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Introduction:  The unbound brain-to-plasma concentration ratio (Kp,uu,brain) is one of the most important indicators for brain penetration in the area of CNS drug discovery and development. Kp,uu,brain can be calculated by combining the total brain-to-plasma concentration ratio (Kp,brain),  the brain free fraction (fu,brain) and  the plasma free fraction (fu,p).

Aim:  This study has three purposes, to calculate Kp,uu,brain from publications in humans,  to collect data regarding species differences in Kp,uu,brain and to see whether Kp,uu,brain in humans differs in different  brain regions or not.

Materials and Methods:  The values of Kp, brain were derived from positron emission tomography (PET), MRS (Magnetic Resonance Spectroscopy), and brain surgery for tumor removal. fu,brain and fu,p were collected from brain homogenate, equilibrium dialysis and ultrafiltration studies.

Results:  Data on Kp,brain was sparse in the literature. Kp,uu,brain was calculated for sixteen different drugs in humans. According to the calculation, nine of these sixteen compounds were found to be actively influxed into the brain, six were actively effluxed from the BBB and one had a passive diffusion. Depending on the compound, Kp,uu,brain was higher or smaller in humans compared to mice and rats.  Kp,uu,brain for five compounds were calculated for different brain regions. Four compounds had a higher Kp,uu,brain value in almost all other regions than the cerebellum and one had a higher Kp,uu,brain in cerebellum than in the other regions.

Conclusions:  No definite conclusion on Kp,uu,brain in humans, species differences in Kp,uu,brain  or Kp,uu,brain  in different human brain regions could be reached in this study. In view of the importance of Kp,uu,brain  in CNS drug discovery and development, more studies on Kp,uu,brain in humans and in the other species are required.

Introduction: Febrile neutropenia (FN) is a frequent complication of chemotherapy use in cancer patients. There is evidence to suggest that the time to antibiotic administration is associated with increase survival and effective clinical outcome. The Australian consensus guidelines for the management of FN in adult cancer patients recommends treatment within 30 minutes to patients with features of systemic compromise. A study performed at The Alfred Hospital in 2010 revealed a median time of 145 minutes to first antibiotic administration. A new guideline was therefore developed and education was implemented. This study was conducted to evaluate the intervention. Aim: To determine time to first antibiotic prescribing and administration for patients with suspected FN presenting to the Alfred Emergency and Trauma centre. Materials and Methods: The electronic medical record of 112 episodes of suspected FN presenting between March and August 2012 were reviewed.  Data were retrospective collected according to a FN data spreadsheet. An observational study were also performed at  The Alfred Emergency and Trauma centre during October and November 2012 to determine time to first antimicrobial prescribing, because this data could not be collected from the electronic medical record. Results: The median time from presentation to antibiotic prescribing was 68 minutes. The median time from presentation to antibiotic administration was 121 minutes. Conclusions: The implementation of the new guidelines has reduced the time with 16.6%, but the target first antibiotic administration within 30 minutes has not been reached.

Objective: Beehive air therapy is recognized as a potential remedy for treating asthma, bronchitis, lung fibrosis, and respiratory tract infections. Developed countries in which beehive air therapy is currently authorized include Germany, Hungary, Slovenia, and Austria. However, scientific proof of its efficacy is lacking which warrants further chemical and biological analyses as a proof of concept. In this study, bee-hive air volatile profile was determined for the first time along with its individual components (bees, venom, honey, and beeswax).

Methods: Volatile compounds were collected from beehive air using solid phase micro-extraction (SPME) coupled to gas chromatography-mass spectrometry (GC-MS). Antimicrobial assay of the air released from 4 beehive products was further performed against Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and multi drug-resistant Staphylococcus aureus (MRSA) using the in vitro agar-well diffusion and microtiter plate assays.

Results and conclusions: A total of 56 volatile compounds were identified from beehive air, venom, bee insect and wax air including 6 fatty acids, 6 alcohols, 10 aldehydes, 5 esters, 1 ether, 9 hydrocarbons, 1 phenol, 7 ketones, 1 nitrogenous compound and 10 terpenes. The most abundant constituents were short-chain fatty acids (26.32%) while the lowest were the nitrogenous compounds (0.82%). The principal component analysis (PCA) scores plot of the UPLC/MS dataset showed the similarity of the beehive air to the insect bee's aroma profile. With regards to antimicrobial assay, beehive air and venom exerted the strongest antimicrobial activity among the examined bee products against S. aureus, K. pneumoniae, A. baumannii, and MRSA in agar-well diffusion assay but failing to exert an effect using microtiter plate assay as in case of bee venom against the aforementioned bacteria.

