The effects of modulation of CICR on spontaneous and systolic Ca2+ release were investigated in isolated rat ventricular myocytes. Spontaneous waves of Ca2 + release were initially abolished and then resumed at a lower frequency during exposure to 100 J.LMtetracaine. Both the duration of the initial quiescent period and oscillation frequency in tetracaine were dependent on the control oscillation frequency and the concentration of tetracaine applied. Electrophysiological quantification of the SR Ca2+ content of myocytes revealed a significant increase during exposure to tetracaine. The amplitude of spontaneous Ca2 + release was also increased such that despite decreased frequency, efflux per unit time activated by Ca2+ waves was not changed significantly. Using confocal microscopy, the spatial and temporal properties of Ca2+ waves were studied revealing that tetracaine inhibits the propagation of Ca2 + release. The increased SR Ca2+ content and the increased amplitude of Ca2+ release can reverse this effect. Application of 100 J.LMtetracaine to electrically stimulated cells transiently depressed systolic Ca2+ release and contraction but had no effect in the steady state. Removal of tetracaine was associated with potentiation of systolic Ca2+ release followed by gradual recove~. Quantification of the SR Ca2+ content revealed that in tetracaine the SR Ca + content was significantly increased in the steady state. This increase was accounted for by inhibition of systolic Ca2+ release activating less Ca2+ efflux in the presence of the same or increased Ca2+ influx on the L-type Ca2+ current. As the SR Ca2+ content increases, more efflux is activated until eventually efflux and influx balance in the steady state. The transient potentiation of contraction on removal of tetracaine is due to the increased SR Ca2 + content, which increases the gain of CICR in the absence of inhibition of Ca2 + release. The mechanism of post rest potentiation in rat cardiac tissue has not been conclusively elucidated by previous studies. This investigation provides evidence that changes in SR Ca2 + content and recovery of channels from inactivation could contribute to the potentiation of contraction observed in rat ventricle after a period of rest. Tetracaine enhances the degree of potentiation of contraction, which can only partially be attributed to its ability to enhance SR Ca2+ accumulation. During myocardial ischaemia dramatic changes in the substrate and metabolite levels in cells occur and a number of these changes are known to affect the RyR. However, the overall effects of metabolic blockade on the sensitivity CICR in intact cells have been overlooked. Experiments were carried out to investigate the effect of metabolic inhibition on spontaneous Ca2+ release and SR Ca2+ content in isolated rat ventricular myocytes. The results show that CICR is inhibited during metabolic inhibition. This could contribute to the degree of damaging and potentially fatal Ca2+ overload experienced on reperfusion of ischaemic tissue.

No description available.

No description available.

The genus Salvia belongs to the family Lamiaceae and encompasses 900 species worldwide of which 26 are found in southern Africa and many of them are used in local traditional medicine. However, the phytochemistry and pharmacological activities of the South African species have not been extensively investigated. The leaf trichome morphology that may be used to distinguish species was investigated with the scanning electron and light microscopy. Both glandular (capitate or peltate) and non-glandular trichomes were identified in all species. The essential oils were isolated by hydro-distillation and analysed by GC and GC-MS methods. The oil yield was relatively low and ranged from 0.004 (S. radula) to 0.50% (S. muirii) (w/w). Major components identified include α-pinene, 1,8-cineole, linalool, limonene, myrcene, β-caryophyllene, spathulenol, β-caryophyllene oxide, viridiflorol, δ-3- carene and α-bisabolol. High performance liquid chromatography analysis was used to identify phenolic compounds in 17 solvent extracts. Betulafolientriol oxide was detected in all species. Rosmarinic acid was only absent in S. verbenaca, while S. garipensis and S. radula were the only species which lacked oleanolic acid/ursolic acid. Various in vitro biological activities were investigated. Nearly all the solvent extracts displayed anti-oxidant activity with IC50 values ranging from 1.61 to 74.50 μg/ml using the DPPH· radical, while the IC50 values ranged from 11.88 to 69.26 μg/ml with the ABTS·+ radical. The solvent extract of S. schlechteri was three times more active than vitamin C. Total phenolic content based on gallic acid equivalents (GAE) revealed the presence of total soluble phenolics in the extract at 45 to 211 mg of GAE dry sample. Almost all the essential oils exhibited promising anti-inflammatory activity (5-lipoxygenase assay) with IC50 values ranging from 22.81 to 77.32 μg/ml. The antimalarial activity was determined using [3H]-hypoxanthine method on the Plasmodium falciparum (FCR-3) strain. The IC50 values of the essential oils ranged from 1.20 to 13.50 μg/ml and were low compared to the solvent extracts (IC50 values ranging from 3.91 to 26.01 μg/ml). Betulafolientriol oxide and salvigenin isolated from S. radula inhibited the growth of malaria parasites with IC50 values of 4.95 and 24.60 μg/ml, respectively. With the exception of S. radula, all the solvent extracts displayed moderate to good activity against Staphylococcus aureus, vii Bacillus cereus, Klebsiella pneumoniae, Escherichia coli and Mycobacterium tuberculosis with the MIC values ranging from 0.03 to 8.00 mg/ml. Four compounds, namely carnosol, 7-O-methylepirosmanol, oleanolic acid and its isomer ursolic acid were isolated from S. chamelaeagnea as the active principles against S. aureus. The solvent extracts of Salvia species were tested for in vitro anticancer activity against human breast adenocarcinoma (MCF-7), colon adenocarcinoma (HT-29) and glioblastoma (SF-268) using the sulforhodamine B assay. The extracts inhibited cell proliferation of all three cell lines to varying degrees, with the IC50 values ranging between 9.69 and 43.65 μg/ml and 8.72 and 59.12 μg/ml against the MCF-7 and SF-268 cell lines, respectively. The IC50 values against the HT-29 cell line ranged from 17.05 to 57.00 μg/ml. The in vitro toxicity profile of 28 samples (17 solvent extracts and 11 essential oils) was evaluated on human kidney epithelial cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5 dimethyl tetrazolium bromide method. The samples displayed some degree of toxicity with IC50 values ranging from 1.79 to 22.9 μg/ml for the essential oils and from 12.12 to 53.34 μg/ml for the solvent extracts. The essential oil composition of S. africana-caerulea, S. africana-lutea and S. lanceolata, collected at the same locality throughout the 2004/2005 growing season, was compared in terms of essential oil yields, chemical composition and biological activities. Mostly quantitative, rather than qualitative variation was observed. Major seasonal fluctuations of certain essential oil compounds were observed in all three species. Variations in biological activities of the solvent extracts over seasons were noted. The biological activities of the solvent extracts of three Salvia species (Salvia africanacaerulea, S. africana-lutea and S. lanceolata) were evaluated in the presence and absence of essential oils. The solvent extract of S. africana-caerulea without essential oil exhibited the best activity against Gram-positive bacteria (MIC value: 0.1 mg/ml), while the solvent extract containing essential oil of S. africana-lutea was the most active against Gramnegative bacteria. The toxicity profile of all three species was significantly higher (P < 0.05) with the solvent extracts containing essential oils. The in vitro biological activities add scientific support to the use of Salvia species in traditional medicine.

