The polymerization of lactic acid anhydrosulphite by anionic initiators

This thesis is primarily concerned with the synthesis and polymerization of 5-methyl-1;3, 2-dioxathiolan-4-one-2-oxide (lactic acid anhydrosulphite (LAAS)) using anionic initiators under various conditions. Poly(lactic acid) is a biodegradable polymer which finds many uses in biomedical applications such as drug-delivery and wound-support systems. For such applications it is desirable to produce polymers having predictable molecular weight distributions and crystallinity, The use of anionic initiators offers a potential route to the creation of living polymers. The synthesis of LAAS was achieved by means of an established route though the procedure was modified to some extent and a new method of purification of the monomer using copper oxides was introduced, Chromatographic purification methods were also examined but found to be ineffective. An unusual impurity was discovered in some syntheses and this was identified by means of 1H and 13C NMR, elemental analysis and GC-MS. Since poly-α-esters having hydroxyl-bearing substituents might be expected to have high equilibrium water contents and hence low surface tension characteristics which might aid bio-compatibility, synthesis of gluconic acid anhydrosulphite was also attempted and the product characterised by 1H and 13C NMR. The kinetics of the decomposition of lactic acid anhydrosulphite by lithium tert-butoxide in nitrobenzene has been examined by means of gas evolution measurements. The kinetics of the reaction with potassium tert-butoxide (and also sec-butyl lithium) in tetrahydrofuran has been studied using calorimetric techniques. LAAS was block co-polymerized with styrene and also with 1,3-butadiene in tetrahydrofuran (in the latter case a statistical co-polymer was also produced).

Functionalised polymers

Synthetic routes to polymers possessing functional groups were studied. Direct functionalisation of poly(vinyltoluene) by lithiation and carboxylation resulted in the expected carboxylic acid but reaction was complicated by the production of a mixture of products. Reaction occurred both at the polymer backbone and at the pendant methyl group. Reaction with ethyl formate was also difficult to control and a secondary alcohol was formed even when an excess of the carbonyl compounds was employed. Grignard formation of poly(bromostyrene) was successful but once formed, the derivative rearranged resulting in chain scission and degradation of the polymer. Therefore subsequent reactions of the Grignard reagent with carbonyl groups were unsuccessful in producing functionalised polymers. Reactions of vinyltoluene monomer were more successful. Although complications arose when lithiation and carboxylation of the monomer were carried out using lithium diisopropylamide because the carboxylic acid product reacted with the excess lithium diisopropylamide present, metallation by potassium t-butoxide followed by reaction with 2-(3-chloropropyl)-2-methyl-1,3-dioxalane resulted in the formation of 2-methyl-2(4-(vinylphenyl)-butyl-1,3,-dioxalane. The butyllithium initiated anionic polymerisation of this protected monomer resulted in a polymer which had a very narrow molecular weight distribution (Mw/Mn= 1.05) and subsequent hydrolysis of the polymer resulted in poly(6(vinylphenyl)-hexan-2-one) which was derivatised with 2,4 dinitrophenyl-hydrazine. Functionalisation by modification of the siloxane derivative 3-(methylpropenoxycarbonyl)ltrimethoxysilane was unsuccessful. The acid catalysed exchange reactions of this monomer with alcohols such as eugenol, octan-1-ol, pentan-1-ol, and hexan-1-ol were inefficient, resulting in a mixture of products and unreacted starting materials.

Activation of calcium-sensitive potassium channels in L6 skeletal myocytes by arginine vasopressin requires extracellular calcium

The effects of extracellular application of arginine vasopressin (AVP) upon membrane currents in L6 skeletal myocytes was investigated using the whole-cell configuration of the patch-clamp technique. At O mV AVP produced large amplitude, transient outward currents that reversed when the clamping potential was changed to -100 mV (negative to EK) The effects of alterations in the extracellular K+ concentration upon the current reversal potential suggested that the current elicited by AVP was carried mainly by K+ ions. Intracellular dialysis with 10 μM inositol 1,4,5-trisphosphate (InsP3) elicited similar currents but only in 6/14 cells. Inclusion of 5 mg ml-1 heparin in the intracellular solutions was ineffective at inhibiting the current responses to AVP. The AVP-induced current was totally abolished when the intracellular EGTA concentration was increased from 0.05 mM to 10 mM or Ca2+ was removed from the extracellular perfusing solution. These results suggest that AVP produces activation of a Ca2+-sensitive K+ conductance in L6 skeletal myocytes by a process dependent upon extracellular Ca2+ and not intracellular Ca2+ release. © 1995 Academic Press. All rights reserved.

