The work presented in this thesis details the synthetic modification of the clinically important aminoglycoside antibiotics, neomycin B, paromomycin and tobramycin. We sought to modify aminoglycosides by attaching lipophilic groups, including fatty acids and steroids, with a view to improving the bacterial membrane permeability of these species, and ultimately their efficacy in the treatment of tuberculosis. Our initial synthetic strategy involved direct and specific functionalization of the singular primary hydroxyl group of the aminoglycoside antibiotic neomycin B, with lipophilic groups containing carboxylic acid functions via Mitsunobu esterification. Although, direct and selective Mitsunobu acylation of the primary hydroxyl group proved unsuccessful in the case of the pseudo tetrasaccharide neomycin B, the Mitsunobu reaction did however result in selective chemistry elsewhere in the molecule and this has been exploited for modification of the ido (ring IV) and streptamine (ring II) ring systems. Under carefully controlled conditions, the Mitsunobu reaction has been used for the selective dehydration of the ido ring, to give the talo epoxide, and, under more forcing Mitsunobu dehydration conditions, an aziridine function has been introduced into the streptamine moiety. Both the epoxide and the epoxide-aziridine neomycin building blocks were utilized as synthons in subsequent chemical transformations. Seventeen novel neomycin derivatives featuring modification of ring IV and/or ring II were obtained using this approach. Explicit structural elucidation of all the synthetic intermediates and the final products was achieved using high temperature NMR spectroscopy. Direct and specific functionalization of the singular primary hydroxyl group at the C5 position of the ribose ring (ring III) of neomycin B was achieved, via a procedure based in part on selective tripsylation of the C5III primary hydroxyl group of neomycin B reported previously, followed by subsequent displacement of the tripsyl group by azide. Terminal alkyne containing lipophilic esters were then successfully attached to the ribose residue of neomycin B via Cu(I)-mediated azide-alkyne coupling reaction. In addition to the isolation of two fortuitous, new and versatile synthons i.e. monoanhydro neomycin and bis-anhydro neomycin for modification of ring IV and ring II of neomycin, a third synthon based on neomycin framework, allowing stepwise modification of ring III and ring IV was designed and synthesized. This synthon features an epoxide function in the ido ring, and a protected amine function at the C5 position of the ribose ring. Examples of the stepwise use of this synthon for further synthetic modification of the neomycin framework were demonstrated. Fourteen novel neomycin derivatives featuring modification of ring III and /or ring IV were obtained and characterized. Regioselective Mitsunobu esterification of the single primary hydroxyl group of the pseudo trisaccharide tobramycin was utilized successfully to link a variety of hydrophobic esters with tobramycin. Nine lipophilic tobramycin derivatives with significant structural diversity were synthesised and characterized. In a preliminary study, the applicability of the Mitsunobu dehydration reaction for the regioselective formation of an epoxide ring in the ido moiety of the pseudo tetrasaccharide aminoglycoside antibiotic paromomycin system was confirmed. The regioselective ring-opening of the derived epoxide with azide at C3IV of paromomycin was also successfully demonstrated. In total, forty-two new potential aminoglycoside antibiotics have been synthesized and characterized.

