Raul-Allan Kiivet

Behavioral differences in an elevated plus-maze: correlation between anxiety and decreased number of GABA and benzodiazepine receptors in mouse cerebral cortex

SummaryIn an elevated plus-maze model of anxiety mice treated with the benzodiazepine inverse agonist DMCM (0.5–1.5 mg/kg i. p.) spent significantly less time on the open arms and showed the decreased number of open arm entries. The opposite i. e. increased time spent on the open arms and the higher number of open arm entries was registered after diazepam (1.5 mg/kg). The results are consistent with the results obtained in the other animal tests and support the idea that this procedure is suitable for detecting anxiolytic/anxiogenic effects of benzodiazepine receptor ligands. After testing of 84 mice in an elevated plus-maze substantial differences were detected between the individuals. According to the behavioral response two subgroups of animals with DMCM or diazepam like exploratory activity (as compared to the whole group data) termed as “anxious” or “non-anxious”, respectively, were chosen for further binding studies. “Anxious” animals had significantly lower numbers of 3H-flunitrazepam and 3H-muscimol binding sites as compared to “non-anxious” animals in cerebral cortex but not in cerebellum. No differences in the affinity were found between the two groups studied. The results indicate that behavioral anxiety in mice is in correlation with the decreased number of GABA and benzodiazepine receptors in cerebral cortex.

Measuring burden of disease in Estonia to support public health policy

BACKGROUND Many countries have an overview on mortality and morbidity but few have performed contextualized national burden of disease studies. The objective of the present study is to provide a first set of national and sub-national burden of disease estimates for Estonia. Further, we present the causes and age-gender distribution of the burden. We conclude with the description of result uptake and impact of the study in Estonian public health policy arena. METHODS A burden of disease estimation procedure modified for best fit to country situation was used. That included disease classification reflecting Estonian disease profile, national disease severity assessments, mortality and morbidity prevalence data. Calculations were performed on national and sub-national levels. RESULTS Estonian population lost 446 361 (327/1000 persons) disability adjusted life-years in 2002. Premature mortality caused majority of the burden and cardiovascular diseases, external causes (e.g. suicide and injuries) and cancers were main sources of burden. Working age population (16-64 years) shouldered 60% of the burden. Sub-national levels of burden range from 114 to 725 disability adjusted life-years per 1000 persons and are correlated to regional socioeconomic development. CONCLUSION Cardiovascular disease and injuries, premature mortality, working age population, male and people from economically less developed regions should be the priority targets for public health interventions. Estonian main public health strategies now address burden of disease concerns highlighted by our study.

Drug use in Estonia in 1994-1995: a follow-up from 1989 and comparison with two Nordic countries.

AbstractObjective: To determine the patterns of drug use in Estonia for the years 1989 and 1994–1995, i.e. for the years before and after the pharmaceutical services in the country changed from a state monopoly to a competitive market. Methods: The wholesale data from Estonia and the defined daily doses methodology were used. For comparison, national statistics on medicines from Finland and Sweden for the years 1994–1995 are shown. Results: The general sales of drugs in Estonia decreased almost twofold in all major pharmacological groups from 1989 to 1994 and subsequently increased by 10%–30% in 1995. Substantial differences in patterns of drug use between Estonia and the two Nordic countries were observed. The amount of prescription-only medicines used in Estonia was approximately 25% of that used in Finland and Sweden. The amount of over-the-counter drugs used was 61% of that used in Finland and 58% of that used in Sweden. In the drug use patterns in Estonia, some common trends can be noted: (1) persistent traditions, such as the low use of diuretics, beta-blockers, antithrombotics and inhalant anti-asthmatic drugs; (2) changes in prescription preferences – central anti-adrenergic drugs, pyrazolones, aminoglycosides and barbiturates are being replaced by calcium channel blockers and angiotensin-converting-enzyme inhibitors, propionic acid derivatives, cephalosporins and benzodiazepines, respectively; (3) rapidly increasing use of drugs not prescribed in the 1980s, such as hormonal contraceptives, opioids and antiulcer drugs, which strongly improves the quality of pharmacotherapy in Estonia. Conclusion: The general trends in Estonia and the two Nordic countries are similar – the use of newer and more effective drugs is increasing and that of older ones decreasing. The changes are more rapid in Estonia than in Finland and Sweden, but, because of a short observation period, the use of newer drugs not yet prevailing. The international differences in drug utilization observed in this study may possibly be related mainly to the prescription preferences (e.g. therapeutic traditions) and less dependent on the respective health care systems (e.g. reimbursement schemes) and economic state of the country.

