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Thesis (M.Sc.) -- University of Adelaide, Dept. of Physiology and Pharmacology, 1973.

<p>Diss. (sammanfattning) Umeå : Umeå universitet, 1983, härtill 5 uppsatser</p> / digitalisering@umu

I den här avhandlingen har vi studerat hur man kan göra nya tensider. En tensid är en speciell molekyl som har förmågan att lösa sig i både vatten och olja. Man kan göra följande experiment hemma: Fyll en glasburk till hälften med vatten och tillsätt en droppe matolja. Oljan bildar en droppe ovanpå vattnet, därför att vatten och olja inte är blandbara. Vatten är polärt och olja är opolärt. Om man rör om med en sked kommer oljedroppen förvisso att dela upp sig i mindre droppar, men så snart man slutar att röra kommer dessa att lägga sig på vattenytan igen. Sätt nu en droppe diskmedel till blandningen och rör om. Nu sprider sig oljedropparna mycket bättre i vattnet, och de lägger sig heller inte på vattenytan lika fort när man slutar att röra. Det här beror på att diskmedel innehåller en tensid, som har en polär och en opolär del. Den polära delen passar ihop med det polära vattnet, medan den opolära delen passar ihop med den opolära oljan. På så vis kan tensiden hjälpa till att lösa upp opolära ämnen i polära vätskor. Den aktiva delen av ett läkemedel består ofta av opolära ämnen, vilka inte löser sig i polära vätskor såsom vatten. Eftersom kroppen består till stor del av vatten måste man ändå försöka få läkemedlet vattenlösligt, för att möjliggöra transport via blodet till problemområdet. Det kan man uppnå genom att tillsätta tensider. Om läkemedel-tensidblandningen ska ges till djur eller människor får inte tensiden orsaka någon skada i kroppen. Vi har försökt framställa tensider som ska kunna användas för att just lösa läkemedel i vatten. För att kunna framställa nya tensider måste man ha kunskap i organisk syntes. Det betyder att man måste veta hur man från små intermediat (”byggstenar”) successivt kan bygga upp nya molekyler som har de önskvärda egenskaperna. Genom olika typer av organisk syntes har vi byggt upp tre nya tensidtyper, vars egenskaper vi studerat med olika mätningar. Ingen av dessa tensider lämpade sig som tillsats till läkemedel, men vårt arbete har givit mycket ny kunskap om hur framtida tensidmolkyler kan tillverkas och vilka egenskaper de får. / This thesis deals with the synthesis and characterization of new polyhydroxy surfactants. The first part describes the synthesis of three new surfactant classes, and the second part concerns the surface chemical characterization of the synthesized surfactants. A stereodivergent route for preparation of hydrophilic head groups was developed, that featured consecutive stereoselective dihydroxylations of a diene. This method provided in total four different polyhydroxylated head groups. These surfactant head groups were natural and unnatural sugar analogues, and were used for the coupling with two different hydrophobic tail groups. Another approach took advantage of a metathesis reaction and provided a polyhydroxylated compound that was coupled to 12-hydroxy stearic acid The third class of surfactants contained an amide linkage between the hydrophilic and the hydrophobic parts. The hydrophilic part consisted of two glucose units, and 12-hydroxy stearic acid was used as the hydrophobic part. The hydroxy moiety in the tail group was further functionalized as aliphatic esters, which provided in total four different surfactants. A selection of the surfactants was used to investigate the chiral discrimination in Langmuir monolayers at an air-water interface. The isotherms showed a remarkable difference in compressibility between diastereomeric surfactants and also a pronounced chiral discrimination between racemic and enantiomerically pure surfactants, favoring heterochiral discrimination. The monolayers were also investigated with Brewster angle microscopy (BAM) and grazing incidence X-ray diffraction (GIXD). It was not possible to observe any chirality dependent features from the BAM images, but the GIXD measurement supported the conclusion that heterochiral discrimination governed the intermolecular forces within the racemic monolayer. The third class of surfactants, containing an amide linkage between the glucose units and 12-hydroxy stearic acid was evaluated with respect to the CMC and the haemolytic activity. These surfactants were all haemolytic close to their respective CMC. / QC 20101015