Objetivo: Avaliar limiares auditivos através de audiometria em frequências ultra-altas (UHF) para detecção precoce de alterações auditivas assintomáticas nos pacientes com Fibrose Cística (FC). Material e métodos: Estudo transversal, tipo caso-controle, incluindo 69 indivíduos de 7 a 20 anos, 35 do grupo em estudo (GE) - com FC e 34 do grupo controle (GC) - sem FC. Foi realizada audiometria tonal convencional (250 a 8.000 Hz) e em UHF (9.000 a 16.000 HZ), comparando limiares auditivos entre GE e GC, através de método descendente, utilizando audiômetro Unity PC-Siemens, fones HDA 200, calibração conforme norma ANSI S 3.6-1989; imitanciometria com equipamento AZ26 Interacoustics. Resultados: Foram avaliados 69 indivíduos com média de idade de 12,6 (± 3,65). Não houve diferença estatisticamente significativa na variável idade e sexo entre o GE e GC, bem como na avaliação auditiva entre as orelhas intragrupos. As orelhas foram analisadas através de sua média em cada frequência, devido à ausência de diferenças significativas entre elas. Houve diferença estatisticamente significativa nos limiares auditivos nas freqüências de 2.000 Hz (p = 0,049) e 8.000 Hz (p = 0,006) e nas frequências ultra-altas de 10.000 Hz (p = 0,004) e 16.000 Hz (p < 0,001) entre GE e GC, maior no GE. Na análise entre as frequências, na audiometria convencional, no GE, as frequências de 6.000 Hz e 8.000 Hz apresentaram os limiares auditivos mais rebaixados e, no GC, o limiar mais rebaixado foi na frequência de 6.000 Hz . Nas frequências ultra-altas, no GE, a frequência de 14.000 Hz apresentou o menor limiar. No GC, as frequências de 9.000 e 11.200 apresentaram limiares mais rebaixados. Conclusão: O rebaixamento dos limiares a partir de 6.000 Hz, a diferença estatisticamente significante em 8.000, 10.000 e 16.000 Hz entre GE e GC e o maior número de pacientes do GE com alteração apenas em UHF sugerem a avaliação nestas frequências como instrumento de diagnóstico e monitoração de alterações auditivas em pacientes em uso de fármacos potencialmente ototóxicos. A audiometria em UHF parece identificar danos auditivos mais precocemente, ainda assintomáticos, no sistema auditivo no grupo com FC. / Objective: Assess the hearing thresholds through ultra-high frequency (UHF) audiometry for early detection of asymptomatic hearing alterations among patients with Cystic Fibrosis (CF). Material and methods: Sixty nine subjects having a mean age from 7 to 20 years, where 35 belong to the group study SG -diagnosed with CF and 34 to the control group CG - not diagnosed with CF - participated in a cross - sectional, case-control type study. Conventional tonal audiometric (250 Hz to 8.000 Hz) and ultra-high frequency audiometric (9.000 Hz a 16.000 Hz) tests were conducted, comparing the hearing thresholds between GS and CC. Descend technique using Unity PC-Siemens audiometer, HDA 200 phones, calibration according to ANSI s 3.6-1989 rule, imitanciometry using AZ26 Interacoustics equipment. Results: Sixty nine subjects having a mean age of 12,6 (± 3,65) were evaluated. The variable age and sex between GS and CG and the hearing assessment between the intra-group ears presented no statistically significant difference. The ears were analyzed through the average in each frequency due to lack of significantly differences between them. There was statistically significant difference in the hearing threshold in the 2.000 Hz (p = 0,049) and 8.000 Hz (p = 0,006) frequencies and in the ultra-high frequencies of 10.000 Hz (p = 0,004) and 16.000 Hz (p < 0,001) between GS and CG - higher in GC. Analyzing the frequencies in the GS by conventional audiometry, the 6.000 Hz and 8.000 Hz frequencies presented lowered hearing thresholds and in the CG, the most lowered threshold was at 6.000 HZ. In ultra-high frequencies in GS, the 14000 Hz frequency presented the lowest threshold. In GC the frequencies between 9.000 and 11.200 presented even lowered threshold. Conclusion: The increase of the thresholds from 6.000 Hz on, the statistically significant difference in 8.000, 10.000 and 16.000 Hz between GS and CG and the greater number of patients of GS presenting alterations in UHF only, suggest that the evaluation of these frequencies as a diagnostic and monitoring instrument of hearing alterations in patients undertaking treatment with potentially ototoxic drugs. The audiometry in UHF appears to early identify hearing damage in the hearing system of the group diagnosed with CF but still asymptomatic.