Correlation between exploratory activity in an elevated plus-maze and number of central and peripheral benzodiazepine binding sites

SummaryTwo groups of rats were selected from a small animal population on the basis of their exploratory activity in an elevated plus-maze model of anxiety. One group had a considerably lower and the other one a higher exploratory activity than the average total population. These subgroups were termed “anxious” and “nonanxious”, respectively. In both groups central benzodiazepine binding sites in various brain structures were labelled with 3H-flunitrazepam. Peripheral benzodiazepine binding sites labelled in vitro with different tritiated ligands were also studied in several peripheral organs including blood platelets and lymphocytes. “Anxious” animals had a significantly lower number of 3H-flunitrazepam binding sites in the cerebral cortex but not in the hippocampus and cerebellum. In this subgroup 3H-Ro 5-4864 binding to peripheral benzodiazepine recognition sites was also lower than in the other one in adrenals, kidneys, platelets and lymphocytes. In the heart no differences of 3H-Ro 5-4864 binding between subgroups studied were found. Although in “anxious” rats 3H-diazepam and 3H-PK 11195 binding was significantly lower only in lymphocytes, a somewhat decreased binding to these ligands was also present in platelets. No significant differences in the affinity were found between the two groups throughout the experiments described. The results indicate that behavioral anxiety in rats is correlated not only with the lower number of central benzodiazepine receptors but also with a lower density of peripheral benzodiazepine binding sites in several peripheral organs including platelets and lymphocytes.

Debrisoquine and S-mephenytoin hydroxylation polymorphisms in a Russian population living in Estonia

AbstractObjective: To investigate the CYP2D6 and CYP2C19 phenotypes and genotypes in a Russian population of Estonia. Methods: Two hundred and eighteen unrelated healthy subjects of Russian origin were studied. All participants took 10 mg debrisoquine and 100 mg S/R-mephenytoin for phenotyping. The CYP2D6 genotype was analysed by PCR amplification for the CYP2D6*3 and CYP2D6*4 alleles and subjects with S/R-mephenytoin ratios of greater than 0.5 were genotyped with respect to CYP2C19*2 and CYP2C19*3 alleles. Results: Seventeen subjects (7.8%) were classified as poor metabolisers of debrisoquine and 5 (2.3%) as poor metabolisers of S-mephenytoin. The frequency of CYP2D6*4 was 14.4% and that of CYP2D6*3 1.4%. Seven of 15 poor metabolisers of debrisoquine (47%) carried two defective CYP2D6 alleles (CYP2D6*3 or CYP2D6*4). Six of the 10 S-mephenytoin poor-metaboliser alleles (60%) carried either the CYP2C19*2 or CYP2C19*3. Conclusion: The frequencies of poor metabolisers of debrisoquine and S-mephenytoin among Russians were similar to those in other Caucasian populations. The CYP2D6 poor-metaboliser phenotype was predicted by PCR-based amplification for the CYP2D6*3 and CYP2D6*4 alleles with 47% accuracy. The frequency of the CYP2D6*4 allele was lower in Russians than in other Caucasian populations studied so far.