Bakgrund: Hjälpämne definieras som de inaktiva ingredienserna som tillsätts till läkemedel och som inte är avsedda att utöva terapeutiska effekter. Majoriteten av läkemedelsprodukter innehåller hjälpämne där hjälpämnena utgör ca. 50% av totala vikten av de fasta beredningsformerna. Hjälpämnen används för att överkomma de begränsningar som den farmaceutiska substansen har men även för att möjliggör hantering och användning av en läkemedelsberedning samt underlätta frisättningsegenskaper. Forskning har visat att hjälpämne är mer än inerta komponenter, utan hjälpämne har förmågan att reagera med andra ingredienser i formuleringen och påverka läkemedelsabsorptionen. Syftet: Att beskriva med hjälp av exempel hur hjälpämne kan påverka läkemedelsabsorptionen. Uppsatsen kommer att fokusera på vissa delprocesser av absorptionen. Metod: En allmän litteraturstudie där 18 artiklar inkluderades. Analysen av artiklarna resulterade i teman. Resultat: Tre huvudteman formulerades. Hjälpämnes effekter på absorptionsvariabler utifrån dess egenskaper där studier har visat att egenskaper hos hjälpämne kan avspegla om dessa kommer att bidra till en förbättrad eller försämrad absorption. Hjälpämnes effekter på transportproteiner där det framkom att hjälpämne modulerar aktiviteter av en del effluxtransportörer. Koncentrationsberoende effekter av hjälpämne på läkemedelsabsorption där koncentrationen av hjälpämne är en avgörande faktor för en förbättrad respektive försämrad absorption. Diskussion: Hjälpämnens effekter kan inte generaliseras, även inom en viss läkemedelsklass. Mycket forskning i in-vivo är nödvändigt för att förbättra förståelsen och utveckling av hjälpämne samt deras inverkan på läkemedelsabsorption.

Sterile alpha motif and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate triphosphohydrolase with ara-CTPase activity that confers cytarabine (ara -C) resistance in several hematological malignancies. Targeting SAMHD1's ara-CTPase activity has recently been demonstrated to enhance ara -C ef fi cacy in acute myeloid leukemia. Here, we identify the transcription factor SRY-related HMGbox containing protein 11 (SOX11) as a novel direct binding partner and fi rst known endogenous inhibitor of SAMHD1. SOX11 is aberrantly expressed not only in mantle cell lymphoma (MCL), but also in some Burkitt lymphomas. Coimmunoprecipitation of SOX11 followed by mass spectrometry in MCL cell lines identi fi ed SAMHD1 as the top SOX11 interaction partner, which was validated by proximity ligation assay. In vitro, SAMHD1 bound to the HMG box of SOX11 with low-micromolar af fi nity. In situ crosslinking studies further indicated that SOX11-SAMHD1 binding resulted in a reduced tetramerization of SAMHD1. Functionally, expression of SOX11 inhibited SAMHD1 ara-CTPase activity in a dose-dependent manner resulting in ara -C sensitization in cell lines and in a SOX11-inducible mouse model of MCL. In SOX11-negative MCL, SOX11-mediated ara-CTPase inhibition could be mimicked by adding the recently identi fi ed SAMHD1 inhibitor hydroxyurea. Taken together, our results identify SOX11 as a novel SAMHD1 interaction partner and its fi rst known endogenous inhibitor with potentially important implications for clinical therapy strati fi cation.

Clofazimine is classified as a WHO group B drug for the treatment of rifampin-resistant tuberculosis. QT prolongation, which is associated with fatal cardiac arrhythmias, is caused by several antitubercular drugs, including clofazimine, but there are no data quantifying the effect of clofazimine concentration on QT prolongation. Our objective was to describe the effect of clofazimine exposure on QT prolongation. Fifteen adults drug-susceptible tuberculosis patients received clofazimine monotherapy as 300mg daily for 3 days, followed by 100mg daily in one arm of a 2-week, multiarm early bactericidal activity trial in South Africa. Pretreatment Fridericia-corrected QT (QTcF) (105 patients, 524 electrocardiograms [ECGs]) and QTcFs from the clofazimine monotherapy arm matched with clofazimine plasma concentrations (199 ECGs) were interpreted with a nonlinear mixed-effects model. Clofazimine was associated with significant QT prolongation described by a maximum effect (Emax) function. We predicted clofazimine exposures using 100-mg daily doses and 2 weeks of loading with 200 and 300mg daily, respectively. The expected proportions of patients with QTcF change from baseline above 30 ms (DQTcF. 30) were 2.52%, 11.6%, and 23.0% for 100-, 200-, and 300-mg daily doses, respectively. At steady state, the expected proportion with Delta QTcF of >30 ms was 23.7% and with absolute QTcF of >450 ms was 3.42% for all simulated regimens. The use of loading doses of 200 and 300mg is not predicted to expose patients to an increased risk of QT prolongation, compared with the current standard treatment, and is, therefore, an alternative option for more quickly achieving therapeutic concentrations.