Objetivo: Avaliar limiares auditivos através de audiometria em frequências ultra-altas (UHF) para detecção precoce de alterações auditivas assintomáticas nos pacientes com Fibrose Cística (FC). Material e métodos: Estudo transversal, tipo caso-controle, incluindo 69 indivíduos de 7 a 20 anos, 35 do grupo em estudo (GE) - com FC e 34 do grupo controle (GC) - sem FC. Foi realizada audiometria tonal convencional (250 a 8.000 Hz) e em UHF (9.000 a 16.000 HZ), comparando limiares auditivos entre GE e GC, através de método descendente, utilizando audiômetro Unity PC-Siemens, fones HDA 200, calibração conforme norma ANSI S 3.6-1989; imitanciometria com equipamento AZ26 Interacoustics. Resultados: Foram avaliados 69 indivíduos com média de idade de 12,6 (± 3,65). Não houve diferença estatisticamente significativa na variável idade e sexo entre o GE e GC, bem como na avaliação auditiva entre as orelhas intragrupos. As orelhas foram analisadas através de sua média em cada frequência, devido à ausência de diferenças significativas entre elas. Houve diferença estatisticamente significativa nos limiares auditivos nas freqüências de 2.000 Hz (p = 0,049) e 8.000 Hz (p = 0,006) e nas frequências ultra-altas de 10.000 Hz (p = 0,004) e 16.000 Hz (p < 0,001) entre GE e GC, maior no GE. Na análise entre as frequências, na audiometria convencional, no GE, as frequências de 6.000 Hz e 8.000 Hz apresentaram os limiares auditivos mais rebaixados e, no GC, o limiar mais rebaixado foi na frequência de 6.000 Hz . Nas frequências ultra-altas, no GE, a frequência de 14.000 Hz apresentou o menor limiar. No GC, as frequências de 9.000 e 11.200 apresentaram limiares mais rebaixados. Conclusão: O rebaixamento dos limiares a partir de 6.000 Hz, a diferença estatisticamente significante em 8.000, 10.000 e 16.000 Hz entre GE e GC e o maior número de pacientes do GE com alteração apenas em UHF sugerem a avaliação nestas frequências como instrumento de diagnóstico e monitoração de alterações auditivas em pacientes em uso de fármacos potencialmente ototóxicos. A audiometria em UHF parece identificar danos auditivos mais precocemente, ainda assintomáticos, no sistema auditivo no grupo com FC. / Objective: Assess the hearing thresholds through ultra-high frequency (UHF) audiometry for early detection of asymptomatic hearing alterations among patients with Cystic Fibrosis (CF). Material and methods: Sixty nine subjects having a mean age from 7 to 20 years, where 35 belong to the group study SG -diagnosed with CF and 34 to the control group CG - not diagnosed with CF - participated in a cross - sectional, case-control type study. Conventional tonal audiometric (250 Hz to 8.000 Hz) and ultra-high frequency audiometric (9.000 Hz a 16.000 Hz) tests were conducted, comparing the hearing thresholds between GS and CC. Descend technique using Unity PC-Siemens audiometer, HDA 200 phones, calibration according to ANSI s 3.6-1989 rule, imitanciometry using AZ26 Interacoustics equipment. Results: Sixty nine subjects having a mean age of 12,6 (± 3,65) were evaluated. The variable age and sex between GS and CG and the hearing assessment between the intra-group ears presented no statistically significant difference. The ears were analyzed through the average in each frequency due to lack of significantly differences between them. There was statistically significant difference in the hearing threshold in the 2.000 Hz (p = 0,049) and 8.000 Hz (p = 0,006) frequencies and in the ultra-high frequencies of 10.000 Hz (p = 0,004) and 16.000 Hz (p < 0,001) between GS and CG - higher in GC. Analyzing the frequencies in the GS by conventional audiometry, the 6.000 Hz and 8.000 Hz frequencies presented lowered hearing thresholds and in the CG, the most lowered threshold was at 6.000 HZ. In ultra-high frequencies in GS, the 14000 Hz frequency presented the lowest threshold. In GC the frequencies between 9.000 and 11.200 presented even lowered threshold. Conclusion: The increase of the thresholds from 6.000 Hz on, the statistically significant difference in 8.000, 10.000 and 16.000 Hz between GS and CG and the greater number of patients of GS presenting alterations in UHF only, suggest that the evaluation of these frequencies as a diagnostic and monitoring instrument of hearing alterations in patients undertaking treatment with potentially ototoxic drugs. The audiometry in UHF appears to early identify hearing damage in the hearing system of the group diagnosed with CF but still asymptomatic.

