<p><em>Bakgrund</em>: Många kunder tycker det är svårt att dela tabletter när de blir ordinerade att göra det och en orsak kan vara att tabletterna smulas sönder vid delning. Följsamheten kan påverkas negativt av att tabletterna smulas sönder. Cirka 10 % av kunderna i tidigare studier har fått kassera tabletter på grund av delningsproblem. Syftet med studien är att ta reda på i vilken utsträckning kunder upplever att tabletterna smulas sönder när de försöker dela dem samt vad kunden gör med smulorna.</p><p><em>Metod</em>: Intervjuer med apotekskunder, 18 år och äldre som har fått ett recept med dosering på delade tabletter expedierat.</p><p><em>Resultat</em>: Totalt intervjuades 475 av 572 tillfrågade apotekskunder. Det visade det sig att 174 apotekskunder har upplevt att tabletterna smular vid delning och att 29 apotekskunder upplever smulning som ett problem. 93 apotekskunder samlar ihop smulorna och använder dem medan 80 apotekskunder slänger smulorna och delar en ny tablett.</p><p><em>Konklusion</em>: En stor andel, mer än 40 % av apotekskunder som talar svenska i hemmet och som delar tabletter, upplever att tabletterna smular men bara 7 % tycker att smulning är ett problem. Det som utmärker dem som upplevt att tabletterna smular är att en större andel använder verktyg för att dela tabletterna. Många samlar ihop och använder smulorna trots att osäkerheten kring hur mycket läkemedel de får i sig är stor.</p> / <p>In Sweden, about 10 percent of the prescriptions have a dosage with split tablets. Many patients have problems with breaking tablets into two or more parts as the tablet may crumble or break into many small pieces. The aim with this work is to examine to which extent patients experience crumbled tablets when trying to split tablets and what the patient does with the crumbles.</p><p>In order to examine patients experience with crumbled tablets, interviews with patients who collected a prescription with a dosage with divided tablets in one of twelve pharmacies, were done. Included patients had to be 18 years or older.</p><p>Of the 416 included patients with experience of splitting tablets, 123 had problems with tablet splitting and out of these 29 found the issue with tablets crumbling to be a problem. Overall, 174 patients experienced crumbled tablets. Patients, who didn’t experience crumbled tablets, were less likely to split tablets with a tool than patients who did experience crumbled tablets. 93 of 380 patients collected crumbles equivalent to half a tablet and consumed the crumbles while 80 patients discarded the crumbles (threw them away).</p><p>Many patients use the crumbles instead of throwing them away even though it is difficult to tell how much of the drug you obtain with the crumbles. It seems as if the way you choose to divide the tablet (with or with out a tool) is affecting whether you experience crumbling or not. Most people don’t experience crumbling and of those who do only one out of six considers it to be a problem. In Sweden in whole the interviews give a slight estimate for how many patients the problem is persistent. In rough numbers it is estimated that 37- 47.000 had experienced crumbled tablets whereas 4.500-10.500 found it be a problem.</p>

<p>In this thesis, the strength-enhancing mechanisms of dry binders in direct compression were studied. The systems investigated were binary mixtures containing various compounds and binders. Among the binders used were a series of different molecular weights of polyethylene glycol. The proposed simplified tablet model describing the fracture path in a tablet during strength testing offers an explanation for the increase in tablet strength caused by the binder. The model and results in this thesis indicate that fractures will usually propagate around the tablet particles and through the interparticulate voids during tablet strength testing.</p><p>One important characteristic of the binder is its ability to be effectively and evenly distributed through the interparticulate voids in a compound tablet. Characteristics such as high plasticity, low elasticity and a small particle size were associated with a more even distribution and a consequent pronounced effect on pore structure and marked improvement in tablet strength. The strength of tablets containing less plastic binders was governed more by the compactibility of the binder. The tablet porosity, bonding mechanisms and volume reduction mechanisms of the compound also influenced the effect of the binder. For example, the plasticity and particle size of the binder had the most significant effects on tablet strength when the tablet porosity of the com-pound was relatively low. A combination of the plasticity and the compactibility of the binder determined the strength of tablets when the tablet of a compound was more porous. The positive effect of a binder on pore structure and tablet strength resulted in an increase in the disintegration time. Although addition of a superdisintegrant generally improved the disintegration time, the effect was decreased when the formulation included more deformable binders.</p><p>The choice of a suitable binder for a tablet formulation requires extensive knowledge of the relative importance of binder properties for enhancing the strength of the tablet and also of the interactions between the various materials constituting a tablet. Thus, the increased knowledge of the functionality of a binder obtained in this thesis enables a more rational approach to tablet formulation.</p>