Background: Clofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization. Objectives: To determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients. Patients and methods: Clinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6 months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-Linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25 mg/L. Results: We analysed 1570 clofazimine concentrations from 139 participants; 79 (57%) had drug-resistant TB and 54 (39%) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5 L/h and peripheral volume 10500 L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a Loading dose of 200 mg daily for 2 weeks would achieve average daily concentrations above a target efficacy concentration 37 days earlier in a typical TB participant. Conclusions: Clofazimine was widely distributed with a Long elimination half-Life. Disposition was strongly influenced by body fat content, with potential dosing implications for women with TB.

Background 

An evidence-and experience-based pediatric drug information system, ePed, was developed in Sweden to gather pediatric drug therapy information. Recently a database, Advanced Reconstitution Module (ARM), was designed to detect errors in the reconstitution of high-risk drugs. ARM is integrated with ePed and has a front-end system called ReVal that facilitates communication between the database and DrugLog (an ultraviolet spectrophotometer).  

Aim 

The study’s main aim was to ensure correct drug management of high-risk drugs in the neonatal units at Karolinska University Hospital. The study had three objectives; (1) Determination of the prevalence of dilution error for high-risk drugs, (2) Evaluation of the staff experiences with the ARM-system, (3) Investigation of the adsorption of insulin on plastic material.  

Methods

Stage 1: Random samples of nine different diluted high-risk drugs used in clinical practice were collected and measured with DrugLog. Stage 2: Recruited participants prepared insulin using ARM. The reconstituted insulin from stage 2 was further studied. 

Results

Stage 1: Out of 168 samples, 44.6 % (95 %CI 37.3 %-52.2 %) contained concentrations outside of the acceptable limit (± 10 %). Stage 2: None of the participants found the ARM process difficult, and 34 % of the insulin prepared was outside of the acceptable range. No difference in adsorption (PVC vs. PVC-free lines) was found for insulin.  

Conclusions

The first objective of this study was to determine the prevalence of dilution error. With an overall rate of error of 44,6 % the main conclusion that can be drawn from this study is the need for a system that can help minimize this rate of error. The second objective was to evaluate the staff experiences with ARM which was identified to be a simple method according to the participants. More profound studies have to be performed in order to investigate insulins adsorption to plastic which was the studies third objective.  

Alzheimers sjukdom är en neurodegenerativ sjukdom vars orsak är okänd, kännetecknas av en gradvis försämring av kognitiva funktioner. Alzheimers sjukdom och Diabetes Mellitus har flera gemensamma patofysiologiska samband, bland annat insulinresistens. Försämrad insulinsignalering kan leda till kognitiv funktionsförsämring, som i sin tur kan leda till Alzheimers sjukdom. Båda insulin och amyloid-β metaboliseras av insulinnedbrytande enzym (IDE), defekt i IDE kan delvis orsaka amyloid-β ansamlingar. Syftet med detta arbete är att undersöka om försämrad insulinsignalering kan leda till kognitiv försämring och påskynda utvecklingen av Alzheimers sjukdom.

Jag har gjort en systematisk litteraturöversikt för att undersöka detta. Det är större risk att drabbas av Alzheimers sjukdom om man har Diabetes Mellitus. Man såg ett samband mellan försämrad insulinsignalering och försämrad kognitiv funktion. Förhöjda glukosnivåer var förenade med kognitiv försämring, medan nedsatt glukosnivå inte hade någon betydelse vid kognitiv försämring. Dessutom påskyndar en hög glukosnivå omvandlingen från MCI (mild kognitivs vikt) till Alzheimers sjukdom. Trots detta resultat krävs det mer forskning inom området eftersom olika metoder användes på de olika studierna vilket kan ge ett falskt samband.

