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Purpose: The aim of this study was to investigate the usefulness of formulation approaches to minimise injection site reactions for poorly soluble drugs. The specific objectives were to modify the injection site reactions by identification of irritant components in the formulation and control of their release kinetics; and to gain understanding of formulation approaches to create a favourable microenvironment in the tissues allowing better tissue tolerance and drug absorption. Methods: Physicochemical properties of the model drug, ricobendazole (RBZ) were characterised using conventional methods. Three formulation approaches to minimise irritancy of the low pH RBZ solution were assessed. An in vitro method using 96-well microplates and a microtiter plate reader was used for detection of drug precipitation on dilution for formulation characterisation. Cellular damage by the formulations was investigated in L929 fibroblasts using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy phenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) and lactate dehydrogenase (LDH) assays. Tissue tolerance and pharmacokinetics were simultaneously investigated after subcutaneous injection in sheep. A low pH RBZ solution was used as a reference formulation. Results: Preformulation studies showed that RBZ was practically insoluble in water and oils, and was slightly soluble in commonly used co-solvents. Solubility was slightly improved by complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD, K₁:₁ = 311 M⁻�) or a combination of low pH (> 2) with surfactants or co-solvents. A U-shaped pH-solubility profile in aqueous solutions indicated that RBZ is an ampholyte. pKa values measured by absorbance spectroscopy and pH solubility methods were 3.45 and 3.76 (basic) and 9.82 and 9.53 (acidic) respectively. The partition coefficient was 14.3 - 15.2 at pH 6 - 9 and less at higher or lower pH. In aqueous solutions, RBZ showed a V-shaped pH-degradation rate profile and was most stable at pH 4.8. Degradation pathways were identified as hydrolysis and oxidation. Three RBZ injectables (5%) were obtained by modification of the low pH RBZ solution; addition of 20% HP-β-CD, incorporation into a w/o emulsion, and a microemulsion (ME). On dilution with SPB, the onset time of drug precipitation was prolonged and the rate was reduced in the presence of HP-β-CD. The w/o emulsion had a low viscosity (< 60 mPa.s) and exhibited Newtonian flow. Drug release versus the square root of time was linear and the release rate could be adjusted by phase ratio and droplet size. Drug release was found to be by diffusion. A coarse emulsion layer appeared at the interface between the ME and buffer. Drug release from the ME was faster than from the emulsion and was linear with the square root of time. On titration into SPB, the three formulations showed controlling effects on the release of H₃O⁺ compared to the reference formulation. RBZ (0.1 mg/ml) was more toxic to L929 cells than the co-solvent propylene glycol (50 mg/ml). The formulations showed greater cytotoxicity than their vehicles in the order: ME > RBZ solution = emulsion > HP-β-CD. HP-β-CD and emulsion excipients showed little or no cytotoxicity. The MEs exhibited more toxicity in the LDH assay than in the MTS assay. A reversed phase HPLC assay for simultaneous determination of RBZ and its metabolite in sheep plasma using an isocratic system with UV detection was developed and used in the pharmacokinetic studies. Plasma samples were prepared by solid phase extraction. A suitable internal standard was selected by quantitative structure-retention relationships analysis. The composition of a ternary mobile phase was optimised with the assistance of multiple linear regression. The assays were linear over the concentration range 10 - 1000 ng/ml for both analytes (r > 0.999) with satisfactory inter-day and intra-day precision and accuracy (CV < 10%). The recoveries for all analytes were > 96%. A pilot study in sheep suggests that injection of the vehicles (the CD, emulsion and ME) caused virtually no pain on injection or site reactions. Both the reference formulation and its vehicle induced pain on injection and resulted in swollen tissues. Histology after two weeks showed granulation for the formulation, but not the vehicle. In contrast, animals showed virtually no injection site reactions with the ME and emulsion. The HP-β-CD formulation gave transient pain on injection but a two-fold increase in bioavailability compared with the reference. The emulsion produced sustained drug release and increased drug absorption. In the main study, the HP-β-CD vehicle showed good tissue compatibility. Irritation by the HP-β-CD formulation was attributed to the low pH. Cmax, tmax and AUC0-[infinity] for the reference formulation were 1.3 � 0.3 [mu]g/ml, 9.6 � 2.9 h and 36.7 � 9.2 [mu]g�h/ml respectively, while the corresponding data for the HP-β-CD formulation were 2.9 � 0.8 [mu]g/ml, 5.0 � 0.6 h and 54.5 � 15.3 [mu]g�h/ml respectively. The half-life following the injection of the HP-β-CD formulation (5.5 � 2.8 h) was shorter than that of the reference formulation (8.5 � 3.4 h). Conclusions: Injection site reactions may be minimised by identification of irritant components in a formulation and by controlling their release. Controlling the burst release of the poorly water soluble drug RBZ in a low pH solution could improve tissue tolerance and minimise post-injection precipitation, and hence increase drug bioavailability. In addition, HP-β-CD was a useful local injectable carrier which significantly enhanced the absorption of RBZ after subcutaneous injection in sheep.