In this thesis, the strength-enhancing mechanisms of dry binders in direct compression were studied. The systems investigated were binary mixtures containing various compounds and binders. Among the binders used were a series of different molecular weights of polyethylene glycol. The proposed simplified tablet model describing the fracture path in a tablet during strength testing offers an explanation for the increase in tablet strength caused by the binder. The model and results in this thesis indicate that fractures will usually propagate around the tablet particles and through the interparticulate voids during tablet strength testing. One important characteristic of the binder is its ability to be effectively and evenly distributed through the interparticulate voids in a compound tablet. Characteristics such as high plasticity, low elasticity and a small particle size were associated with a more even distribution and a consequent pronounced effect on pore structure and marked improvement in tablet strength. The strength of tablets containing less plastic binders was governed more by the compactibility of the binder. The tablet porosity, bonding mechanisms and volume reduction mechanisms of the compound also influenced the effect of the binder. For example, the plasticity and particle size of the binder had the most significant effects on tablet strength when the tablet porosity of the com-pound was relatively low. A combination of the plasticity and the compactibility of the binder determined the strength of tablets when the tablet of a compound was more porous. The positive effect of a binder on pore structure and tablet strength resulted in an increase in the disintegration time. Although addition of a superdisintegrant generally improved the disintegration time, the effect was decreased when the formulation included more deformable binders. The choice of a suitable binder for a tablet formulation requires extensive knowledge of the relative importance of binder properties for enhancing the strength of the tablet and also of the interactions between the various materials constituting a tablet. Thus, the increased knowledge of the functionality of a binder obtained in this thesis enables a more rational approach to tablet formulation.

<p>Crohns sjukdom är en kronisk inflammatorisk tarmsjukdom som kan drabba hela mag- tarmkanalen och karakteriseras av återkommande skov eller kontinuerliga besvär. Symptomen beror på lokaliseringen av sjukdomen, inflammationsgrad och komplikationer. Målen vid farmakabehandling vid Crohns sjukdom är bland annat erhållande av klinisk remission och bevarande av remission. Biologiska läkemedel för behandling av Crohns sjukdom introducerades under slutet av 1990-talet och till dem hör TNF-α-hämmare. Det proinflammatoriska cytokinet TNF-α spelar troligtvis en central roll i patogenesen vid Crohns sjukdom. När konventionell behandling som exempelvis glukokortikoider och immunmodulerande farmaka inte är tillräcklig kan behandling med TNF-α-hämmare bli aktuell. TNF-α-hämmaren adalimumab godkändes i Sverige för behandling av Crohns sjukdom i juni 2007.</p><p>Syftet med denna studie var att undersöka adalimumabs effekt avseende klinisk remission vid Crohns sjukdom, både vad beträffar att uppnå klinisk remission och bevarande av remission. Sekundär frågeställning var uppkomst av eventuella allvarliga infektiösa tillstånd vid adalimumabbehandling.</p><p>Metoden för studien har varit en litteraturstudie där fem vetenskapliga artiklar har studerats. Tre av studierna var RCT-studier och två var öppna studier.</p><p>I två studier var skillnaden signifikant högre vad gäller klinisk remission i vecka 56 i adalimumabgrupperna jämfört med placebogruppen. I en studie påvisades remission i signifikant högre grad i adalimumabgruppen än i placebogruppen vecka 4. I en annan studie visades signifikant större remissionsgrad vecka 52 jämfört med vecka 0 med adalimumabbehandling. En studie visade på erhållande av remission hos patienter med luminal sjukdom och hos patienter med fistulerande sjukdom med adalimumabbehandling. I tre av studierna hade man inga fall av allvarliga infektioner. I en studie rapporterades ett fåtal fall av allvarliga infektioner i placebogruppen men inga i adalimumabgruppen. I en studie rapporterades 7 fall av allvarliga infektioner i adalimumabgrupperna och 9 fall i placebogruppen under den blindade studien.</p><p>Sammanfattningsvis visade studierna att behandling med adalimumab kan inducera och bevara remission vid Crohns sjukdom upp till 56 veckor. Dessutom visade studierna på låg biverkningsprofil gällande allvarliga infektioner.</p>