Organic reactions in ionic liquids: N-alkylation of cyclic imides with alkyl halides promoted by potassium fluoride

An ionic liquid based on 1-butyl-3-methylimidazolium hexafluorophosphate is used as an efficient reusable reaction medium in the N-alkylation of cyclic imides with alkyl halides promoted by fluoride ion.

Organic reactions in ionic liquids: synthesis of alkyl aryl trithiocarbonates by the S-arylation of potassium carbonotrithioates with diaryliodonium salts

Various alkyl aryl trithiocarbonates were readily prepared in good yields by the S-arylation of potassium carbonotrithioates with diaryliodonium salts in the room-temperature ionic liquid, 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF4). The ionic liquid can be recycled and reused.

Organic reactions in ionic liquids: ionic liquid-accelerated nucleophilic substitution reaction of alpha-tosyloxyketones with potassium salts of aromatic acids

The room temperature ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF4]) is used as a ‘green' recyclable alternative to classical molecular solvents for the nucleophilic substitution reaction of a-tosyloxy ketones with potassium salts of aromatic acids. Significant rate enhancement and improved yields have been observed.

Fibre optics sensors in tear electrolyte analysis:towards a novel point of care potassium sensor

The diagnosis of ocular disease is increasingly important in optometric practice and there is a need for cost effective point of care assays to assist in that. Although tears are a potentially valuable source of diagnostic information difficulties associated with sample collection and limited sample size together with sample storage and transport have proved major limitations. Progressive developments in electronics and fibre optics together with innovation in sensing technology mean that the construction of inexpensive point of care fibre optic sensing devices is now possible. Tear electrolytes are an obvious family of target analytes, not least to complement the availability of devices that make the routine measurement of tear osmolarity possible in the clinic. In this paper we describe the design, fabrication and calibration of a fibre-optic based electrolyte sensor for the quantification of potassium in tears using the ex vivo contact lens as the sample source. The technology is generic and the same principles can be used in the development of calcium and magnesium sensors. An important objective of this sensor technology development is to provide information at the point of routine optometric examination, which would provide supportive evidence of tear abnormality.

Uncatalysed and potassium-catalysed pyrolysis of the cell-wall constituents of biomass and their model compounds

Cell-wall components (cellulose, hemicellulose (oat spelt xylan), lignin (Organosolv)), and model compounds (levoglucosan (an intermediate product of cellulose decomposition) and chlorogenic acid (structurally similar to lignin polymer units)) have been investigated to probe in detail the influence of potassium on their pyrolysis behaviours as well as their uncatalysed decomposition reaction. Cellulose and lignin were pretreated to remove salts and metals by hydrochloric acid, and this dematerialized sample was impregnated with 1% of potassium as potassium acetate. Levoglucosan, xylan and chlorogenic acid were mixed with CHCOOK to introduce 1% K. Characterisation was performed using thermogravimetric analysis (TGA) and differential thermal analysis (DTA). In addition to the TGA pyrolysis, pyrolysis-gas chromatography-mass spectrometry (PY-GC-MS) analysis was introduced to examine reaction products. Potassium-catalysed pyrolysis has a huge influence on the char formation stage and increases the char yields considerably (from 7.7% for raw cellulose to 27.7% for potassium impregnated cellulose; from 5.7% for raw levoglucosan to 20.8% for levoglucosan with CHCOOK added). Major changes in the pyrolytic decomposition pathways were observed for cellulose, levoglucosan and chlorogenic acid. The results for cellulose and levoglucosan are consistent with a base catalysed route in the presence of the potassium salt which promotes complete decomposition of glucosidic units by a heterolytic mechanism and favours its direct depolymerization and fragmentation to low molecular weight components (e.g. acetic acid, formic acid, glyoxal, hydroxyacetaldehyde and acetol). Base catalysed polymerization reactions increase the char yield. Potassium-catalysed lignin pyrolysis is very significant: the temperature of maximum conversion in pyrolysis shifts to lower temperature by 70 K and catalysed polymerization reactions increase the char yield from 37% to 51%. A similar trend is observed for the model compound, chlorogenic acid. The addition of potassium does not produce a dramatic change in the tar product distribution, although its addition to chlorogenic acid promoted the generation of cyclohexane and phenol derivatives. Postulated thermal decomposition schemes for chlorogenic acid are presented. © 2008 Elsevier B.V. All rights reserved.