abstract: In the United States, 12% of women are typically diagnosed with breast cancer, where 20-30% of these cases are identified as Triple Negative Breast Cancer (TNBC). In the state of Arizona, 810 deaths occur due to breast cancer and more than 4,600 cases are diagnosed every year (American Cancer Society). The lack of estrogen, progesterone, and HER2 receptors in TNBC makes discovery of targeted therapies further challenging. To tackle this issue, a novel multi-component drug vehicle is presented. Previously, we have shown that mitoxantrone, a DNA damaging drug, can sensitize TNBC cells to TRAIL, which is a protein that can selectively kill cancer cells. In this current study, we have formulated aminoglycoside-derived nanoparticles (liposomes) loaded with mitoxantrone, PARP inhibitors, for delivery to cancer cells. PARP inhibitors are helpful in preventing cancer cells from repairing their DNA following damage with other drugs (e.g. mitoxantrone). Various treatment liposome groups, consisting of lipid-containing polymers (lipopolymers) synthesized in our laboratory, were formulated and characterized for their size, surface charge, and stability. PARP inhibitors and treatment of cells for in-vitro and in-vivo experiments with these liposomes resulted in synergistic death of cancer cells. Finally, studies to evaluate the pre-clinical efficacy of these approaches using immuno-deficient mouse models of TNBC disease have been initiated. / Dissertation/Thesis / Masters Thesis Chemical Engineering 2018

Objetivo: Avaliar limiares auditivos através de audiometria em frequências ultra-altas (UHF) para detecção precoce de alterações auditivas assintomáticas nos pacientes com Fibrose Cística (FC). Material e métodos: Estudo transversal, tipo caso-controle, incluindo 69 indivíduos de 7 a 20 anos, 35 do grupo em estudo (GE) - com FC e 34 do grupo controle (GC) - sem FC. Foi realizada audiometria tonal convencional (250 a 8.000 Hz) e em UHF (9.000 a 16.000 HZ), comparando limiares auditivos entre GE e GC, através de método descendente, utilizando audiômetro Unity PC-Siemens, fones HDA 200, calibração conforme norma ANSI S 3.6-1989; imitanciometria com equipamento AZ26 Interacoustics. Resultados: Foram avaliados 69 indivíduos com média de idade de 12,6 (± 3,65). Não houve diferença estatisticamente significativa na variável idade e sexo entre o GE e GC, bem como na avaliação auditiva entre as orelhas intragrupos. As orelhas foram analisadas através de sua média em cada frequência, devido à ausência de diferenças significativas entre elas. Houve diferença estatisticamente significativa nos limiares auditivos nas freqüências de 2.000 Hz (p = 0,049) e 8.000 Hz (p = 0,006) e nas frequências ultra-altas de 10.000 Hz (p = 0,004) e 16.000 Hz (p < 0,001) entre GE e GC, maior no GE. Na análise entre as frequências, na audiometria convencional, no GE, as frequências de 6.000 Hz e 8.000 Hz apresentaram os limiares auditivos mais rebaixados e, no GC, o limiar mais rebaixado foi na frequência de 6.000 Hz . Nas frequências ultra-altas, no GE, a frequência de 14.000 Hz apresentou o menor limiar. No GC, as frequências de 9.000 e 11.200 apresentaram limiares mais rebaixados. Conclusão: O rebaixamento dos limiares a partir de 6.000 Hz, a diferença estatisticamente significante em 8.000, 10.000 e 16.000 Hz entre GE e GC e o maior número de pacientes do GE com alteração apenas em UHF sugerem a avaliação nestas frequências como instrumento de diagnóstico e monitoração de alterações auditivas em pacientes em uso de fármacos potencialmente ototóxicos. A audiometria em UHF parece identificar danos auditivos mais precocemente, ainda assintomáticos, no sistema auditivo no grupo com FC. / Objective: Assess the hearing thresholds through ultra-high frequency (UHF) audiometry for early detection of asymptomatic hearing alterations among patients with Cystic Fibrosis (CF). Material and methods: Sixty nine subjects having a mean age from 7 to 20 years, where 35 belong to the group study SG -diagnosed with CF and 34 to the control group CG - not diagnosed with CF - participated in a cross - sectional, case-control type study. Conventional tonal audiometric (250 Hz to 8.000 Hz) and ultra-high frequency audiometric (9.000 Hz a 16.000 Hz) tests were