<p>Kakaobönan har använts av människan i tusentals år. Framför allt användes kakaon som dryck men under det senaste århundradet även till choklad. De senaste tio åren har det framkommit att kakaon är rik på flavonoider och då främst flavanolerna epikatekin och katekin. Det är främst epikatekinerna som bidrar till olika kardiovaskulära effekter, som påverkan på blodtrycket, förändringar i HDL- och LDL-balansen och plackbildning i kärlen beroende på LDL-oxidation. Jag har gjort en litteraturstudie där dessa teorier undersöks. För att undersöka detta har sex stycken artiklar använts. Dessa bygger på olika studier som har gjorts av kakaons effekter på blodtrycket. Studierna varierar i längd, från två dagar upp till 18 veckor. Fem av studierna använder sig av deltagare som inte genomgår någon behandling för någon kardiovaskulär sjukdom. I den sjätte studien har samtliga deltagare en kranskärlssjukdom som de behandlas för. Den enda effekt som framkommer är en marginell sänkning av blodtrycket över tid. Däremot framkommer det ingen skillnad för de personer som har en kardiovaskulär sjukdom. Detta kan tyda på att flavanolerna har en förebyggande effekt snarare än en läkande effekt. Studierna kunde heller inte påvisa någon större förändring i kolesterolbalansen eller LDL-oxidationen. Eftersom epikatekin är en instabil molekyl som försvinner vid vissa tillverkningsprocesser är det svårt att veta vilken mängd epikatekin det finns i kommersiell kakao. Det är även andra faktorer som påverkar koncentrationen epikatekin i kakaon, såsom växtförhållande, genuppsättning och skördetid.</p><p>2008:F18</p>

Background Osteoporosis is a disease with reduced bone mass and deterioration of bone structure, which leads to increased risk of fractures (1.9). Approximately one in four men and one in two women will at some time in life suffer a fracture due to osteoporosis. Supplemental calcium and vitamin D have long been a cornerstone of osteoporosis treatment. Drugs that are also used clinically for the treatment of osteoporosis include bisphosphonates, denosumab, selective estrogen receptor modulators (SERM), and strontium (3). Bisphosphonates are the most used osteoporosis drugs (4). The bisphosphonates alendronate, risedronate and zoledronic acid are interchangeable as first choice treatment of osteoporosis in postmenopausal women. Denosumab is another drug with antiresorptive effects that has been registered for the treatment of postmenopausal osteoporosis in recent years. Teriparatide (PTH) is an anabolic drug used for osteoporosis (3.6). Objective: The objective of this study was to examine the efficacy of alendronate, denosumab and teriparatide on fracture risk and bone mineral density in postmenopausal women with osteoporosis with the help of published meta-analyses and clinical trials. Result: Examined articles showed that alendronate treatment for at least one year reduces the risk of vertebral fractures with NNT = 17-50 and the risk of non-vertebral fractures with NNT = 50. PTH reduced the risk of vertebral fractures with NNT = 9.8 and non-vertebral fractures with NNT = 29. A statistically significant increase in BMD was also observed with an increase in BMD of 8.14% in the spine and 2.48% in the hip. PTH treatment compared with alendronate treatment was found to have a statistically significant difference (P=0.004) in the reduction of non-vertebral fracture risk with NNT = 10,4. Teriparatid treatment also showed more positive effects as compared to alendronate on BMD increases. Denosumab treatment for 36 months reduced the risk of fractures with a relative reduction of 68% for vertebral fractures and a relative reduction of 20% for non-vertebral fractures. Denosumab treatment for 12 months compared with alendronate therapy in postmeopausala women showed no statistically significant difference in fracture risk (p=0,19). The increase in BMD was, however, greater in the denosumab group than in the alendronate group, with 0.53% in the distal radius, 1.14% in the hip , 0.77% in the lumbar spine and 0.79% in the femoral neck.   Conclusion: These studies show that all three drugs, alendronate, PTH and denosumab, have good effects on reducing the risk of fractures in postmenopausal women. All drugs lead to increases in BMD in different parts of the skeleton. Reduction of fracture risk was greater for both denosumab treatment and PTH treatment compared to alendronate treatment, also BMD increased more with denosumab or PTH treatment compared with alendronate treatment. / Bakgrund Osteoporos är ett sjukdomstillstånd med reducerad benmassan och försämringar i benvävnadens struktur, som leder till att man lättare kan få benbrott. Ungefär var fjärde man och varannan kvinna drabbas någon gång i livet av en fraktur på grund av osteoporos. Tillägg av kalcium och vitamin D har länge varit en grundval inom osteoporosbehandlingen. Läkemedel som också används kliniskt för osteoporosbehandling inkluderar bisfosfonater, denosumab, selektiva östrogenreceptormodulatorer (SERM), samt strontiumsalt. Bisfosfonater är den mest använda gruppen av osteoporosläkemedel. Bisfosfonater som alendronate, risedronat och zoledronsyra vilka är utbytbara mot varandra räknas som förstahandsval i behandling av osteoporos hos postmenopausala kvinnor. Denosumab är ett annat osteoporosläkemedel med antiresorptiv effekt som registrerats för behandling av postmenopausal osteoporos de senaste åren. Teriparatid (PTH) är ett anabolt läkemedel som också används mot osteoporos. Syftet: Syftet med detta arbete var att med hjälp av publicerade meta-analyser och kliniska studier undersöka effekterna av alendronat, denosumab och teriparatid på frakturrisk och bentäthet hos postmenopausala kvinnor med osteoporos. Resultat: Granskade artiklar på postmenopausala kvinnor visar att alendronatbehandling under minst ett år minskar risken för vertebrala frakturer med NNT =17-50 och för icke-vertebrala frakturer med NNT=50. PTH minskade risken för vertebrala frakturer med NNT=9,8 och icke-vertebrala frakturer med NNT= 29. Statistiskt signifikant ökning i BMD förelåg också med 8.14% i ryggrad och 2,48% i höften. PTH behandling jämfört med alendronat visade en statistiskt signifikant skillnad (p=0.004) för minskning av icke-vertebrala frakturer med NNT=10,4. Teriparatidbehandling visade också mer positiva effekter jämfört med alendronat avseende ökningar i BMD. Denosumabbehandling i 36 månader minskade risken för frakturer med en relativ minskning på 68 % för vertebrala frakturer och en relativ minskning på 20% för icke-vertebrala frakturer. Denosumabbehandling under 12 månader jämfört med alendronatbehandling hos postmenopausala kvinnor gav ingen statistiskt signifikant skillnad (p =0.19) i frakturrisk. Ökning av BMD var dock större i denosumabgruppen än i alendronatgruppen, 0.53%  i distala radius, 1.14 % i höften, 0.77% i ländryggen  och 0.79% i lårbenhalsen. Slutsats: Studierna visade att alla tre undersökta läkemedel, alendronat, PTH och denosumab, har goda effekter på minskning av frakturrisk hos postmenopausala kvinnor. Samtliga läkemedel leder till ökning av BMD i olika delar av skelettet. Minskningen av frakturrisk var större för både denosumabbehandling och PTH-behandling jämfört med alendronat, även BMD ökade mer vid denosumab- eller PTH-behandling jämfört med alendronatbehandling.