<p>I den här avhandlingen har vi studerat hur man kan göra nya tensider. En tensid är en speciell molekyl som har förmågan att lösa sig i både vatten och olja.</p><p>Man kan göra följande experiment hemma: Fyll en glasburk till hälften med vatten och tillsätt en droppe matolja. Oljan bildar en droppe ovanpå vattnet, därför att vatten och olja inte är blandbara. Vatten är polärt och olja är opolärt. Om man rör om med en sked kommer oljedroppen förvisso att dela upp sig i mindre droppar, men så snart man slutar att röra kommer dessa att lägga sig på vattenytan igen. Sätt nu en droppe diskmedel till blandningen och rör om. Nu sprider sig oljedropparna mycket bättre i vattnet, och de lägger sig heller inte på vattenytan lika fort när man slutar att röra. Det här beror på att diskmedel innehåller en tensid, som har en polär och en opolär del. Den polära delen passar ihop med det polära vattnet, medan den opolära delen passar ihop med den opolära oljan. På så vis kan tensiden hjälpa till att lösa upp opolära ämnen i polära vätskor.</p><p>Den aktiva delen av ett läkemedel består ofta av opolära ämnen, vilka inte löser sig i polära vätskor såsom vatten. Eftersom kroppen består till stor del av vatten måste man ändå försöka få läkemedlet vattenlösligt, för att möjliggöra transport via blodet till problemområdet. Det kan man uppnå genom att tillsätta tensider. Om läkemedel-tensidblandningen ska ges till djur eller människor får inte tensiden orsaka någon skada i kroppen.</p><p>Vi har försökt framställa tensider som ska kunna användas för att just lösa läkemedel i vatten. För att kunna framställa nya tensider måste man ha kunskap i organisk syntes. Det betyder att man måste veta hur man från små intermediat (”byggstenar”) successivt kan bygga upp nya molekyler som har de önskvärda egenskaperna. Genom olika typer av organisk syntes har vi byggt upp tre nya tensidtyper, vars egenskaper vi studerat med olika mätningar. Ingen av dessa tensider lämpade sig som tillsats till läkemedel, men vårt arbete har givit mycket ny kunskap om hur framtida tensidmolkyler kan tillverkas och vilka egenskaper de får.</p> / <p>This thesis deals with the synthesis and characterization of new polyhydroxy surfactants. The first part describes the synthesis of three new surfactant classes, and the second part concerns the surface chemical characterization of the synthesized surfactants.</p><p>A stereodivergent route for preparation of hydrophilic head groups was developed, that featured consecutive stereoselective dihydroxylations of a diene. This method provided in total four different polyhydroxylated head groups. These surfactant head groups were natural and unnatural sugar analogues, and were used for the coupling with two different hydrophobic tail groups.</p><p>Another approach took advantage of a metathesis reaction and provided a polyhydroxylated compound that was coupled to 12-hydroxy stearic acid</p><p>The third class of surfactants contained an amide linkage between the hydrophilic and the hydrophobic parts. The hydrophilic part consisted of two glucose units, and 12-hydroxy stearic acid was used as the hydrophobic part. The hydroxy moiety in the tail group was further functionalized as aliphatic esters, which provided in total four different surfactants.</p><p>A selection of the surfactants was used to investigate the chiral discrimination in Langmuir monolayers at an air-water interface. The isotherms showed a remarkable difference in compressibility between diastereomeric surfactants and also a pronounced chiral discrimination between racemic and enantiomerically pure surfactants, favoring heterochiral discrimination. The monolayers were also investigated with Brewster angle microscopy (BAM) and grazing incidence X-ray diffraction (GIXD). It was not possible to observe any chirality dependent features from the BAM images, but the GIXD measurement supported the conclusion that heterochiral discrimination governed the intermolecular forces within the racemic monolayer.</p><p>The third class of surfactants, containing an amide linkage between the glucose units and 12-hydroxy stearic acid was evaluated with respect to the CMC and the haemolytic activity. These surfactants were all haemolytic close to their respective CMC.</p>