Objective: To study midwives management, practice and reasoning regarding contraceptive counseling for women who are experiencing "mild" side effects of the pill Methods: Four focus groups, made up of three to five midwives per group, participated in focus group discussions. Qualitative design with the method “Think-Aloud” has been used to collect data and the material was analyzed using content analysis. Results: The study identified three categories, the first "How midwives practice regarding the side effects of the pill," shows that midwives have a systematic approach when meeting with women who are experiencing side effects of the pill. The next category "Using a holistic and professional approach for women" highlights that the midwives take women's side effects seriously and that midwives respect individual woman’s autonomy. Finally in the third category "Lack of evidence about side effects becomes a women's dilemma" here midwives describe varying ways of interpreting side effects as well as attitudes and socio-economic conditions in society that affect women's choice of contraception. Conclusion: The midwives express that side effects such as loss of libido, depression and weight gain are complex and often difficult to attribute solely to the pill. The midwives' work is characterized by a holistic approach. We see the benefits of sharing information in groups, therefor we suggest that midwives create mediums where they can learn from each other by sharing their valuable experience and knowledge.

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Cimetidine is a histamine H2-receptor antagonist that is among the most widely prescribed drugs in the world. In addition to its inhibitory action on gastric acid secretion, a possible role in kidney tubulointerstitial disease has been suggested. Isolated reports have also suggested an association between cimetidine administration and acute interstitial nephritis. The present study examined the effect of cimetidine on renal function in the rat. The nine rats used in this study had normal renal function and urinalyses before treatment with cimetidine. The cimetidine treated rats then developed a clinical picture of weakness, hematuria, proteinuria, casturia, oliguria, and increases in serum blood urea nitrogen and creatinine.Following the 6 weeks treatment period, all rats were sacrificed and their kidneys prepared for microscopic study. Histologically, the patchy, intense tubulointerstitial infiltration of lymphocytes, plasma cells, and other cells observed in the cortex of the rat kidneys is quite similar to findings described in human cases of drug-induce hypersensitivity tubulointerstitial disease. In addition, other pathologic conditions which can cause tubulointerstitial disease were adequately ruled out. Specifically, bacterial pyelonephritis was excluded as a result of the consistently sterile urine test. In conclusion, the author feels that the clinical, aboratory, and histologic findings in this study strongly suggests an association between of tubulointerstitial disease and the use of cimetidine. / Department of Physiology and Health Science

Purpose: The aim of this study was to investigate the usefulness of formulation approaches to minimise injection site reactions for poorly soluble drugs. The specific objectives were to modify the injection site reactions by identification of irritant components in the formulation and control of their release kinetics; and to gain understanding of formulation approaches to create a favourable microenvironment in the tissues allowing better tissue tolerance and drug absorption. Methods: Physicochemical properties of the model drug, ricobendazole (RBZ) were characterised using conventional methods. Three formulation approaches to minimise irritancy of the low pH RBZ solution were assessed. An in vitro method using 96-well microplates and a microtiter plate reader was used for detection of drug precipitation on dilution for formulation characterisation. Cellular damage by the formulations was investigated in L929 fibroblasts using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy phenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) and lactate dehydrogenase (LDH) assays. Tissue tolerance and pharmacokinetics were simultaneously investigated after subcutaneous injection in sheep. A low pH RBZ solution was used as a reference