Philosophy as a Path to Happiness : Attainment of Happiness in Arabic Peripatetic and Ismaili Philosophy

The aim of the dissertation is to explore the idea of philosophy as a path to happiness in classical Arabic philosophy. The starting point is in comparison of two distinct currents between the 10th and early 11th centuries, Peripatetic philosophy, represented by al-Fārābī and Ibn Sīnā, and Ismaili philosophy represented by al-Kirmānī and the Brethren of Purity. They initially offer two contrasting views about philosophy in that the attitude of the Peripatetics is rationalistic and secular in spirit, whereas for the Ismailis philosophy represents the esoteric truth behind revelation. Still, they converge in their view that the ultimate purpose of philosophy lies in its ability to lead man towards happiness. Moreover, they share a common concept of happiness as a contemplative ideal of human perfection, which refers primarily to an otherworldly state of the soul s ascent to the spiritual world. For both the way to happiness consists of two parts: theory and practice. The practical part manifests itself in the idea of the purification of the rational soul from its bodily attachments in order for it to direct its attention fully to the contemplative life. Hence, there appears an ideal of philosophical life with the goal of relative detachment from the worldly life. The regulations of the religious law in this context appear as the primary means for the soul s purification, but for all but al-Kirmānī they are complemented by auxiliary philosophical practices. The ascent to happiness, however, takes place primarily through the acquisition of theoretical knowledge. The saving knowledge consists primarily of the conception of the hierarchy of physical and metaphysical reality, but all of philosophy forms a curriculum through which the soul gradually ascends towards a spiritual state of being along an order that is inverse to the Neoplatonic emanationist hierarchy of creation. For Ismaili philosophy the ascent takes place from the exoteric religious sciences towards the esoteric philosophical knowledge. For Peripatetic philosophers logic performs the function of an instrument enabling the ascent, mathematics is treated either as propaedeutic to philosophy or as a mediator between physical and metaphysical knowledge, whereas physics and metaphysics provide the core of knowledge necessary for the attainment of happiness.