Bakgrund: Opioidförgiftningar är ett framträdande folkhälsoproblem i många länder runt om i världen. Det misstänks att kombinationen mellan opioider och sederande läkemedel ökar risken för död även vid lägre doser opioider. Syftet med denna studie var att studera hur andra sederande läkemedel, bensodiazepiner, hypnotika, antiepileptika, antidepressiva och antihistaminer skulle kunna öka risken för opioidförgiftningar även vid lägre doser. Samt att identifiera andra möjliga riskfaktorer för opioidöverdos. 

Metod: Detta är en retrospektiv registerstudie som analyserar forensiska och toxikologiska data för samtliga personer obducerade inom rättsmedicin, avlidna i Skåne mellan 2011–2018 (N= 1395) på grund av intoxikation av minst en opioid. Datan analyserades med hjälp av independet sample t-test samt frekvensberäkningar för att analysera gruppskillnader. 

Resultat: Majoriteten av dödsfallen (84,6%) var relaterade till kombination mellan opioider och minst ett sederande läkemedel. Morfin/heroin var den vanligaste opioid i studien (36,2%) och bensodiazepiner (65,7%) var den mest frekventa sederande läkemedel i studien. Bensodiazepiner, hypnotika samt antiepileptika ledde till att signifikant lägre doser av morfin/heroin, fentanyl respektive tramadol krävdes till död på grund av överdos. Vissa grupper identifierades för att kunna tillhöra riskzonen. 

Slutsats: Den studerade populationen kännetecknades av omfattande kombination mellan opioider och bensodiazepiner. Dessutom rapporterades ett signifikant samband mellan förskrivning av bensodiazepiner, hypnotika samt antiepileptika och ökad risk för överdosdödsfall vid lägre doser opioider. Därför bör förskrivning av dessa läkemedel begränsas till opioidanvändare. 

Triple negative breast cancers (TNBC) are defined by the absence of estrogen andprogesterone receptors and the absence of HER2 protein overexpression. TNBC cancersrepresent a heterogeneous breast cancer subtype with poor prognosis. The heterogeneity of thedisease has limited the successful development of targeted therapy in unselected patientpopulations. Currently there are no approved targeted therapies for TNBC. However, intenseresearch is ongoing to identify specific targets and develop additional and better systemictreatment options. Recently researchers have found that the PDGF pathway plays a significantpart in communication between cancer cells and cells in the surrounding tissue. In thisliterature study evaluated if the PDGFR inhibition is a treatment strategy for triple negativebreast cancer. Method: literature original articles from database Pubmed was used in thisstudy. Results: results show that PDGF is more overexpressed in tissue cells than tumor cells.PDGF isoforms like PDGFRalfa and PDGF-C can increase the risk of distant recurrence tocentral nervsystem and early recurrence of primary breast cancer. The TNBC subtype (MES)is more likely to overexpress PDGF and inhibition with PDGF specific aptamer have shownsignificantly decreased tumor cell growth. Triple combination treatment with MEK1/2 and(JAK2) inhibitors resulted in significant reduction of cell growth and immunological inducedcell death through CD8+ t-cells. Single treatment with PDGFR inhibitors like Ponatinib andSunitinib reduced cell growth and cell migration in TNBC, but a combination treatment withDoxorubicin showed far greater inhibitor effect on cell growth and migration it also causedcell death. Chemotherapy Doxorubicin combination with a PDGFR- inhibitor resulted inbetter treatment compared to a single PDGFR- inhibitor to treat TNBC.Conclusion: It has been proven that PDGF isoforms have different significance in thedevelopment of TNBC. The PDGFC ligand is significantly more expressed in TNBCcompared to other PDGF isoforms. Ligand and receptor binding PDGFC-PDGFRα expressionis increased during breast cancer progression. PDGFRbeta signaling pathway plays a crucialrole in mediating vascular properties and therefore may be a good marker for reducing newvessel formation in endothelial cells. Combination therapy appears to be promising drugtreatment in TNBC. PDGFR inhibitors combined with cytostatic drugs or JAK & MEK1/2inhibitors can provide a pharmacological synergistic effect or activate the immune systemCD8+ T cells. Combination therapy reduces emergence of resistance mechanisms, howeverthere is a lack of studies on toxicity side effects. Nyckelord: Trippelnegativ bröstcan

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