A new method for the quantitation of acute phlebitis in superficial veins is investigated. This method capitalizes on local temperature elevations which result from the inflammatory process. The thermally based detection method is more objective than traditional procedures which utilize simple visual evaluations of symptoms. Several irritating parenteral drugs and their vehicles as well as many commonly used cosolvents were tested for their potential to produce phlebitis. The water soluble compounds and the cosolvents produced little if any irritation. In cases where significant phlebitis was produced, it was the drug and not the vehicle which was found to be responsible. This method shows promise as a tool for screening compounds and vehicles for their potential to produce local venous side-effects. The hemolytic method for assessing the venous compatibility of parenterals was compared with the thermal method. It was found that hemolysis testing can give false positive suggestions of phlebitis, which could result in the elimination of promising new formulations. The effect of injection rate on the severity of phlebitis is investigated using parenteral amiodarone HCl. As the injection rate is increased the severity of phlebitis also increases to a limiting value. At rates above this value there is less phlebitis produced. The reason for this behavior is explained below. Amiodarone was found to precipitate upon dilution with physiological fluids. Incomplete dilution of the formulation in the blood results in a physically stable "plug" within the vein. Where there is plug flow, and the drug is soluble in the plug, there is no precipitation. It was shown in vitro that plug flow of the partially diluted formulation correlates with the decrease in phlebitis observed in vivo at rapid injection rates. The immediate precipitation of amiodarone HCl upon dilution is pH dependent. Amiodarone is reformulated in a buffered version of the original vehicle in an attempt to reduce this precipitation. Buffering the amiodarone formulation significantly improved the precipitation problem of this drug. By characterizing the variables which influence the physical stability of amiodarone we were able to produce a new formulation which is resistant to dilution-induced precipitation.

A study of hospital pharmacy practice in the Republic of China was conducted in the Summer of 1987. The status of selected innovative pharmaceutical services and the attitudes of pharmacy directors toward developing and implementing those services were assessed. The innovative services were unit dose drug distribution, pharmacy-prepared i.v. admixtures, pharmacy computerization, drug information and clinical pharmacy services. A questionnaire was used to obtain data and information from a random sample of hospitals in Taiwan, R.O.C.. Most of selected services were performed in about 25% of the surveyed hospitals. The i.v. admixture program was performed by the lowest percent of general hospitals as compared to the other services in this study. Pharmacy directors indicated that their attitudes toward selected innovative pharmaceutical services in terms of seven possible effects or outcomes were positive, but the scores relating to the other professionals and operating expenses were neutral or negative.

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Cryptolepine is a tetracyclic, aromatic natural product, isolated from West African shrubs of the Cryptolepis species, consisting of fused indole and quinoline rings. Due to its polyaromatic character it is able to intercalate into DNA showing a unique selectivity for non-alternating GC base pairs. Cryptolepine, and especially its halogenated analogues, have been investigated for their anti-malarial and anti-cancer activity, the latter being the area of interest of this thesis. A number of novel halogenated indoloquinoline cryptolepine analogues were synthesised in order to determine their abilities to interact with DNA, and to inhibit topoisomerase II activity. In vitro cytotoxicity testing was carried out using human tumor cell lines MCF-7 (breast cancer), 5637 (bladder cancer), DLD-1 (colon cancer) and A-549 (lung cancer) via the MTT assay. The halogenated cryptolepine analogues were allowed to bind to calf thymus DNA and the melting points of these complexes measured. An increase in melting temperature between 4.5 and 12°C was seen when compared to naked DNA. Inhibition of topoisomerase II was seen at concentrations between 0.5 and 0.020 μM compared to 5 μM for cryptolepine. All compounds showed cytotoxic activity in the range 0.07 to 73.87 μM against the tumor cell lines after 96 hr exposure. 11-lodocryptolepine was found to be the most potent on all of the cell lines tested, with IC₅₀ values down to sub micro molar levels. This analogue was also one of the most potent at topoisomerase II inhibition (0.5 μM) and had a ΔTm of 12.0°C. However, despite 11-chlorocryptolepine being the most potent at inhibiting topoisomerase II (0.02 μM), it was found to be the least potent in vitro and had one of the lowest ΔTm values (5.0°C). Cellular incorporation of the analogues was investigated by using laser confocal microscopy which showed that 11-iodo and 11-bromocryptolepines had nuclear localisation, whereas, the 11-chlorocryptolepine analogues remain in the cell membrane.