Thesis (MTech (Biomedical Technology))--Cape Peninsula University of Technology, 2016. / Biochemical and haematological changes occur in red blood cellular products during the recommended storage period of 35 to 42 days at 1°C to 6°C. The restriction of the sodium/potassium pump at specified temperatures result in low intracellular potassium ion levels while an increase in sodium ion levels are observed and acidosis occurs as a result of low pH concentrations due to glucose consumption. Structural and morphological changes occur such as the release of free haemoglobin, lactate dehydrogenase and potassium into the supernatant causing the formation of spheroechinocytes and osmotic fragility. All these factors negatively impact the rheological properties of blood. These changes that transpire in the red cells during the storage period are referred to as “storage lesions”. Transfusion-associated graft versus host disease is an immunological and often fatal adverse transfusion reaction with gamma irradiation of cellular blood products used as a preventative measure. Gamma irradiation exacerbates storage lesions and of particular concern has been the increased potassium levels resulting in neonatal and infant hyperkalaemia. The storage lesions occurring in non-irradiated red blood cellular products are well documented although the literature regarding its irradiated counterparts has been less studied. A study of this nature has not previously been done in Cape Town, South Africa.

Haemolysis and other biochemical evaluations of vacuum-assisted venous drainage in cardiac surgery Aims of the study: Vacuum-assisted venous drainage (VAVD) improves the quality of venous return in procedures using extracorporeal circulation systems (ECC). Nevertheless, there is not an evidence that such high negative pressure applied to ECC in combination with selective bicaval cannulation due to open heart surgery cause a trauma to blood elements and deteriorates organ function. A prospective randomised study was designed to demonstrate that negative pressure of -20 mm Hg to -80 mm Hg does not cause a significant haemolysis and organ deterioration in such procedures. Materials and methods: 85 consecutive patients undergoing combined cardiac surgery procedure with two separate venous cannulas were randomised in three groups A, B and C. VAVD with negative pressure of -20 to -45 mm Hg was applied to 28 patients in group A and negative pressure of -45 mm Hg to -80 mmHg was applied to 28 patients in group B. There was zero negative pressure applied to 29 patients in group C. Six blood samples were taken from each patient and examinated for haemolysis and other indicators of organ deterioration such as hemoblobin, platelet count, free hemoglobin, aptoglobin, lactate-dehydrogenase, aspartate-amino-transferase,...

Haemolysis and other biochemical evaluations of vacuum-assisted venous drainage in cardiac surgery Aims of the study: Vacuum-assisted venous drainage (VAVD) improves the quality of venous return in procedures using extracorporeal circulation systems (ECC). Nevertheless, there is not an evidence that such high negative pressure applied to ECC in combination with selective bicaval cannulation due to open heart surgery cause a trauma to blood elements and deteriorates organ function. A prospective randomised study was designed to demonstrate that negative pressure of -20 mm Hg to -80 mm Hg does not cause a significant haemolysis and organ deterioration in such procedures. Materials and methods: 85 consecutive patients undergoing combined cardiac surgery procedure with two separate venous cannulas were randomised in three groups A, B and C. VAVD with negative pressure of -20 to -45 mm Hg was applied to 28 patients in group A and negative pressure of -45 mm Hg to -80 mmHg was applied to 28 patients in group B. There was zero negative pressure applied to 29 patients in group C. Six blood samples were taken from each patient and examinated for haemolysis and other indicators of organ deterioration such as hemoblobin, platelet count, free hemoglobin, aptoglobin, lactate-dehydrogenase, aspartate-amino-transferase,...

Pulmonary hypertension is becoming a recognized complication of the hereditary and acquired haemolytic anaemias, associated with a poor prognosis. Recently we reported that patients with paroxysmal nocturnal haemoglobinuria (PNH) have high levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), a biomarker associated with both right and left ventricular dysfunction and cardiac dysfunction. In the current study we evaluated a cohort of patients (N = 29) with haemolytic PNH for elevated pulmonary artery systolic pressure and cardiac function by Doppler-echocardiography. Of the 29 patients, eight were further studied using cardiac magnetic resonance imaging (MRI), as well as two additional patients (number of patients studied using cardiac MRI = 10). Plasma from the first cohort (N = 29) demonstrated intravascular haemolysis associated with a 12-fold increase in median nitric oxide (NO) consumption when compared with healthy volunteers (P < 0·001). Doppler echocardiography demonstrated normal left ventricular function and elevated pulmonary artery systolic pressure in 41% of patients. Cardiac MRI from the second cohort (N = 10) demonstrated depressed right ventricular function in 80% of PNH patients tested, and 60% had findings suggestive of subclinical small pulmonary emboli. Together, these data suggest a high prevalence of haemolysis-associated NO scavenging, Doppler-estimated systolic pulmonary hypertension, and depressed right ventricular function in patients with PNH.