Alcohol consumption, smoking and overweight as a burden for health care services utilization: a cross-sectional study in Estonia

BackgroundAlcohol consumption, smoking and weight problems are common risk factors for different health problems. We examine how these risk factors are associated with the use of health care services.MethodsData for 6500 individuals in the 25–64 age group came from three cross-sectional postal surveys conducted in 2004, 2006, and 2008 in Estonia. The effect of alcohol consumption, smoking and weight problems on the use of primary and specialist care services, hospitalizations and ambulance calls was analysed separately for men and women by using binary logistic regression.ResultsOverweight and/or obesity were strongly related to the use of primary care and out-patient specialist services for both genders, and to hospitalizations and ambulance calls for women. Current smoking was related to ambulance calls for both genders, whereas smoking in the past was related to the use of primary care and specialist services among men and to hospitalizations among women. Beer drinking was negatively associated with all types of health care services and similar association was found between wine drinking and hospitalizations. Wine drinking was positively related to specialist visits. The frequent drinking of strong alcohol led to an increased risk for ambulance calls. Drinking light alcoholic drinks was positively associated with all types of health care services (except ambulance calls) among men and with the use of specialist services among women.ConclusionsOverweight and smoking had the largest impact on health care utilization in Estonia. Considering the high prevalence of these behavioural risk factors, health policies should prioritize preventive programs that promote healthy lifestyles in order to decrease the disease burden and to reduce health care costs.

Thymopentin antagonizes stress-induced changes of GABA/benzodiazepine receptor complex

Intraperitoneal administration of thymopentin, a thymopentin II-derived pentapeptide, had no stable and evident effect in the two anxiety models (elevated plus-maze and licking-conflict test) studied. However, in the elevated plus-maze test thymopentin antagonized the behavioral effects of DMCM, a beta-carboline derivative with anxiogenic properties. Further, it was demonstrated that the licking-conflict test procedure itself produced a significant elevation of plasma corticosterone levels, increased the number of [3H]flunitrazepam and decreased the number of [3H]muscimol binding sites in rat hippocampus. The forced-swimming stress similarly to the licking-conflict test also caused an increase in hippocampal [3H]flunitrazepam binding sites. Although ineffective behaviorally in the tests for anxiety, thymopentin pretreatment effectively reversed the changes in corticosterone levels caused by the licking-conflict test. Moreover, it normalized the changed number of benzodiazepine and GABA receptors after stressful stimuli. It is well known that not all anxiolytic drugs (i.e. buspirone) are equally active in behavioral tests for anxiety. According to our data we propose that thymopentin has stress-protective activity. As in vivo and in vitro thymopentin did not change [3H]-flunitrazepam and [3H]muscimol binding, the direct effect of this peptide on the GABA-benzodiazepine-Cl- ionophore receptor complex is unlikely. The action of this peptide on GABA release and/or metabolism can be suggested.

Variation in behavioral response to baclofen: correlation with benzodiazepine binding sites in mouse forebrain.

SummaryMice treated with (±)baclofen (2 mg/kg i.p.) displayed profound differences to the motor depressant action of this drug. Mice were divided into three groups termed as responders (20%), moderate responders (65%) and nonresponders (15%). No differences were detected in the spontaneous motor activity between the selected groups. When the animal population in the home cages was kept unchanged the different responses to baclofen were reproducible three weeks after selection. A borderline dose of diazepam (1.5 mg/kg) decreased highly significantly motor activity in baclofen responders but failed to do this in nonresponders group. Ex vivo studies with 3H-flunitrazepam (labelling in vivo and binding carried out in vitro) demonstrated that 3H-flunitrazepam binding in mouse forebrain was significantly smaller in baclofen responders than in nonresponders. Further, the apparent number of 3H-flunitrazepam binding sites in vitro was significantly decreased in the forebrain of baclofen responders. It is concluded that some actions of baclofen depend on the functional state of benzodiazepine recognition sites.