Kaakkois-Suomen lapinraunioiden ikä ja kulttuurikonteksti

Lapinrauniot ovat Järvi-Suomen varhaismetallikautiseen (n. 1900 eaa.-300 jaa.) pyyntiväestöön yhdistettyjä kiviröykkiöitä. Tavallisesti ne esiintyvät yksittäisinä tai korkeintaan muutaman röykkiön ryhminä. Monista lapinraunioita on löytynyt palanutta ihmisen luuta ja joistakin myös hauta-anneiksi tulkittuja esineitä. Osasta ei ole kyetty paikallistaman mitään merkkejä hautauksesta. Jotkut ovat vaikuttaneet löytöjensä perusteella uhriröykkiöiltä. Tässä tutkielmassa selvitellään Etelä-Savon, Etelä-Karjalan ja Pohjois-Kymenlaakson lapinraunioiden ikää ja kulttuuri-kontekstia uusien lapinraunioajoitusten, alueelta aiemmin saatujen luonnontieteellisten ajoitusten ja sijaintitutki-musten avulla. Luonnontieteellisen keskusmuseon ajoituslaboratoriossa teetettiin tutkielmaa varten AMS-ajoitukset tutkimusalueen kolmesta riittävästi luulöytöjä tuottaneesta lapinrauniosta. Sijaintitutkimuksia toteutettiin suorittamalla tilastollisia vertailuja kaikkien tutkimusalueen lapinraunioiden sijoittumisesta suhteessa tekstiilikeramiikkaa (n. 1900-500 eaa.) ja/tai Sär2-keramiikkaa (n. 900 eaa. 300 jaa.) sisältäviin asuinpaikkakohteisiin. AMS-ajoitusten perusteella Iitin Hiidensalmen palanutta luuta, kvartsi-iskoksia ja astiamaisen luonnonkiven sisältänyt lapinraunio on rakennettu 1505-1385 eaa., Ristiinan Haukkavuoren palanutta luuta sisältänyt lapinraunio 1450-1305 eaa. ja Savonlinnan Häyrynjärvi A:n lapinrauniokohteen palanutta luuta, kvartsi-iskoksia sekä Sär2-keramiikan siruja sisältänyt röykkiö kaksi 415-230 eaa. Ajoitustulokset osoittavat, että lapinrauniorakentaminen on omaksuttu Järvi-Suomen kaakkoisosissa jo varhaismetallikauden alussa. Yhdessä aiempien lapinraunioajoitusten kanssa tämä viittaa siihen, että röykkiörakentaminen ei ole levinnyt Järvi-Suomen alueelle lounaisen Suomen pronssikautisesta rannikkokulttuurista (n. 1500-500 eaa), vaan sen taustalta löytyy luultavammin Perämeren rannikolla jo kivikaudella harjoitettu röykkiörakentaminen, jota ei ole kyetty yhdistämään minkäänlaisiin hautausrituaaleihin. Ajoitukset myös vahvistavat hypoteesia, jonka mukaan lapinrauniotradition varhaisvaiheisiin ei ole kuulunut esineiden eikä keramiikan laittaminen röykkiöihin. Ajoitusten vertailu tutkimusalueen aiempiin arkeologisiin ajoituksiin osoittaa, että lapinrauniot eivät ainakaan heti korvanneet maalauskallioita rituaalipaikkoina, vaan kalliomaalausten luona suoritettiin uhrirituaaleja vielä lapinrauniotradition omaksumisen jälkeen. Pienimuotoista kaskiviljelyä on harjoitettu alueella jo ennen lapinrauniorakentamisen omaksumista, mutta pyynti pysyi alueen pääelinkeinona ilmeisesti koko varhaismetallikauden. Varhaismetallikautiset asuinpaikat ovat alueella tyypillisesti leirimäisiä, mikä viittaa harvaan ja liikkuvaan asutukseen. Tutkimusalueen lapinrauniot ja tekstiilikeramiikkaa/Sär2-keramiikkaa sisältävät asuinpaikat ovat tässä tutkielmassa suoritettujen sijaintitutkimusten perusteella keskittyneet toistensa läheisyyteen, vaikka kaikkien lapinraunioiden läheisyydestä ei varhaismetallikautista asuinpaikkaa löydykään. Erityisen usein lapinraunioiden läheisyydessä näyttävät sijaitsevan asuinpaikat, joista on löydetty sekä tekstiilikeramiikkaa että Sär2-keramiikkaa. Tämä viittaa siihen, että lapinraunioiden luokse on palattu yhä uudelleen ja uudelleen. Ne ovat ilmeisesti toimineet rituaalisina kiinnekohtina liikkuvaa elämää viettäville yhteisöille. Roomalaiselle rautakaudelle (0-400 jaa.) ajoitetuista lapinraunioista on muualla Suomessa tyypillisesti löydetty metalliesineitä. Tutkimusalueen lapinrauniosta ei ole tehty yhtäkään metalliesinelöytöä. Tämän perusteella on mahdollista, että lapinrauniotradition myöhäisimpiä kehitysvaiheita ei ole alueella koskaan omaksuttu.

Mesoporous silica- and silicon-based materials as carriers for poorly water soluble drugs

New chemical entities with unfavorable water solubility properties are continuously emerging in drug discovery. Without pharmaceutical manipulations inefficient concentrations of these drugs in the systemic circulation are probable. Typically, in order to be absorbed from the gastrointestinal tract, the drug has to be dissolved. Several methods have been developed to improve the dissolution of poorly soluble drugs. In this study, the applicability of different types of mesoporous (pore diameters between 2 and 50 nm) silicon- and silica-based materials as pharmaceutical carriers for poorly water soluble drugs was evaluated. Thermally oxidized and carbonized mesoporous silicon materials, ordered mesoporous silicas MCM-41 and SBA-15, and non-treated mesoporous silicon and silica gel were assessed in the experiments. The characteristic properties of these materials are the narrow pore diameters and the large surface areas up to over 900 m²/g. Loading of poorly water soluble drugs into these pores restricts their crystallization, and thus, improves drug dissolution from the materials as compared to the bulk drug molecules. In addition, the wide surface area provides possibilities for interactions between the loaded substance and the carrier particle, allowing the stabilization of the system. Ibuprofen, indomethacin and furosemide were selected as poorly soluble model drugs in this study. Their solubilities are strongly pH-dependent and the poorest (< 100 µg/ml) at low pH values. The pharmaceutical performance of the studied materials was evaluated by several methods. In this work, drug loading was performed successfully using rotavapor and fluid bed equipment in a larger scale and in a more efficient manner than with the commonly used immersion methods. It was shown that several carrier particle properties, in particular the pore diameter, affect the loading efficiency (typically ~25-40 w-%) and the release rate of the drug from the mesoporous carriers. A wide pore diameter provided easier loading and faster release of the drug. The ordering and length of the pores also affected the efficiency of the drug diffusion. However, these properties can also compensate the effects of each other. The surface treatment of porous silicon was important in stabilizing the system, as the non-treated mesoporous silicon was easily oxidized at room temperature. Different surface chemical treatments changed the hydrophilicity of the porous silicon materials and also the potential interactions between the loaded drug and the particle, which further affected the drug release properties. In all of the studies, it was demonstrated that loading into mesoporous silicon and silica materials improved the dissolution of the poorly soluble drugs as compared to the corresponding bulk compounds (e.g. after 30 min ~2-7 times more drug was dissolved depending on the materials). The release profile of the loaded substances remained similar also after 3 months of storage at 30°C/56% RH. The thermally carbonized mesoporous silicon did not compromise the Caco-2 monolayer integrity in the permeation studies and improved drug permeability was observed. The loaded mesoporous silica materials were also successfully compressed into tablets without compromising their characteristic structural and drug releasing properties. The results of this research indicated that mesoporous silicon/silica-based materials are promising materials to improve the dissolution of poorly water soluble drugs. Their feasibility in pharmaceutical laboratory scale processes was also confirmed in this thesis.