Malaria affects millions of people annually especially in third world countries. Increase in resistance and limited research being conducted adds to the global burden of malaria. Mefloquine, known for unwanted adverse reactions and neurotoxicity, is highly lipophilic and is still used as treatment and prophylaxis. Lipid drug delivery systems are commonly used to increase solubility and efficacy and decrease toxicity. The most generally used lipid drug delivery system is liposomes. The lipid bilayer structure varying in size from 25 nm to 100 μm can entrap both hydrophilic and lipophilic compounds. Similar in structure and size to liposomes, Pheroid™ technology consist of natural fatty acids and is also able to entrap lipophilic and hydrophilic compounds. The aim of this study was to formulate liposomes and Pheroid™ vesicles loaded with mefloquine and evaluate the physiochemical characteristic of the formulations followed by efficacy and toxicity studies. Pheroid™ vesicles and liposomes with and without mefloquine were evaluated in size, morphology, pH and entrapment efficacy during three month accelerated stability testing. Optimization of size determination by flow cytometry lead to accurate determination of size for both Pheroid™ vesicles and liposomes. During the three months stability testing, Pheroid™ vesicles showed a small change in size from 3.07 ± 0.01 μm to approximately 3 μm for all three temperatures. Confocal laser scanning microscopic evaluation of the liposomes showed structures uniform in spherical shape and size. No difference in size or structure between the Pheroid™ vesicles with and without mefloquine were obtained. Significant increase (p=0.027) in size from 6.46 ± 0.01 μm to above 10 μm was observed for liposomes at all the temperatures. Clearly formed lipid bilayer structures were observed on micrographs. With the addition of mefloquine to the liposome formulation, a decrease in the amount of bilayer structures and an increase in oil droplets were found. Entrapment efficacy was determined by firstly separating the entrapped drug from the unentrapped drug utilizing a Sephadex®G50 mini column. This was followed by spectrophotometric evaluation by UV-spectrophotometry at 283 nm. Initial entrapment efficacy of both Pheroid™ vesicles and liposomes was above 60%. An increase in entrapment efficacy was observed for Pheroid™ vesicles. The addition of mefloquine to already formulated Pheroid™ vesicles illustrated entrapment efficacy of 60.14 ± 5.59% after 14 days. Formulations loaded with mefloquine resulted in lower pH values as well as a decrease in pH over time. Optimization of efficacy studies utilizing propidium iodide was necessary due to the similarity in size and shape of the drug delivery systems to erythrocytes. A gating strategy was successfully implemented for the determination of the percentage parasitemia. Efficacy testing of mefloquine loaded in Pheroid™ vesicles and liposomes showed a 186% and 207% decrease in parasitemia levels compared to the control of mefloquine. Toxicity studies conducted include haemolysis and ROS (reactive oxygen species) analysis on erythrocytes as well as cell viability on mouse neuroblastoma cells. Pheroid™ vesicles with and without mefloquine resulted in a dose dependent increase in ROS and haemolysis over time. A dose dependent increase in ROS and haemolysis in both liposome formulations were observed, but to a lesser extent. Mefloquine proved to be neurotoxic with similar results obtained when mefloquine was entrapped in liposomes. Pheroid™ vesicles seem to have neuroprotective properties resulting in higher cell viability. Mefloquine could be entrapped successfully in Pheroid™ vesicles and less in liposomes. Pheroid™ vesicles was more stable over a three months accelerated stability testing with more favourable characteristics. The increase in ROS levels of Pheroid™ vesicles could be responsible for the higher efficacy and haemolytic activity. DL-α-Tocopherol in Pheroid™ vesicles possibly acted as a pro-oxidant due to the presence of iron in the erythrocytes. DL-α-Tocopherol showed possible antioxidant properties in the neurotoxicity evaluation resulting in higher cell viability. Even though liposomes illustrated higher efficacy and little haemolysis and ROS production, no difference in neurotoxicity was observed together with unfavourable properties during stability testing makes this drug delivery system less favourable in comparison to Pheroid™ vesicles. Mefloquine was successfully incorporated into Pheroid™ vesicles resulted in high efficacy and showed possible neuroprotection and therefore makes it an ideal system for treatment of malaria. / Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011