A high proportion of prostate cancer and benign prostatic hyperplasia (BPH) have been shown to be dependent on androgen biosynthesis. The biosynthesis of androgens is undertaken by a number of important enzymes such as 17a-hydroxylase/17,20-lyase and 17[beta]-hydroxysteroid dehydrogenase. Through the inhibition of these enzymes it is possible to. reduce the amount of androgens present, which in turn reduces the stimulation of androgen-dependent prostatic diseases. Within the current study, we have undertaken the biochemical evaluation of a number of compounds of varying structural features and which were synthesised within our group as potential enzyme inhibitors in the tretament of androgen-dependent diseases. In general, the results from the current study show that the compounds evaluated against the enzyme complex 17a-hydroxylase/17,20-lyase possessed good inhibitory activity. In particular, the imidazole-based inhibitors were found to be more potent against 17,20-lyase in comparison to 17a-hydroxylase, and were more potent than the triazole-based compounds. The most potent compounds within the current study include: 1-(7-phenyl-heptyl)-1H-imidazole (171) (lC50=98.5±15.6nM, K¡=55.3±3AnM against 17,20-lyase and IC50=O.32±O.05I-lM, K¡=O.21±O.01¡.¡M against 17a-hydroxylase), 1-[7 -(4-fluoro-phenyl)-heptyl]-1 H-imidazole (179) (IC50=57.5±1.5nM, K¡=21.5±O.1nM against 17,20-lyase and IC50=173.62±7.00nM, K¡=77.5±2.5nM against 17 a-hydroxylase) and 1-[5-(4-bromo-phenyl)-pentyl]-1 H-imidazole (187) (IC50=58.1±5.2nM against 17,20-lyase and IC50=O.50±O.04I-lM against 17a-hydroxylase), these compounds were all potent inhibitors compared to the standard inhibitor ketoconazole (1) (lC50=1.66±O.15¡.JM, K¡=O.67±O.02¡.¡M against 17,20-lyase and IC50=3.76±O.01I-lM, K¡=1.24±O.01¡.¡M against 17a-hydroxylase). In an effort to discover lead compounds in the inhibition of the 17[beta]-hydroxysteroid dehydrogenase (17[beta]-HSD) family of enzymes, a range of commercially available compounds based on phenyl ketones were initially evaluated against type 1 (17[beta]-HSD1) and 3 (17[beta]-HSD3) of 17[beta]-HSD which are responsible for the reduction of estrone and androstenedione to estradiol and testosterone respectively. The majority of these compounds were found to possess weak inhibitory activity, however, some were found to possess good inhibitory activity. As such, a number of compounds were synthesised within our group as potential inhibitors of 17[beta]-HSD1 and 17[beta]-HSD3. The results show that the 4-hydroxyphenyl ketone-based compounds were found to be . highly potent against type 3 in comparison to type 1. For example, 1-(4-hydroxy-phenyl)-nonan-1-one (254) was found to possess (against type 3) inhibitory activity of 83.53±OA8% (at [1]=100¡.¡M) (IC5o of 2.86 ± O.03¡.¡M). Under similar conditions, 254 was found to possess 36.32±O.33% (at [1]=100¡.¡M) inhibitory activity against type1. A range of compounds were also synthesised based on the biphenyl ketones, however, these were found to be weaker inhibitors of type 3 in comparison to the 4- hydroxyphenyl ketones although they possessed greater inhibitory activity against type 1. In an effort to determine the selectivity of these compounds against the overall class of HSD enzymes, all inhibitors were evaluated for 3[beta]-hydroxysteroid dehydrogenase (3[beta]-HSD) inhibitory activity. We discovered that in general, all of the synthesised compounds possessed weak inhibitory activity against this enzyme at inhibitor concentration of 100¡.¡M and 500¡.¡M, as such, these synthesised compounds could be considered to be good lead compounds for the inhibition of 17[beta]-HSD.

Aim: To establish whether Chinese Herbal Medicine (CHM) has any positive effect on human endometrial receptivity to embryo implantation. Design: A prospective interventional clinical study. The measurements used in this study were: serum follicle stimulating hormone (FSH), serum progesterone, endometrial thickness (ET), sub endometrial 3D-PDA ultrasound indices; vascularisation index (VI), flow index (FI), vascularisation flow index (VFI) and pregnancy outcome. Setting: A private London natural female heath practice specialising in treating infertility with Naturopathic and Traditional Chinese Medicine (TCM). The study period was between November 2005 and April 2008. Patient(s): Fifty primary or secondary infertile women who had failed at least two In Vitro Fertilisation (IVF) treatment cycles (the treatment group) with no pathological cause after investigation by infertility specialists and diagnosed as suffering with unexplained infertility. In addition, a reference group of fifty normal healthy volunteer women (the reference group) randomised and double blinded who received either placebo or treatment. Interventions: Both the treatment group and the reference group received CHM for three menstrual cycles. The reference group on a randomised basis received either CHM or placebo. All staff at the clinic and the reference group volunteers were double blinded to who received placebo or treatment until the end of the study. ii Results: The treatment group results indicated that there was a statistically significant positive difference between pre and post treatment for all variables examined (p < 0.001). The reference group results were not as significant but never the less, still indicated that the improvement was statistically significant between the two arms (treatment and placebo) for all measures, with the exception of sub endometrial FI, where there was no significant difference between groups. The number of pregnancies achieved in the treatment group at 6 months post commencement of the last patient was 17 pregnancies, 10 live births, 2 miscarriages and 5 ongoing pregnancies (34% overall pregnancy rate). Conclusions: The study demonstrated that within the treatment group of 50 failed IVF patients CHM did improve all the 6 physiological parameters known to affect endometrial receptivity by a statistically significant amount and provided a 34% pregnancy outcome. The findings of this study show that administration of CHM did have a positive effect on the endometrial receptivity measures used in this study and that the pregnancy rate achieved in the treatment group was encouraging, however without a control arm it is impossible to attribute the pregnancy rate outcome to treatment or reduced stress from the placebo effect of receiving treatment. The study also demonstrated statistically significant improvement in treatment arm of the reference group whilst the placebo arm showed no significant improvement in the same parameters. None of the participants in the study experienced any adverse reactions or side effects from treatment.