Procedural pain is still under managed in practice, resulting in immediate and long-term negative sequellae for children. Accreditation guidelines identify health care professionals as responsible for providing procedural pain management, however recent evidence supports the idea that parents can be assisted to provide effective pain management through non-pharmacological strategies. Using Appreciative Inquiry, twelve nurses were interviewed about their knowledge of the evidence, work context, and factors that facilitate their ability to engage parents in procedural pain management. Focus groups verified the findings and made suggestions for practical application. From the data, four predominant patterns emerged: 1) Establishing meaningful interpersonal connections; 2) Fostering a culture of collaboration; 3) Pain as a priority – moving from a philosophy to a standard; 4) Sustaining practices through advanced knowledge and skills. Findings will contribute to the literature that guides education, policies, and standards that engage all resources to promote more effective pain relieving practices.

No description available.

Orientador: Marileda Bonafim Carvalho / Banca: Delphim da Graça Macoris / Banca: Anderson Farias / Resumo: O DMSO tem sido amplamente utilizado para estudos farmacológicos em modelos experimentais e testes clínicos. Um amplo espectro de propriedades farmacológicas do DMSO tem sido relatado. Há poucos estudos avaliando os efeitos do DMSO sobre a função renal. Com o propósito de testar a hipótese de que este medicamento pode modular a taxa de filtração glomerular e a função renal tubular, este estudo foi conduzido. O DMSO a 10% foi administrado IV, a cada 12 horas, na dose de 1,Og/kg, durante três dias consecutivos, em cinco cães sadios, que foram mantidos em gaiolas metabólicas. Avaliações clínicas e laboratoriais foram realizadas antes do início do tratamento, a cada 12 horas durante os três dias de administração de DMSO, 24, 48 e 120 horas e 30 dias após a última dose do fármaco. Houve aumento significativo no clearance de creatinina, na excreção urinária de proteína e na excreção fracionada de sódio, durante o período de tratamento. Outras alterações foram observadas na maioria dos parâmetros estudados relacionados à homeostase de água e sódio, como por exemplo, aumentos na concentração sérica de sódio e nas osmolalidades. O DMSO determinou aumentos na TFG, no volume de urina e na tonicidade sérica, sem sinais de lesões renais e de toxicidade. / Abstract: DMSO have been extensively used for pharmacologic studies in laboratory experimental models and for clinical testing. A large spectrum of pharmacological properties of DMSO have been reported. There are a few studies focusing the DMSO effects on renal function. In order to test the hypothesis that this drug carl modulate glomerular filtration rate and renal tubule-interstitial function this study was conducted. DMSO 10% was administered IV, bid, in a dosage of 1.0glkg, during three consecutive days, to five healthy dogs maintained in metabolic cages. Clínical and laboratory evaluations were done once before the treatment, each 12 hours during the three days of DMSO administration, 24, 48 and 120 hours and 30 days after the last dosage. It was found significant increase of creatinine clearance, urinary protein excretion and sodium fractional excretion during the treatment. Minor changes were observed in many of the studied parameters related to the sodium and water homeostasis, like increases in serum sodium and osmolalities. DMSO promoted increases in the GFR, volume urine, and serum tonicity, however was not observed signs of renal injuries, neither toxicity. / Mestre