conducted, comparing the hearing thresholds between GS and CC. Descend technique using Unity PC-Siemens audiometer, HDA 200 phones, calibration according to ANSI s 3.6-1989 rule, imitanciometry using AZ26 Interacoustics equipment. Results: Sixty nine subjects having a mean age of 12,6 (± 3,65) were evaluated. The variable age and sex between GS and CG and the hearing assessment between the intra-group ears presented no statistically significant difference. The ears were analyzed through the average in each frequency due to lack of significantly differences between them. There was statistically significant difference in the hearing threshold in the 2.000 Hz (p = 0,049) and 8.000 Hz (p = 0,006) frequencies and in the ultra-high frequencies of 10.000 Hz (p = 0,004) and 16.000 Hz (p < 0,001) between GS and CG - higher in GC. Analyzing the frequencies in the GS by conventional audiometry, the 6.000 Hz and 8.000 Hz frequencies presented lowered hearing thresholds and in the CG, the most lowered threshold was at 6.000 HZ. In ultra-high frequencies in GS, the 14000 Hz frequency presented the lowest threshold. In GC the frequencies between 9.000 and 11.200 presented even lowered threshold. Conclusion: The increase of the thresholds from 6.000 Hz on, the statistically significant difference in 8.000, 10.000 and 16.000 Hz between GS and CG and the greater number of patients of GS presenting alterations in UHF only, suggest that the evaluation of these frequencies as a diagnostic and monitoring instrument of hearing alterations in patients undertaking treatment with potentially ototoxic drugs. The audiometry in UHF appears to early identify hearing damage in the hearing system of the group diagnosed with CF but still asymptomatic.

Segundo a Organização Mundial de Saúde (OMS), mais de um bilhão de pessoas estão infectadas com uma ou mais doenças tropicais endêmicas encontradas especialmente entre as populações pobres da África, Ásia e América Latina. Nos últimos 25 anos, apenas 1% de todos os medicamentos desenvolvidos no mundo foram destinados ao tratamento de doenças tropicais, como a doença de Chagas. A doença de Chagas é causada por um protozoário intracelular, o Trypanosoma cruzi, e atualmente apenas dois compostos tem sido empregados para tratamento etiológico da doença de Chagas: nifurtimox e benznidazol. Entretanto, ambos os compostos apresentam considerável toxicidade sistêmica. Nesse contexto, o objetivo do presente trabalho foi desenvolver complexos híbridos de rutênio, com potencial atividade tripanocida, que possam atuar com maior eficácia em sítios biológicos específicos do Trypanosoma cruzi e com reduzida toxicidade sistêmica. Para tal efeito, moléculas com conhecida atividade microbicida como derivados aminoglicosídeos, óxido nítrico e benznidazol foram coordenados a complexos de rutênio originando as espécies Ru(desoxiestreptamina), Ru(neamina), cis-[Ru(bpy)2(Bz)(NO)](PF6)3 e cis-[Ru(NO2)(bpy)2(Bz)]PF6. Os complexos foram caracterizados por espectroscopia de absorção no UV-vis e FTIR, espectrometria de massa, análise elementar, voltametria cíclica e voltametria de pulso diferencial. Nossos estudos sugerem que os complexos Ru(desoxiestreptamina), Ru(neamina), cis-[Ru(bpy)2(Bz)(NO)](PF6)3 e cis-[Ru(NO2)(bpy)2(Bz)]PF6 apresentam propriedades químicas que suportam o sucesso da coordenação dos ligantes ao íon metálico rutênio(II) ou (III). Dentre todos os compostos estudados, cis-[Ru(NO2)(bpy)2(Bz)]PF6, apresentou maior potência tripanocida desprovida de citotoxicidade, a julgar pelos estudos in vitro. IC50 foi ao redor de 0,24 ?mol.L-1, o que é 47 vezes menor do que a droga comumente usada em tratamento de Doença de Chagas. Isto determinou avaliação in vivo, no que foi observado aumento da sobrevida dos animais infectados com tripomastigotas, para 60 dias. Os estudos desenvolvidos com complexos de rutênio no presente trabalho reafirmam o sucesso na obtenção de tais complexos inicialmente propostos, implementando importantes informações e perspectivas no que diz respeito a complexos nitrosilos de rutênio e seus potenciais terapêuticos na doença de Chagas. / Ru(bpy)2(Bz)(NO)](PF6)3 and cis-[Ru(NO2)(bpy)2(Bz)]PF6 complexes. The compounds were characterized by UV-vis absorption spectroscopy, FTIR, mass spectrometry, elemental