formulation. Results: Preformulation studies showed that RBZ was practically insoluble in water and oils, and was slightly soluble in commonly used co-solvents. Solubility was slightly improved by complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD, K₁:₁ = 311 M⁻�) or a combination of low pH (> 2) with surfactants or co-solvents. A U-shaped pH-solubility profile in aqueous solutions indicated that RBZ is an ampholyte. pKa values measured by absorbance spectroscopy and pH solubility methods were 3.45 and 3.76 (basic) and 9.82 and 9.53 (acidic) respectively. The partition coefficient was 14.3 - 15.2 at pH 6 - 9 and less at higher or lower pH. In aqueous solutions, RBZ showed a V-shaped pH-degradation rate profile and was most stable at pH 4.8. Degradation pathways were identified as hydrolysis and oxidation. Three RBZ injectables (5%) were obtained by modification of the low pH RBZ solution; addition of 20% HP-β-CD, incorporation into a w/o emulsion, and a microemulsion (ME). On dilution with SPB, the onset time of drug precipitation was prolonged and the rate was reduced in the presence of HP-β-CD. The w/o emulsion had a low viscosity (< 60 mPa.s) and exhibited Newtonian flow. Drug release versus the square root of time was linear and the release rate could be adjusted by phase ratio and droplet size. Drug release was found to be by diffusion. A coarse emulsion layer appeared at the interface between the ME and buffer. Drug release from the ME was faster than from the emulsion and was linear with the square root of time. On titration into SPB, the three formulations showed controlling effects on the release of H₃O⁺ compared to the reference formulation. RBZ (0.1 mg/ml) was more toxic to L929 cells than the co-solvent propylene glycol (50 mg/ml). The formulations showed greater cytotoxicity than their vehicles in the order: ME > RBZ solution = emulsion > HP-β-CD. HP-β-CD and emulsion excipients showed little or no cytotoxicity. The MEs exhibited more toxicity in the LDH assay than in the MTS assay. A reversed phase HPLC assay for simultaneous determination of RBZ and its metabolite in sheep plasma using an isocratic system with UV detection was developed and used in the pharmacokinetic studies. Plasma samples were prepared by solid phase extraction. A suitable internal standard was selected by quantitative structure-retention relationships analysis. The composition of a ternary mobile phase was optimised with the assistance of multiple linear regression. The assays were linear over the concentration range 10 - 1000 ng/ml for both analytes (r > 0.999) with satisfactory inter-day and intra-day precision and accuracy (CV < 10%). The recoveries for all analytes were > 96%. A pilot study in sheep suggests that injection of the vehicles (the CD, emulsion and ME) caused virtually no pain on injection or site reactions. Both the reference formulation and its vehicle induced pain on injection and resulted in swollen tissues. Histology after two weeks showed granulation for the formulation, but not the vehicle. In contrast, animals showed virtually no injection site reactions with the ME and emulsion. The HP-β-CD formulation gave transient pain on injection but a two-fold increase in bioavailability compared with the reference. The emulsion produced sustained drug release and increased drug absorption. In the main study, the HP-β-CD vehicle showed good tissue compatibility. Irritation by the HP-β-CD formulation was attributed to the low pH. Cmax, tmax and AUC0-[infinity] for the reference formulation were 1.3 � 0.3 [mu]g/ml, 9.6 � 2.9 h and 36.7 � 9.2 [mu]g�h/ml respectively, while the corresponding data for the HP-β-CD formulation were 2.9 � 0.8 [mu]g/ml, 5.0 � 0.6 h and 54.5 � 15.3 [mu]g�h/ml respectively. The half-life following the injection of the HP-β-CD formulation (5.5 � 2.8 h) was shorter than that of the reference formulation (8.5 � 3.4 h). Conclusions: Injection site reactions may be minimised by identification of irritant components in a formulation and by controlling their release. Controlling the burst release of the poorly water soluble drug RBZ in a low pH solution could improve tissue tolerance and minimise post-injection precipitation, and hence increase drug bioavailability. In addition, HP-β-CD was a useful local injectable carrier which significantly enhanced the absorption of RBZ after subcutaneous injection in sheep.