Effect of aminoglycoside antibiotics on erythrocyte membrane potassium ion transport

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Population pharmacokinetic model of canrenone after intravenous administration of potassium canrenoate to paediatric patients

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Little is known about the pharmacokinetics of potassium canrenoate/canrenone in paediatric patients WHAT THIS STUDY ADDS • A population pharmacokinetic model has been developed to evaluate the pharmacokinetics of canrenone in paediatric patients who received potassium canrenoate as part of their therapy in the intensive care unit. AIMS To characterize the population pharmacokinetics of canrenone following administration of potassium canrenoate to paediatric patients. METHODS Data were collected prospectively from 23 paediatric patients (2 days to 10 years of age; median weight 4 kg, range 2.16–28.0 kg) who received intravenous potassium canrenoate (K-canrenoate) as part of their intensive care therapy for removal of retained fluids, e.g. in pulmonary oedema due to chronic lung disease and for the management of congestive heart failure. Plasma samples were analyzed by HPLC for determination of canrenone (the major metabolite and pharmacologically active moiety) and the data subjected to pharmacokinetic analysis using NONMEM. RESULTS A one compartment model best described the data. The only significant covariate was weight (WT). The final population models for canrenone clearance (CL/F) and volume of distribution (V/F) were CL/F (l h−1) = 11.4 × (WT/70.0)0.75 and V/F (l) = 374.2 × (WT/70) where WT is in kg. The values of CL/F and V/F in a 4 kg child would be 1.33 l h−1 and 21.4 l, respectively, resulting in an elimination half-life of 11.2 h. CONCLUSIONS The range of estimated CL/F in the study population was 0.67–7.38 l h−1. The data suggest that adjustment of K-canrenoate dosage according to body weight is appropriate in paediatric patients.

Potassium canrenoate treatment in paediatric patients:a population pharmacokinetic study using novel dried blood spot sampling

Objective: To characterize the population pharmacokinetics of canrenone following administration of potassium canrenoate (K-canrenoate) in paediatric patients. Methods: Data were collected prospectively from 37 paediatric patients (median weight 2.9 kg, age range 2 days–0.85 years) who received intravenous K-canrenoate for management of retained fluids, for example in heart failure and chronic lung disease. Dried blood spot (DBS) samples (n = 213) from these were analysed for canrenone content and the data subjected to pharmacokinetic analysis using nonlinear mixed-effects modelling. Another group of patients (n = 16) who had 71 matching plasma and DBS samples was analysed separately to compare canrenone pharmacokinetic parameters obtained using the two different matrices. Results: A one-compartment model best described the DBS data. Significant covariates were weight, postmenstrual age (PMA) and gestational age. The final population models for canrenone clearance (CL/F) and volume of distribution (V/F) in DBS were CL/F (l/h) = 12.86 ×  (WT/70.0)0.75 × e [0.066 ×  (PMA - 40]) and V/F (l) = 603.30 ×  (WT/70) × (GA/40)1.89 where weight is in kilograms. The corresponding values of CL/F and V/F in a patient with a median weight of 2.9 kg are 1.11 l/h and 20.48 l, respectively. Estimated half-life of canrenone based on DBS concentrations was similar to that based on matched plasma concentrations (19.99 and 19.37 h, respectively, in 70 kg patient). Conclusion: The range of estimated CL/F in DBS for the study population was 0.12–9.62 l/h; hence, bodyweight-based dosage adjustment of K-canrenoate appears necessary. However, a dosing scheme that takes into consideration both weight and age (PMA/gestational age) of paediatric patients seems more appropriate.

