Infantile hemangiomas (IHs), benign vascular lesions present on the surface of the skin of children, are treated with systemic or topical beta-adrenergic antagonists (known as “beta-blockers”). However, systemic beta-blocker therapy is associated with serious adverse events in pediatric patients, and there are currently no topical formulations optimized for the skin. The objectives of this work were to 1) evaluate the local skin concentrations and drug permeation through the skin using novel beta-blocker formulations, and 2) characterize the epidermal properties and skin surface inflammatory mediators of IH skin. Skin concentrations and drug permeation through the skin from current topical treatment options were quantified in vitro; these data served as benchmarks to which other treatment paradigms in later studies were compared. Microneedle (MN)-mediated delivery of two beta-blockers, propranolol and timolol, was evaluated in vitro using solid MNs and two dissolving MN array formulations. Solid MNs increased skin concentrations of timolol compared to intact skin, while producing similar skin concentrations of propranolol. Drug permeation through the skin was increased for both drugs after MN pretreatment. Both formulations of dissolving MN arrays were ineffective at increasing local skin concentrations compared to intact skin. This was likely due to the small loading capacity of drug into the array. Drug-loaded microemulsions (ME) of varying composition were formulated and characterized. All ME formulations had solubilization properties, and water rich MEs had the greatest cumulative release through a homogenous membrane compared to surfactant rich MEs. Drug-loaded MEs did not increase local skin concentrations in vitro compared to a drug solution; however, water rich ME formulations produced greater skin-to-receiver ratio of drug concentration, indicating their potential for skin accumulation. MN pretreatment increased the skin-to-receiver ratios for surfactant rich formulations but not for water rich formulations, indicating this enhancement in skin retention after MN pretreatment is formulation dependent. These results demonstrate the potential for topical treatment of IHs upon further optimization of delivery and formulation parameters. The epidermal properties and skin surface mediators of IH skin were compared to normal, unaffected skin. Significant differences in barrier function and color, as well as chemokine and growth factor concentrations, were observed between the two sites. These results provide a greater understanding of the IH properties that have previously not been quantified. Similar changes in lesion color, which correlate to efficacy, were observed after beginning treatment with oral propranolol or topical timolol, while changes in barrier function were similar between the two treatment groups. These results indicate topical timolol may be a safe alternative for systemic treatment for superficial IHs without a loss of efficacy.

published_or_final_version / Medicine / Master / Doctor of Medicine

Thesis (M.Sc. (Pharmacy)) - Rhodes University, 2006.

Objective: To determine whether echocardiography affects the decisions to use beta blockers or to recommend bacterial endocarditis prophylaxis in patients suspected of having mitral valve prolapse (MVP). Design: Retrospective review of echocardiograms and clinical records. Setting: Military tertiary care hospital. Patients: 127 patients with clinically suspected MVP (105) or incidentally discovered MVP (22). Main results: Beta blockers were used more often in patients with suspected MVP and positive echocardiograms (45%) than in patients with normal echocardiograms (13%, p<0.001). Bacterial endocarditis prophylaxis was recommended more often in patients with suspected MVP and positive echocardiograms (65%) than in patients with normal echocardiograms (11%, p<0.001). Presence or absence of a murmur did not influence the decision to recommend bacterial endocarditis prophylaxis. Patients in whom MVP was incidentally discovered were unlikely to receive either beta blockers or the recommendation for bacterial endocarditis prophylaxis. Conclusions: The results of echocardiography affect the decisions to use beta blockers or to recommend bacterial endocarditis prophylaxis in patients with suspected MVP.

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Dois anti-hipertensivos da classe dos &beta;-bloqueadores, o nadolol ((2R, 3S)-5-[2-hidroxi-3-(terc-butilamino)-propoxi]tetralin-2,3-diol) e o atenolol ((R,S)-2-[4-[2-hidroxi-3-(1-isopropilamino)-propoxi]fenil]acetamida) foram submetidos à análise térmica para caracterização de seus mecanismos de decomposição e o primeiro submetido a estudos sobre polimorfismo. Após fusão em 129,6 &deg;C (&Delta;Hfus = 157,3 J g-1; &Delta;Sfus = 1,18 J &deg;C-1 g-1), a decomposição do nadolol ocorreu em uma única etapa entre 183,7-404,7 &deg;C, com liberação de terc-butil amina e vários fragmento da molécula. Estudos cinéticos baseados em método isoconversional mostraram Ea = 101,4 &plusmn; 0,1 kJ mol-1 fator pré-exponencial de Arrhenius log A = 8,53 &plusmn; 0,02 min-1. No caso do atenolol, a fusão apresentou-se em 153,1 &deg;C (&Delta;Hfus = 142,5 J g-1; &Delta;Sfus = 0,92 J &deg;C-1 g-1), seguida pela decomposição em uma única etapa entre 191,8-900,0 &deg;C, na qual ocorre a liberação de amônia, formando um dímero e as isopropilaminas das extremidades. Seguem-se amônia, isopropanol, gás carbônico e água. Estudos cinéticos baseados em método isoconversional mostraram Ea = 102 &plusmn; 3 kJ mol-1 fator pré-exponencial log A = 9,2 &plusmn; 0,3 min-1. Estudos de polimorfismo do nadolol mostraram que o composto pode ser separado em pelo menos duas de suas formas enantiomórficas por cristalização e que aglomerados cristalinos podem ser obtidos, variando-se o sistema solvente e a temperatura de cristalização. / Two &beta;-blocker antihypertensives nadolol ((2R, 3S)-5-[2-hidroxy-3-(terc-butilamine)-propoxy]tetralin-2,3-diol) and atenolol ((R,S)-2-[4-[2-hidroxy-3-(1-isopropylamine)-propoxy]phenyl]acetamide) were submitted to thermal analysis in order to characterize their decomposition mechanisms and the first was also subject of a polymorphism investigations. After melting at 129,6 &deg;C (&Delta;Hfus = 157,3 J g-1; &Delta;Sfus = 1,18 J &deg;C-1 g-1), the decomposition of nadolol took place in a single step beetwen 183,7-404,7 &deg;C, with release of terc-butyl amine and several fragments of the molecule. Kinetic studies based on the isoconvertional method reveled an activation energy Ea = 101,4 &plusmn; 0,1 kJ mol-1 and a pre-exponential factor log A = 8,53 &plusmn; 0,02 min-1. In atenolol case the melting was detected at 153,1 &deg;C (&Delta;Hfus = 142,5 J g-1; &Delta;Sfus = 0,92 J &deg;C-1 g-1), followed by decomposition in a single step between 191,8-900,0 &deg;C, in which a dimmer is formed after release of ammonia and the isopropylamines in the edges of the molecules. Then ammonia, isporpyl alcohol, carbonic gas and water were released. Kinetic studies by the isoconvertional method showed activation energy Ea = 102 &plusmn; 3 kJ mol-1 and exponential pre-factor log A = 9,2 &plusmn; 0,3 min-1 for the solid state thermal decomposition reaction. Polymorphism studies for nadolol revealed that at least two enantiomeric forms of the compound can be isolated in, by varying the solvent and the temperature of crystallization.