Monitoring of patients prescribed potassium supplements Zuzana Hovorkova Degree Project 30 hp, Pharmacotherapy Department of Pharmaceutical Biosciences/Division of Pharmacokinetics and Drug Therapy Supervisor: Linden Ashfield, Examiner: Margareta Hammarlund-Udenaes Introduction: In Northern Ireland, clinical technicians have been supporting pharmacist in their work in over five decades. From initially having mainly administrative tasks, the role of pharmacy technicians has progressed to more clinical activities. Following recent incidents caused by inadequate monitoring of potassium blood levels it was suggested pharmacy technicians could be utilized to improve patient care. Aim: Aim of this project was to ensure the appropriate monitoring and compliance with treatment guidelines for patients prescribed potassium supplements by extending the role of pharmacy technicians at Antrim Area Hospital. Methods: Training for extending the roles of clinical technicians was developed, following the structure of  a regional training programme. Literature search was made to find appropriate background about the subject of interest. Data about monitoring of potassium levels in the relevant patients was collected. Daily monitoring of these patients before and after the change was implemented were compared. Results: Clinical technicians contribution to monitoring of patients prescribed potassium replacement therapy improved guidelines compliance from 66.6 %  to 90 % (x2-test, p = 0.028). Percentage of successful treatment raised from 66 % to 89.7 % (x2-test, p = 0.028). Conclusion: By extending roles of the clinical technicians, better and appropriate monitoring of patients prescribed potassium supplements can be reached. In future, roles of the pharmacy technicians could be extended further, thus releasing  pharmacists time to expand their role, leading to a more cost- effective system and ensuring medicines optimization.

