Expression of cytochrome P450 enzymes and metabolism of timolol in human ocular tissue

Glaucoma is a group of progressive optic neuropathies causing irreversible blindness if not diagnosed and treated in the early state of progression. Disease is often, but not always, associated with increased intraocular pressure (IOP), which is also the most important risk factor for glaucoma. Ophthlamic timolol preparations have been used for decades to lower increased intraocular pressure (IOP). Timolol is locally well tolerated but may cause e.g. cardiovascular and pulmonary adverse effects due to systemic absorption. It has been reported that approximately 80% of a topically administered eye drop is systemically absorbed. However, only limited information is available on timolol metabolism in the liver or especially in the human eye. The aim of this work was to investigate metabolism of timolol in human liver and human ocular tissues. The expression of drug metabolizing cytochrome P450 (CYP) enzymes in the human ciliary epithelial cells was studied. The metabolism of timolol and the interaction potential of timolol with other commercially available medicines were investigated in vitro using different liver preparations. The absorption of timolol to the aqueous humor from two commercially available products: 0.1% eye gel and 0.5% eye drops and the presence of timolol metabolites in the aqueous humor were investigated in a clinical trial. Timolol was confirmed to be metabolized mainly by CYP2D6 as previously suggested. Potent CYP2D6 inhibitors especially fluoxetine, paroxetine and quinidine inhibited the metabolism of timolol. The inhibition may be of clinical significance in patients using ophthalmic timolol products. CYP1A1 and CYP1B1 mRNAs were expressed in the human ciliary epithelial cells. CYP1B1 was also expressed at protein level and the expression was strongly induced by a known potent CYP1B1 inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The CYP1B1 induction is suggested to be mediated by aryl hydrocarbon receptor (AHR). Low levels of CYP2D6 mRNA splice variants were expressed in the human ciliary epithelial cells and very low levels of timolol metabolites were detected in the human aqueous humor. It seems that negligible amount of CYP2D6 protein is expressed in the human ocular tissues. Timolol 0.1% eye gel leads to aqueous humor concentration high enough to achieve therapeutic effect. Inter-individual variation in concentrations is low and intraocular as well as systemic safety can be increased when using this product with lower timolol concentration instead of timolol 0.5% eye drops.

Neurotrophins and neuronal plasticity in the action of antidepressants and morphine

Neuronal plasticity is a well characterized phenomenon in the developing and adult brain. It refers to capasity of a single neuron to modify morphology, synaptic connections and activity. Neuronal connections and capacity for plastic events are compromised in several pathological disorders, such as major depression. In addition, neuronal atrophy has been reported in depressive patients. Neurotrophins are a group of secretory proteins functionally classified as neuronal survival factors. Neurotrophins, especially brain derived neurotrophic factor (BDNF), have also been associated with promoting neuronal plasticity in dysfunctional neuronal networks. Chronic antidepressant treatment increases plastic events including neurogenesis and arborization and branching of neurites in distinct brain areas, such as the hippocampus. One suggested mode of action is where the antidepressants elevate the synaptic levels of BDNF thus further activating several signaling cascades via trkB-receptor. In our studies we have tried to clarify the mechanisms of action for antidepressants and to resolve the role of BDNF in this process. We found that chronic antidepressant treatment increases amount of markers of neuronal plasticity in both hippocampus and in the medial prefrontal cortex, both of which are closely linked to the etiology of major depression. Secondary actions of antidepressants include rapid activation of the trkB receptor followed by a phosphorylation of transcription factor CREB. In addition, activation of CREB by phosphorylation appears responsible for the regulation of the expression of the BDNF gene. Using transgenic mice we found that BDNF-induced trkB-mediated signaling proved crucial for the behavioral effects of antidepressants in the forced swimming test and for the survival of newly-born neurons in the adult hippocampus. Antidepressants not only increased neurogenesis in the adult hippocampus but also elevated the turnover of hippocampal neurons. During these studies we also discovered that another trkB ligand, NT-4, is involved in morphine-mediated anti-nociception and tolerance. These results present a novel role for trkB-mediated signaling in plastic events present in the opioid system. This thesis evaluates neuronal plasticity and trkB as a target for future antidepressant treatments.

Social factors at work and the health of employees

Masennus, ahdistuneisuus, alkoholiriippuvuus ja alkoholin väärinkäyttö sekä unihäiriöt ovat yleisiä ongelmia työssä käyvän väestön keskuudessa. Nämä sairaudet ja oireet aiheuttavat huomattavia kuluja myös yhteiskunnalle. Sosiaalisen tuen ja työilmapiirin yhteyttä työssä käyvien (n = 3 347–3 430) terveyteen tutkittiin Terveyden ja hyvinvoinnin laitoksen Terveys 2000 -aineistossa. Sosiaalista tukea työssä mitattiin JCQ-kyselyllä (Job Content Questionnaire) ja yksityiselämän sosiaalista tukea SSQ-kyselyllä (Social Support Questionnaire). Työilmapiiriä mitattiin kyselyllä, joka on osa Terve työyhteisö -kyselyä. Mielenterveyshäiriöiden diagnoosit perustuivat CIDI-haastatteluun (Composite International Diagnostic Interview). Tiedot lääkärin määräämistä masennus- ja unilääkkeistä poimittiin Kelan lääkerekisteristä ja tiedot työkyvyttömyyseläkkeistä Eläketurvakeskuksen ja Kelan rekistereistä. Ilmapiirin kokemisessa ei ollut merkitsevää eroa sukupuolten välillä. Sen sijaan naiset kokivat saavansa sosiaalista tukea enemmän sekä työssä että yksityiselämässä. Vähäinen sosiaalinen tuki sekä työssä että yksityiselämässä oli yhteydessä masennukseen, ahdistuneisuushäiriöihin ja moniin uniongelmiin. Huono työilmapiiri oli yhteydessä sekä masennukseen että ahdistuneisuushäiriöihin. Vähäinen tuki sekä esimiehiltä että työtovereilta oli yhteydessä myöhempään masennuslääkkeiden käyttöön. Huono työilmapiiri ennusti myös masennuslääkkeiden käyttöä. Vähäinen sosiaalinen tuki esimieheltä näytti lisäävän työkyvyttömyyseläkkeen todennäköisyyttä. Työhyvinvointiin täytyy kiinnittää huomiota, koska vähäinen sosiaalinen tuki ja huono työilmapiiri ovat yhteydessä mielenterveysongelmiin ja lisäävät työkyvyn menettämisen riskiä. – Englanninkielinen julkaisu. Suomenkielinen yhteenveto s. 89–90.