and cancer patient isolates is an interesting observation. Moreover, xylitol was found to reduce their acetaldehyde production significantly. Significant ADH enzyme activity was found in the analyzed high acetaldehyde producing streptococci and candida isolates. In addition, xylitol was found to reduce the ADH enzyme activity of C. albicans. Some results from the ex vivo study were controversial, since acetaldehyde production did not correlate as expected with the amount of microbes in the samples. Nevertheless, the samples isolated from patients did produce significant amounts of acetaldehyde with a clinically relevant ethanol concentration.

The effects of charge density and concentration on the composition of polyelectrolyte complexes

Polyelectrolyte complex formation involving carboxymethylcellulose and quaternized poly(vinylpyridine) as the polyions has been studied using viscosity and u.v. spectroscopic methods. The influence of charge density and molecular weight of two polycations on the composition of the complex has been investigated at two different concentrations. The charge density of the polycation is found to have different influences on the composition at different concentrations. The molecular weight of the polycation and the location of the ionic site on the polycation do not show any effect on the composition. A drastic increase in the viscosity of the polyion mixture containing quaternized poly(2-vinylpyridine) in the non-stoichiometric ratio shows evidence for the existence of the soluble polyelectrolyte complex. The results are analysed on the basis of the relative extension of the polyelectrolyte chains.

Diurnal variation of atmospheric CO2 concentration and delta C-13 in an urban atmosphere during winter-role of the Nocturnal Boundary Layer

The paper presents the importance of the Nocturnal Boundary Layer in driving the diurnal variability of the atmospheric CO2 mixing ratio and the carbon isotope ratio at ground level from an urban station in India. Our observations are the first of their kind from this region. The atmospheric CO2 mixing ratio and the carbon isotopic ratio were measured for both the morning (05:30-07:30 IST) and afternoon time (16:00-18:00 IST) air samples at 5 m above ground level in Bangalore city, Karnataka State (12 degrees 58' N, 77 degrees 38' E, masl = 920 m) for a 10 day period during the winter of 2008. We observed a change of similar to 7% the in CO2 mixing ratio between the morning and afternoon time air samples. A stable isotope analysis of CO2 from morning samples showed a depletion in the carbon isotope ratio by similar to 2 parts per thousand compared to the afternoon samples. Along with the ground-based measurement of air samples, data of radiosonde measurements were also obtained from the Indian Meteorological Department to identify the vertical atmospheric structure at different time in a day. We proposed the presence or absence of the NBL as a controlling factor for the observed variability in the mixing ratio as well as its isotopic composition. Here we used the Keeling model approach to find out the carbon isotope ratio for the local sources. The local sources have further been characterized as anthropogenic and biological respiration (in %) using a two-component mixing model. We also used a vertical mixing model based on the concept of the mixing of isotopically depleted (carbon isotope) ``polluted air'' (PA) with isotopically enriched ``free atmospheric air'' (FA) above. Using this modeling approach, the contribution of FA at ground level is being estimated for both the morning and afternoon time air samples.

Concentration-dependent NMR and conductivity studies of (PEG)(x)NH4ClO4

Films of (PEG)(x)NH4ClO4 (x = 5 to 1000) were prepared and characterized. The physical properties are observed to be a sensitive function of concentration. Hygroscopicity increases as salt content increases. Conductivity peaks (sigma = 2.7 x 10(-6) S/cm) at x = 46. The H-1 NMR line width has a minimum at x = 46, while that of Cl-35 monotonically increases with salt concentration, indicating that the complex is essentially a protonic conductor.