Cost-effectiveness of HPV vaccination in the context of high cervical cancer incidence and low screening coverage

BACKGROUND Estonia has high cervical cancer incidence and low screening coverage. We modelled the impact of population-based bivalent, quadrivalent or nonavalent HPV vaccination alongside cervical cancer screening. METHODS A Markov cohort model of the natural history of HPV infection was used to assess the cost-effectiveness of vaccinating a cohort of 12-year-old girls with bivalent, quadrivalent or nonavalent vaccine in two doses in a national, school-based vaccination programme. The model followed the natural progression of HPV infection into subsequent genital warts (GW); premalignant lesions (CIN1-3); cervical, oropharyngeal, vulvar, vaginal and anal cancer. Vaccine coverage was assumed to be 70%. A time horizon of 88years (up to 100years of age) was used to capture all lifetime vaccination costs and benefits. Costs and utilities were discounted using an annual discount rate of 5%. RESULTS Vaccination of 12-year-old girls alongside screening compared to screening alone had an incremental cost-effectiveness ratio (ICER) of €14,007 (bivalent), €14,067 (quadrivalent) and €11,633 (nonavalent) per quality-adjusted life-year (QALY) in the base-case scenario and ranged between €5367-21,711, €5142-21,800 and €4563-18,142, respectively, in sensitivity analysis. The results were most sensitive to changes in discount rate, vaccination regimen, vaccine prices and cervical cancer screening coverage. CONCLUSION Vaccination of 12-year-old girls alongside current cervical cancer screening can be considered a cost-effective intervention in Estonia. Adding HPV vaccination to the national immunisation schedule is expected to prevent a considerable number of HPV infections, genital warts, premalignant lesions, HPV related cancers and deaths. Although in our model ICERs varied slightly depending on the vaccine used, they generally fell within the same range. Cost-effectiveness of HPV vaccination was found to be most dependent on vaccine cost and duration of vaccine immunity, but not on the type of vaccine used.

Antikoagulandid virvendusarütmia tüsistuste ennetamisel Eestis –kulutõhusus ja maksumus

Taust ja eesmark. Hinnata virvendusarutmia tusistuste ennetamiseks kasutatavate uute suukaudsete antikoagulantide – dabigatraani ja rivaroksabaani – kulutohusust ja eelarvemoju vorrelduna standardse varfariinraviga. Artikkel tugineb TU tervishoiu instituudis koostatud tervisetehnoloogiate hindamise raportile. Metoodika. Markovi simulatsioonimudeli ja eelarve moju analuusiga hinnati 65aastaste virvendusarutmiaga patsientide hupoteetilise kohordi tervisetulemeid ja ravikulusid eluea perspektiivis. Ravistrateegiatest vorreldi dabigatraani ja rivaroksabaani raviskeeme varfariinraviga, et oleks kaetud sihtruhma ravivajadus. Tulemused. Antikoagulantravi voib pikendada kvaliteetset eluiga 0,83–1,2 aasta vorra, sh lisanduks dabigatraaniga taiendavalt 0,37 kvaliteetset eluaastat (QALYt, ingl qualityadjusted life year) ja rivaroksabaaniga 0,23 QALYt patsiendi kohta vorreldes varfariinraviga. Lisanduva QALY maksumuseks kujuneb dabigatraani kasutamisel 20 696 eurot ning rivaroksabaani kasutamisel 30 215 eurot. Hinnanguliselt kuni 15 000 patsiendi antikoagulantravi kogukulu voib vorreldes 2013. aastaga olla 2018. aastal 1 915 387 – 10 082 443 euro vorra suurem kui 2013. aastal, soltuvalt seni ravita olevate haigete lisandumisest ja uute antikoagulantide soodusmaarade suurenemisest. Jareldused. Uute antikoagulantide kasutamisel lisandub oluliselt kvaliteetseid eluaastaid, kuid selle saavutamiseks tuleb teha markimisvaarseid lisakulutusi, sest kulud antikoagulantravile kasvavad suuremas mahus, kui vaheneksid arahoitud tusistuste ravikulud. Eesti Arst 2016; 95(11):709–715