Siderophores are a series of important iron chelators secreted by many bacteria that normally have high affinity of iron ions and contain hydroxamate, catecholate and carboxylate and other ligand groups. These organic ligands play significant roles in bacterial metabolism: solubilising iron (III) from environments, enabling iron uptake and acting as a cell-signalling molecule to control gene expression. Recent observations of initial stages of Pseudomonas aeriginosa biofilm formation on metal oxides surfaces indicate that siderophores may also facilitate bacterial adhesion to metals. However, details of how siderophores interact with metal surfaces and the relationship of their chemical nature with bacterial adhesion were not fully understood. To test the generality of bacteria attachment to metals via siderophores, the adsorption behaviour of siderophores and their functional ligands groups on particle films of metal oxides were investigated with in-situ ATR-IR spectroscopy. In this study, nanoparticle films of titanium oxide, boehmite, iron oxide and chromium oxyhydroxide were prepared as substrates to simulate titanium, alumnium, stainless steel surface and more detailed work were carried out on titanium dioxide. Monohydroxamic acids (acetohydroxamic acid, N-methylformohydroxamic acid, N-methyl-acetohydroxamic acid and 1-hydroxy, 2-piperidone) and catechol and catechol-like (L-dopa and esculetin) ligands were selected as modelling compounds for the most frequently occured functional groups in natural siderophores. IR spectra of these ligands in aqueous solution and adsorbed on TiO₂ were obtained with a flowing cell system fit to a horizontal accessory by in situ ATR-IR spectroscopy and interpreted based on vibrational mode analysis with density function theory. Results show that all these ligands can form surface complexes with metal surfaces and possible adsorption modes of these molecules were discussed. The pH dependence of absorbance of IR absorption of these adsorbed ligands showed that most of the ligands exhibited maximium adsorption to TiO₂ at about pH 8, only N-methylformohydroxamic acid, 1-hydroxy, 2-piperidone groups having maximum absorption at pH~3 and pH~6. Infrared spectroscopic studies of adsorbed siderophores (desferroximme B, enterobactin and pyoverdine) were also carried out in variation of concentration and pH. Possible adsorption modes of these iron scavenger ligands on TiO₂ and other metal oxides were discussed. Results showed that all these ligands adsorbed on metal oxide surfaces and form surface complex via hydroxamate or catecholate lignd groups which confirm the generality of siderphore-metal bond formation. Siderophore based-bacterial adhesion to metals of was conducted with Pesudomonas aeruginosa and E. coli strains on titanium oxide and iron oxide films. These observations support that siderophore play a significant role in bacterial adhesion to metals. Further work needs to be carried out on the wider involvement of siderophores in bacterial adhesion initiation to metals and siderophore-mediated iron transport.

Norethynodrel, a common progestin in oral contraceptives, produces in female rats several significant physiological, cytological and biochemical changes at dose levels of 1 mg and 20 mg per kg: 1) a relative increase in liver mass 2) modification of appearance and extent of the endoplasmic reticulum 3) augmentation of the protein content of the liver 4) increase of the level of cytochrome P- 450 in the liver as determined by : a) difference spectroscopy b) increases in biotransformation of aniline and aminopyrine in vitro and c) reduction of sleeping times of rats dosed with phenobarbital The significance of these findings becomes evident when it is realized that norethynodrel affects and is affected by the same enzyme system which oxidizes medicaments in general in the body: induction of cytochrome P-450 by administration of norethynodrel may interfere with the action of other drugs . Ethinyl estradiol alone showed none of the inductive effects. At high dose levels (20 mg per kg) both norethynodrel and ethinyl estradiol caused a marked inhibition of growth of the animals, producing a net loss of body mass over the 30- day experimental period. Electron micrographic evidence implies that there is also a lowering of glycogen content and a chemical change in the lipids of adrenocortical and liver cells accompanying the use of these agents.