analysis, and cyclic voltammetry and differential pulse voltammogram. The chemical characterization presented in this work gave evidencie that support the coordination of biological ligand in ruthenium ion such as in Ru(desoxiestreptamina), Ru(neamina), cis-[Ru(bpy)2(Bz)(NO)](PF6)3 and cis-[Ru(NO2)(bpy)2(Bz)]PF6 complexes. Subsequently, in vitro and in vivo studies have been conducted evaluating the cytotoxicity and trypanocidal activity of the ligands and ruthenium complexes. In vitro analysis suggested us that ruthenium complexes are greatly effective against T. cruzi. Among all complexes synthesized cis-[Ru(NO2)(bpy)2(Bz)]PF6 showed higher in vitro trypanocidal activity, which has determined the in vivo assays with this compound. IC50 was around 0,24 ?mol.L-1, which is 47 times less than usual drugs used in Chagas diseases treatment. This was performed using animals infected with T. cruzi in trypomastigote form, animal survivals until 60 days. The studies developed for ruthenium complexes reaffirm the success in obtaining of the complexes originally proposed, implementing important information and perspectives regarding the nitrosyl ruthenium complex and its therapeutic potential in Chagas disease.

Background: Fourteen thousand (14, 000) people fell ill with Multi-Drug Resistant (MDR) or Rifampicin-Resistant (RR) Tuberculosis (TB) in South Africa (SA) in 2019. Aminoglycosides, which are commonly used anti-tuberculosis drugs in the treatment for RR/MDR-TB patients, are associated with ototoxicity (cochlear or vestibular). Aminoglycoside-induced cochleotoxicity is characterised by permanent, bilateral, highfrequency (HF) sensorineural hearing loss (SNHL). The impact of hearing loss (HL) due to aminoglycoside-induced cochleotoxicity can influence a patient's communication, psychological, physical functioning and overall well-being negatively and lead to a reduced quality of life (QoL). To reduce the risk of aminoglycoside-induced cochleotoxicity, patients' hearing thresholds are monitored (i.e., cochleotoxicity monitoring) when they are being treated with cochleotoxic aminoglycosides. Cochleotoxicity monitoring is performed to detect a significant threshold shift (STS) early and prevent further deterioration of hearing thresholds and avoid hearing loss which may end up affecting frequencies that are important for speech perception. When a STS or hearing loss is detected during cochleotoxicity monitoring, there are various intervention strategies that can be implemented by the treating medical personnel to avoid further deterioration of patient's hearing thresholds. These strategies may include discontinuing the aminoglycoside, changing the aminoglycoside to a less cochleotoxic alternative in the regimen or changing the frequency of administration of the aminoglycoside. This study, therefore, aimed to determine the effectiveness of different strategies used when a STS in hearing occurred during cochleotoxicity monitoring to prevent further deterioration in hearing thresholds. Methodology: A descriptive prospective repeated-measures design was used in this study. Patients who underwent RR/MDR-TB treatment with Kanamycin, a cochleotoxic aminoglycoside, at Brooklyn Chest Tuberculosis Hospital (BCH) between June to December 2016 were recruited to participate in the study. Only patients (n= 69) with normal hearing thresholds (i.e., pure tone average (PTA) at 500 Hz, 1 kHz and 2 kHz ≤ 25 dB HL) at baseline and age 18 – 55 years were included. Patients who were receiving two aminoglycosides, were retreatment patients or had active middle ear (ME) pathology were excluded from this study. Participants were sampled via a purposive sampling strategy. All audiological testing was performed in a sound-treated booth and participants underwent the following types of assessment; baseline, periodic monitoring, and diagnostic assessment (when indicated). The following tests were performed at baseline: case history, otoscopy (OT), tympanometry (TYMP), conventional pure tone audiometry (cPTA) including air conduction (AC) and bone conduction (BC), and ultra-high frequency audiometry (UHFA). Follow-up monitoring assessment occurred monthly if there was no significant change in hearing thresholds, and biweekly if an STS was detected. The