Mechanism-based inhibition of CYP2C8 by gemfibrozil in humans : characterisation of time and dose relationships

Drug-drug interactions may cause serious, even fatal clinical consequences. Therefore, it is important to examine the interaction potential of new chemical entities early in drug development. Mechanism-based inhibition is a pharmacokinetic interaction type, which causes irreversible loss of enzyme activity and can therefore lead to unusually profound and long-lasting consequences. The in vitro in vivo extrapolation (IVIVE) of drug-drug interactions caused by mechanism-based inhibition is challenging. Consequently, many of these interactions have remained unrecognised for many years. The concomitant use of the fibrate-class lipid-lowering agent gemfibrozil increases the concentrations of some drugs and their effects markedly. Even fatal cases of rhabdomyolysis occurred in patients administering gemfibrozil and cerivastatin concomitantly. One of the main mechanisms behind this effect is the mechanism-based inhibition of the cytochrome P450 (CYP) 2C8 enzyme by a glucuronide metabolite of gemfibrozil leading to increased cerivastatin concentrations. Although the clinical use of gemfibrozil has clearly decreased during recent years, gemfibrozil is still needed in some special cases. To enable safe use of gemfibrozil concomitantly with other drugs, information concerning the time and dose relationships of CYP2C8 inhibition by gemfibrozil should be known. This work was carried out as four in vivo clinical drug-drug interaction studies to examine the time and dose relationships of the mechanism-based inhibitory effect of gemfibrozil on CYP2C8. The oral antidiabetic drug repaglinide was used as a probe drug for measuring CYP2C8 activity in healthy volunteers. In this work, mechanism-based inhibition of the CYP2C8 enzyme by gemfibrozil was found to occur rapidly in humans. The inhibitory effect developed to its maximum already when repaglinide was given 1-3 h after gemfibrozil intake. In addition, the inhibition was shown to abate slowly. A full recovery of CYP2C8 activity, as measured by repaglinide metabolism, was achieved 96 h after cessation of gemfibrozil treatment. The dose-dependency of the mechanism-based inhibition of CYP2C8 by gemfibrozil was shown for the first time in this work. CYP2C8 activity was halved by a single 30 mg dose of gemfibrozil or by twice daily administration of less than 30 mg of gemfibrozil. Furthermore, CYP2C8 activity was decreased over 90% by a single dose of 900 mg gemfibrozil or twice daily dosing of approximately 100 mg gemfibrozil. In addition, with the application of physiological models to the data obtained in the dose-dependency studies, the major role of mechanism-based inhibition of CYP2C8 in the interaction between gemfibrozil and repaglinide was confirmed. The results of this work enhance the proper use of gemfibrozil and the safety of patients. The information related to time-dependency of CYP2C8 inhibition by gemfibrozil may also give new insights in order to improve the IVIVE of the drug-drug interactions of new chemical entities. The information obtained by this work may be utilised also in the design of clinical drug-drug interaction studies in the future.