<p>Psoriasisartrit (PsA) är en inflammatorisk ledsjukdom som förekommer hos patienter med hudsjukdomen psoriasis. Sjukdomen kan se väldigt olika ut hos olika patienter, allt från några få till väldigt många leder kan vara drabbade. Det är ofta de distala lederna i fingrar och tår som drabbas men även större leder kan ge symtom. Daktylit (korvliknande svullnader av fingrar och tår) och entesit (smärtsamma inflammationer vid seninfästen) är sjukdomsspecifika kännetecken. Vid PsA angriper immunförsvaret kroppens egna vävnader och den inflammatoriska reaktion som uppstår hålls igång och blir kronisk. Man har hittat höga nivåer av TNF-α i ledvätskan och i vävnaden hos patienter med PsA. TNF-α är ett cytokin som på flera olika sätt stimulerar inflammationen. Också höga nivåer av T-lymfocyter kan ses i angripen vävnad vid PsA. PsA kan behandlas med biologiska läkemedel. TNF-α-hämmarna adalimumab, etanercept och infliximab verkar genom att hämma funktionen hos TNF-α medan alefacept och efalizumab angriper T-cellerna genom att på olika sätt blockera den andra signalen i T-cellsaktiveringen. Syftet med den här litteraturstudien var att utreda den kliniska effekten och effekten på strukturella skador som dessa biologiska läkemedel har vid psoriasisartrit. Litteratursökningen gjordes i PubMed. Resultatet visade att alefacept, adalimumab, infliximab och etanercept har klinisk effekt vid PsA. De tre TNF-α-hämmarna inhiberade dessutom de strukturella skador som orsakas av sjukdomen. Det fanns ingen studie med alefacept som utredde effekten på strukturella skador, vilket skulle vara intressant att se i framtiden. Behandling med efalizumab visade sig däremot inte ha någon klinisk effekt vid PsA.</p>

<p>Established quantitative relationships between dose, plasma concentrations and response [pharmacokinetic-pharmacodynamic (PKPD) models] have a high potential in improving therapeutic indices of anticancer drug therapy and in increasing drug development efficiency. PKPD modelling is a helpful tool for characterising and understanding schedule dependence. The aim of this thesis was to develop PKPD models of anticancer drugs for tumour effects and haematological toxicity, which is the most frequent dose-limiting toxicity.</p><p>PK and haematological toxicity after several schedules were studied in rats and semi-physiological PKPD models for the whole time course of myelosuppression were developed from animal and patient data. The possibility to implant hollow fibres filled with tumour cells in immunocompetent rats was investigated for simultaneous assessment of PK, tumour response and haematological toxicity. Population data analyses were performed using the software NONMEM. </p><p>When all injections were administered within eight hours, fractionated schedules of 5-fluorouracil and epirubicin produced similar haematological toxicity in rats as a single dose, when the non-linear PK of 5-fluorouracil was accounted for. When the time interval was extended to two days for 5-fluorouracil, the fractionated regimens were more toxic. </p><p>The developed semi-physiological PKPD models included transit compartments that mimic maturation stages in bone marrow and explain the time lag. Feedback mechanisms characterised the rebound. The models successfully described myelosuppression in patients (DMDC) and rats (5-fluorouracil), after different administration schedules. Further developments made it possible to characterise the time course of myelosuppression after administration of each one of six different drugs, with parameters related to the haematopoietic system consistent across drugs. </p><p>The developed hollow fibre model in immunocompetent rats was successfully applied to monitor PK, toxicity and the time course of antitumour effects. PKPD modelling illustrated that the schedule dependence of the anticancer agent CHS 828 is partly due to dose-dependent bioavailability and partly due to a schedule-dependent PD effect.</p>

<p>Acid related diseases like GERD, duodenal-and gastric ulcers and H. Pylori-positive peptic ulcer disease are primarily managed by reducing gastric acidity. Irreversible proton pump inhibitors (PPIs) inhibit gastric acid secretion effectively throughout the day by irreversibly inhibiting the gastric proton pump, H+, K+-ATPase, in the parietal cells. Reversible gastric proton pump inhibitors are under development, but have not yet reached clinical use.</p><p>The pharmacokinetic/pharmacodynamic (PK/PD) relationships of these compounds are nonlinear, with a delay in the effect-time profile compared to the plasma concentration-time course. PK/PD-modelling was used to characterize and quantify the pharmacological effect with regard to onset, intensity and duration of effect. Models based on functional data, that discriminate between drug-and system-specific parameters, were developed. </p><p>In general, the plasma concentration-time course for each individual was approximated by linear interpolation between time-points and served as input into the pharmacodynamic models. A turnover model of irreversible inhibition of gastric acid secretion by omeprazole in the dog described the data well. The model was challenged and found to be robust under different experimental conditions. This model could predict the effect following different exposure of omeprazole and following different histamine provocation. Different fitting approaches (naïve pooling, standard two-stage and nonlinear mixed effects modelling) were compared and resulted in similar parameter estimates. For the reversible inhibitors, a kinetic binding model was finally selected. With a binding model the delay in the effect-time profile is explained by prolonged binding to the enzyme. </p><p>Use of these results in drug development can be helpful with regard to selection of drugs for further development and to predict the first clinical dose.</p>