ASHA criteria were used to determine STS. The degree of hearing loss was described as mild, moderate, moderately-severe, severe or profound and the type of hearing loss was either conductive, sensorineural, or mixed. Both descriptive and inferential (Chi-squared, Mann-Whitney U and Kruskal-Wallis) statistical tests were used for data analysis. Results: A total of sixty-nine (69) patients who were undergoing treatment for RR/MDR-TB were recruited to participate in this study. Five participants dropped out of the study due to various reasons, therefore, leaving 64 participants in the study. There was 38 males and 26 females. The median age was 31 [range; 18 - 55] years old. An aminoglycoside-induced cochleotoxicity incidence of 90.6% (58/64) was found in this study. There were no statistically significant associations between the occurrence of STS and age (p = 0.487), sex (p = 0.329) and HIV status (p = 0.764). Three types of intervention strategies were used when a participant experienced an STS: (i) discontinue Kanamycin (Strategy A), (ii) modify the frequency of Kanamycin administration (Strategy B), (iii) and leave the regimen unchanged, i.e., no intervention (Strategy C). A smaller proportion of participants, 12 out of 33, experienced further deterioration of hearing thresholds after intervention strategy A (discontinue Kanamycin) was used, when compared to participants who underwent intervention strategies B and C, but the difference was not statistically significant (p = 0.056). Conclusion: This study found a high incidence of cochleotoxicity among patients receiving Kanamycin treatment for RR/MDR-TB. The results showed that discontinuing Kanamycin led to fewer participants developing further deterioration of hearing thresholds, although not statistically significant. There were no statistically significant associations between the occurrence of STS and age, sex, and HIV status. This study had some limitations; only cochlear hearing loss was investigated, participants were not followed up beyond six months, and genetic testing was not performed. Nonetheless, this study revealed that fewer participants had further significant threshold shifts after discontinuing Kanamycin, and for those patients who still receive regimens containing aminoglycosides, these findings are relevant.

BACKGROUND: The Modification of Diet in Renal Disease (MDRD) formula and a modified version of the Cockcroft-Gault (CGm) formula adjusting for body surface area have been found to more accurately estimate glomerular filtration rate (GFR) compared with the original CG equation in specific patient populations. To date, the use of these formulas in determining drug dosage and estimating drug elimination has not been thoroughly investigated. OBJECTIVE: To evaluate the ability of the MDRD and CGm formulas to predict aminoglycoside elimination rate and clearance. METHODS: A 6-month prospective, noninterventional, pharmacokinetic study was conducted at a university teaching hospital. Patients receiving aminoglycoside antibiotics (amikacin, gentamicin, or tobramycin) were eligible for study inclusion. Predicted elimination rate and aminoglycoside clearance were calculated for each patient using the MDRD and CGm formulas. Actual (patient-specific) elimination rate and aminoglycoside clearance were calculated for each patient using measured aminoglycoside serum concentrations. Predictive ability of the formulas was compared through Spearman correlations and Student's t-tests. Accuracy of formula estimates was also evaluated. RESULTS: Seventy-one patients met study inclusion criteria; the majority (82%) were in an intensive care unit. The 6-variable MDRD formula was found to be a significantly better predictor of aminoglycoside clearance (p = 0.035) compared with CGm. There was no statistically significant difference between the 2 methods in predicting patient-specific elimination rates (p = 0.167). Among subgroups, the MDRD formula was a significantly better predictor of aminoglycoside clearance for patients with an estimated GFR less than 60 mL/min (p = 0.027). CONCLUSIONS: The 6-variable MDRD performs better than the CGm formula in predicting aminoglycoside clearance and may be considered as a tool in aminoglycoside dosing recommendations.