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Science in Medicine in Pharmaceutical Affairs. Johannesburg, 2003 / Quinine is a naturally occurring alkaloid found in the bark of the South American cinchona tree. It is used to treat malaria, to relieve nocturnal leg cramps and is used as an antipyretic. Anecdotal evidence, especially from community pharmacists, suggests widespread misuse of quinine sulphate. It has been taken for a range of non-indicated uses ranging from a single dose monthly contraceptive to a post coital “morning after” contraceptive. A self-administered questionnaire, together with a confidentiality and anonymity declaration, was offered to all females requesting quinine sulphate at a pharmacy in Hillbrow, Johannesburg. After completing the questionnaire, the participants were counselled on the proper indications, as well as the consequences of misuse of quinine. / IT2018

<p>The neuropeptide Y (NPY) family of structurally related peptides includes NPY, peptide YY (PYY) and pancreatic polypeptide (PP). They bind to G-protein coupled receptors named Y receptors, and include in mammals Y1, Y2, Y4, Y5, Y6 and in non-mammalian vertebrates also Y7, Yb and Yc. Subtypes Y1 and Y5 stimulate appetite, while Y2 and Y4 have the opposite effect in mammals. The studies described here concern human Y1 and Y4, chicken Y6 and Y7, and zebrafish Y2. </p><p>Site-directed mutagenesis of human Y1 identified sites important for binding of NPY and PYY as well as Y1 antagonists. The results clarify contradictory findings previously reported by others and identify new sites of interaction. A three-dimensional structural model of the Y1 receptor based upon the high-resolution structure of bovine rhodopsin was generated that increases our understanding of ligand-receptor interactions and hopefully will facilitate the design of novel subtype-selective agonists and antagonists. </p><p>Two naturally occurring variants of human Y4 with substitutions R240C and V276M have been found in a sample of obese children. Functional studies in vitro showed that the cellular response to PP was greatly decreased for R240C and may provide a causative link to juvenile obesity. </p><p>The genes for chicken Y6 and Y7 were found to be located ~1 megabase apart on chromosome 13 syntenic to the human Y6 pseudogene. Y6 mRNA has widespread expression whereas Y7 mRNA was found only in adrenal gland. Truncated fragments of PYY had lower affinity to chicken Y7 and zebrafish Y2 than to Y2 from mammals and chicken. The results suggest that Y2 in mammals acquired the ability to bind truncated PYY, i. e. PYY_3-36, fairly recently, which has implications for its role in appetite inhibition.</p><p>These differences between receptor subtypes in sequences and pharmacological properties will be useful to further elucidate the structure and activation of Y receptors by site-directed mutagenesis. </p>

The neuropeptide Y (NPY) family of structurally related peptides includes NPY, peptide YY (PYY) and pancreatic polypeptide (PP). They bind to G-protein coupled receptors named Y receptors, and include in mammals Y1, Y2, Y4, Y5, Y6 and in non-mammalian vertebrates also Y7, Yb and Yc. Subtypes Y1 and Y5 stimulate appetite, while Y2 and Y4 have the opposite effect in mammals. The studies described here concern human Y1 and Y4, chicken Y6 and Y7, and zebrafish Y2. Site-directed mutagenesis of human Y1 identified sites important for binding of NPY and PYY as well as Y1 antagonists. The results clarify contradictory findings previously reported by others and identify new sites of interaction. A three-dimensional structural model of the Y1 receptor based upon the high-resolution structure of bovine rhodopsin was generated that increases our understanding of ligand-receptor interactions and hopefully will facilitate the design of novel subtype-selective agonists and antagonists. Two naturally occurring variants of human Y4 with substitutions R240C and V276M have been found in a sample of obese children. Functional studies in vitro showed that the cellular response to PP was greatly decreased for R240C and may provide a causative link to juvenile obesity. The genes for chicken Y6 and Y7 were found to be located ~1 megabase apart on chromosome 13 syntenic to the human Y6 pseudogene. Y6 mRNA has widespread expression whereas Y7 mRNA was found only in adrenal gland. Truncated fragments of PYY had lower affinity to chicken Y7 and zebrafish Y2 than to Y2 from mammals and chicken. The results suggest that Y2 in mammals acquired the ability to bind truncated PYY, i. e. PYY3-36, fairly recently, which has implications for its role in appetite inhibition. These differences between receptor subtypes in sequences and pharmacological properties will be useful to further elucidate the structure and activation of Y receptors by site-directed mutagenesis.