Potassium catalysis in the pyrolysis behaviour of short rotation willow coppice

Short rotation willow coppice (SRC) and a synthetic biomass, a mixture of the basic biomass components (cellulose, hemicellulose and lignin), have been investigated for the influence of potassium on their pyrolysis behaviours. The willow sample was pre-treated to remove salts and metals by hydrochloric acid, and this demineralised sample was impregnated with potassium. The same type of pre-treatment was applied to components of the synthetic biomass. Characterisation was performed using thermogravimetric analysis with measurement of products by means of Fourier transform infrared spectroscopy (TGA-FTIR) and pyrolysis-gas chromatography-mass spectrometry (PY-GC-MS). A comparison of product distributions and kinetics are reported. While the general features of decomposition of SRC are described well by an additive behaviour of the individual components, there are some differences in the magnitude of the influence of potassium, and on the products produced. For both SRC and the synthetic biomass, TGA traces indicate catalytic promotion of both of the two-stages of biomass decomposition, and potassium can lower the average apparent first-order activation energy for pyrolysis by up to 50 kJ/mol. For both SRC and synthetic biomass the yields and distribution of pyrolysis products have been influenced by the presence of the catalyst. Potassium catalysed pyrolysis increases the char yields markedly and this is more pronounced for synthetic biomass than SRC. Gas evolution profiles during pyrolysis show the same general features for both SRC and synthetic biomass. Relative methane yields increase during the char formation stage of pyrolysis of the potassium doped samples. The evolution profiles of acetic acid and formaldehyde change, and these products are seen in lower relative amounts for both the demineralised samples. A greater variation in pyrolysis products is observed from the treated SRC samples compared to the different synthetic biomass samples. Furthermore, substituted phenols from lignin pyrolysis are more dominant in the pyrolysis profiles of the synthetic biomass than of the SRC, implying that the extracted lignins used in the synthetic biomass yield a greater fraction of monomeric type species than the lignocellulosic cell wall material of SRC. For both types of samples, PY-GS-MS analyses show that potassium has a significant influence on cellulose decomposition markers, not just on the formation of levoglucosan, but also other species from the non-catalysed mechanism, such as 3,4-dihydroxy-3-cyclobutene-1,2-dione. © 2007 Elsevier Ltd. All rights reserved.

Monte Carlo and molecular dynamics simulations of methane in potassium montmorillonite clay hydrates at elevated pressures and temperatures

The structure and dynamics of methane in hydrated potassium montmorillonite clay have been studied under conditions encountered in sedimentary basin and compared to those of hydrated sodium montmorillonite clay using computer simulation techniques. The simulated systems contain two molecular layers of water and followed gradients of 150 barkm-1 and 30 Kkm-1 up to a maximum burial depth of 6 km. Methane particle is coordinated to about 19 oxygen atoms, with 6 of these coming from the clay surface oxygen. Potassium ions tend to move away from the center towards the clay surface, in contrast to the behavior observed with the hydrated sodium form. The clay surface affinity for methane was found to be higher in the hydrated K-form. Methane diffusion in the two-layer hydrated K-montmorillonite increases from 0.39×10-9 m2s-1 at 280 K to 3.27×10-9 m2s-1 at 460 K compared to 0.36×10-9 m2s-1 at 280 K to 4.26×10-9 m2s-1 at 460 K in Na-montmorillonite hydrate. The distributions of the potassium ions were found to vary in the hydrates when compared to those of sodium form. Water molecules were also found to be very mobile in the potassium clay hydrates compared to sodium clay hydrates. © 2004 Elsevier Inc. All All rights reserved.

Carbon monoxide inhibits inward rectifier potassium channels in cardiomyocytes

Reperfusion-induced ventricular fibrillation (VF) severely threatens the lives of post-myocardial infarction patients. Carbon monoxide (CO) - produced by haem oxygenase in cardiomyocytes - has been reported to prevent VF through an unknown mechanism of action. Here, we report that CO prolongs action potential duration (APD) by inhibiting a subset of inward-rectifying potassium (Kir) channels. We show that CO blocks Kir2.2 and Kir2.3 but not Kir2.1 channels in both cardiomyocytes and HEK-293 cells transfected with Kir. CO directly inhibits Kir2.3 by interfering with its interaction with the second messenger phosphatidylinositol (4,5)-bisphosphate (PIP 2). As the inhibition of Kir2.2 and Kir2.3 by CO prolongs APD in myocytes, cardiac Kir2.2 and Kir2.3 are promising targets for the prevention of reperfusion-induced VF. © 2014 Macmillan Publishers Limited. All rights reserved.