The abstract is the summary of three different projects all centered around the generalidea of catalysis which is the general theme of research in the Michaelis laboratory. The firstproject focuses on development of a new heterogeneous catalyst for selective catalysis. In theMichaelis lab, we were interested in the potential of nanoparticle catalysts for regioselectivetransformations. We showed that polymer supported ruthenium nanoparticles performed as areliable catalyst for regioselective reduction of azide to amine. In our study of regioselectivereduction of multiple azide containing substrates, we observed that in presence of ourruthenium nanoparticle catalysts, the least sterically hindered azide group reduced to aminefunctional group. The results were complementary to the conventional methods that employtriphenyl phosphine (Staudinger reaction) as the reductant and target the most electronicallyactive azide group.In the second project, we were looking to develop a new class of hetero-bimetallicNickel-Titanium complexes as an efficient catalyst for organic transformations. We designedand synthesized numerous bidentate ligands including NHC-Phosphine ligand. Our kineticstudies on the Suzuki cross coupling of allylic alcohols and phenyl boronic esters showed thatthe bidentate nature of the ligand was necessary for the success of the catalytic process. Theligand was proved to stabilize the catalyst in the solution by increasing the lifetime of thenickel (0) in the reaction medium. We also discovered a new cooperative titanium-nickelsystem for mild allylic amination of allyl alcohols. The system also represents an idealcatalyst for tandem cyclization amination process.In the Michaelis lab, we were also interested to explore the ability of bimetalliccomplexes in C-H functionalization process. Our efforts in this project led to the discovery ofnew Pallladium dimer complexes with two palladium centers in oxidation state of (I). Thecatalyst showed unique reactivity in C-C bond activation/functionalization. We have alsodiscovered that in presence of catalytic amount of triflic acid and stoichiometric amount ofphenyl boronic acid, cinnamyl alcohol undergoes a boron template dimerization/cyclization.The reaction represents a great synthetic pathway for the synthsis of bis homoallylic alcohols.

Aminoglycosides are a group of broad-spectrum antibiotics that, under neutral pH conditions, carry a positive charge. The net cationic charge arises from the high number of amino groups in the core structure of aminoglycosides. Previous studies performed have shown that negatively charged citrate ligand-capped gold nanoparticles (AuNPs) can interact with various biomolecules such as aminoglycosides. AuNPs bound to biomolecules have been used in conjugation with various assaying techniques to detect and study compounds in vitro and in vivo. AuNPs also have strong light scattering properties that can be used with a wide variety of imaging and assaying techniques. Our laboratory has previously performed experiments on the aminoglycoside antibiotic ribostamycin sulfate. During this experiment, the concentration dependent rod-like assembly of ribostamycin sulfate was characterized. This experiment used three analytical techniques in conjunction with AuNPs: (1) dynamic light scattering (DLS), (2) UV-Vis absorption spectroscopy, and (3) dark field optical microscope imaging (DFM). This suite of techniques was used to analyze mixtures of ribostamycin sulfate at different concentration with different sized AuNPs. The primary objective of this research was to determine if the techniques used to characterize the self-assembly of ribostamycin sulfate could be generalized and applied to other aminoglycoside antibiotics. The secondary objective of this research was to determine if other aminoglycoside antibiotics formed rod-like assemblies. This study demonstrated that AuNPs can be used to detect self-assembled oligomers for different aminoglycoside antibiotics. In addition, this study also revealed that not all aminoglycoside antibiotics will self assemble into rod-like oligomers similar to ribostamycin. It was observed that the aminoglycoside antibiotic amikacin self assembled into rod-like aggregates similar to ribostamycin sulfate but the aminoglycoside antibiotics neomycin sulfate and streptomycin sulfate did not.