Dois anti-hipertensivos da classe dos &beta;-bloqueadores, o nadolol ((2R, 3S)-5-[2-hidroxi-3-(terc-butilamino)-propoxi]tetralin-2,3-diol) e o atenolol ((R,S)-2-[4-[2-hidroxi-3-(1-isopropilamino)-propoxi]fenil]acetamida) foram submetidos à análise térmica para caracterização de seus mecanismos de decomposição e o primeiro submetido a estudos sobre polimorfismo. Após fusão em 129,6 &deg;C (&Delta;Hfus = 157,3 J g-1; &Delta;Sfus = 1,18 J &deg;C-1 g-1), a decomposição do nadolol ocorreu em uma única etapa entre 183,7-404,7 &deg;C, com liberação de terc-butil amina e vários fragmento da molécula. Estudos cinéticos baseados em método isoconversional mostraram Ea = 101,4 &plusmn; 0,1 kJ mol-1 fator pré-exponencial de Arrhenius log A = 8,53 &plusmn; 0,02 min-1. No caso do atenolol, a fusão apresentou-se em 153,1 &deg;C (&Delta;Hfus = 142,5 J g-1; &Delta;Sfus = 0,92 J &deg;C-1 g-1), seguida pela decomposição em uma única etapa entre 191,8-900,0 &deg;C, na qual ocorre a liberação de amônia, formando um dímero e as isopropilaminas das extremidades. Seguem-se amônia, isopropanol, gás carbônico e água. Estudos cinéticos baseados em método isoconversional mostraram Ea = 102 &plusmn; 3 kJ mol-1 fator pré-exponencial log A = 9,2 &plusmn; 0,3 min-1. Estudos de polimorfismo do nadolol mostraram que o composto pode ser separado em pelo menos duas de suas formas enantiomórficas por cristalização e que aglomerados cristalinos podem ser obtidos, variando-se o sistema solvente e a temperatura de cristalização. / Two &beta;-blocker antihypertensives nadolol ((2R, 3S)-5-[2-hidroxy-3-(terc-butilamine)-propoxy]tetralin-2,3-diol) and atenolol ((R,S)-2-[4-[2-hidroxy-3-(1-isopropylamine)-propoxy]phenyl]acetamide) were submitted to thermal analysis in order to characterize their decomposition mechanisms and the first was also subject of a polymorphism investigations. After melting at 129,6 &deg;C (&Delta;Hfus = 157,3 J g-1; &Delta;Sfus = 1,18 J &deg;C-1 g-1), the decomposition of nadolol took place in a single step beetwen 183,7-404,7 &deg;C, with release of terc-butyl amine and several fragments of the molecule. Kinetic studies based on the isoconvertional method reveled an activation energy Ea = 101,4 &plusmn; 0,1 kJ mol-1 and a pre-exponential factor log A = 8,53 &plusmn; 0,02 min-1. In atenolol case the melting was detected at 153,1 &deg;C (&Delta;Hfus = 142,5 J g-1; &Delta;Sfus = 0,92 J &deg;C-1 g-1), followed by decomposition in a single step between 191,8-900,0 &deg;C, in which a dimmer is formed after release of ammonia and the isopropylamines in the edges of the molecules. Then ammonia, isporpyl alcohol, carbonic gas and water were released. Kinetic studies by the isoconvertional method showed activation energy Ea = 102 &plusmn; 3 kJ mol-1 and exponential pre-factor log A = 9,2 &plusmn; 0,3 min-1 for the solid state thermal decomposition reaction. Polymorphism studies for nadolol revealed that at least two enantiomeric forms of the compound can be isolated in, by varying the solvent and the temperature of crystallization.

Abstract not available