RESUMO
Hearing loss is a debilitating disease that affects 10% of adults worldwide. Most sensorineural hearing loss is caused by the loss of mechanosensitive hair cells in the cochlea, often due to aging, noise, and ototoxic drugs. The identification of genes that can be targeted to slow aging and reduce the vulnerability of hair cells to insults is critical for the prevention of sensorineural hearing loss. Our previous cell-specific transcriptome analysis of adult cochlear hair cells and supporting cells showed that Clu, encoding a secreted chaperone that is involved in several basic biological events, such as cell death, tumor progression, and neurodegenerative disorders, is expressed in hair cells and supporting cells. We generated Clu-null mice (C57BL/6) to investigate its role in the organ of Corti, the sensory epithelium responsible for hearing in the mammalian cochlea. We showed that the deletion of Clu did not affect the development of hair cells and supporting cells; hair cells and supporting cells appeared normal at 1 month of age. Auditory function tests showed that Clu-null mice had hearing thresholds comparable to those of wild-type littermates before 3 months of age. Interestingly, Clu-null mice displayed less hair cell and hearing loss compared to their wildtype littermates after 3 months. Furthermore, the deletion of Clu is protected against aminoglycoside-induced hair cell loss in both in vivo and in vitro models. Our findings suggested that the inhibition of Clu expression could represent a potential therapeutic strategy for the alleviation of age-related and ototoxic drug-induced hearing loss.
Assuntos
Clusterina/deficiência , Células Ciliadas Auditivas/fisiologia , Perda Auditiva Neurossensorial/prevenção & controle , Presbiacusia/prevenção & controle , Animais , Limiar Auditivo , Sequência de Bases , Sistemas CRISPR-Cas , Senescência Celular , Clusterina/biossíntese , Clusterina/genética , Clusterina/fisiologia , Sinergismo Farmacológico , Potenciais Evocados Auditivos do Tronco Encefálico , Furosemida/administração & dosagem , Furosemida/toxicidade , Células Ciliadas Auditivas/efeitos dos fármacos , Perda Auditiva Neurossensorial/induzido quimicamente , Canamicina/administração & dosagem , Canamicina/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Cultura de Órgãos , Órgão Espiral/patologia , Emissões Otoacústicas Espontâneas , RNA Mensageiro/biossíntese , RNA Mensageiro/genéticaRESUMO
Herein, carboxymethyl chitosan and poly(vinylpyrrolidone) based hydrogels were synthesized by electron beam irradiation with dose variations (15 kGy, 30 kGy, and 45 kGy) for drug delivery applications. Irradiation crosslinked hydrogels were characterized for swellings in different medias, chemical, thermal, cell cytotoxicity, and drug release aspects. Swelling analysis was evaluated in distilled water, buffer, and saline solutions. Fourier transform infrared analysis revealed the establishment of physical interactions and confirmed the presence of functional groups present in the drug carriers. Scanning electron microscopy depicted the porous structure, which is responsible for swelling, drug loading, and release. Cell cytotoxicity assays indicated good cell viability on RAW 264.7 cells and anticancer activity on cancerous AGS cell lines. Cumulative drug release (%) of kanamycin in PBS at pH 7.4 was more than 90 % at 168 h. These drug carriers show promise to be developed as a sustained drug delivery system.
Assuntos
Antineoplásicos/administração & dosagem , Quitosana/análogos & derivados , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Hidrogéis/química , Canamicina/administração & dosagem , Povidona/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Quitosana/química , Reagentes de Ligações Cruzadas/química , Preparações de Ação Retardada , Difusão , Liberação Controlada de Fármacos , Elétrons , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Canamicina/farmacologia , Camundongos , Microscopia Eletrônica de Varredura , Porosidade , Células RAW 264.7 , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
BACKGROUND: Since a meta-analysis showed little or no effect of second-line injectables on treatment success, and using injectables may induce ototoxicity, injectable-free rifampicin-resistant tuberculosis (RR-TB) treatment regimens are recommended. However, acquired resistance preventing activity was overlooked. No previous study assessed the effect of shortening the duration of kanamycin administration to 2 months during the intensive phase of the RR-TB shorter treatment regimen (STR). METHODS: Retrospective cohort study of the effect of using 2 months of kanamycin instead of the standard 4(+) months (extension if lack of smear conversion at 4 months) on recurrence (either treatment failure or relapse) and fluoroquinolone acquired drug resistance, in patients treated with a gatifloxacin-based STR in Damien Foundation supported clinics in Bangladesh. Logistic regression was used to estimate associations. RESULTS: Five of 52 (9.6%) treated with a STR containing two months of kanamycin had recurrence, compared to 21 of 738 (2.8%) patients treated with the standard STR containing 4(+) months of kanamycin (OR 3.7; 95%CI:1.5-10.3). In those with initially fluoroquinolone-susceptible TB, acquired resistance to fluoroquinolone was detected in none of 639 patients treated with 4(+) months of kanamycin and two (4.5%) of 44 treated with two months of kanamycin (OR 75.2; 95%CI:3.6-1592.1). CONCLUSION: Two months of kanamycin was insufficient to prevent recurrence with acquired resistance to gatifloxacin, the core drug of the most effective RR-TB STR. Injectable mediated resistance prevention is important to reach high effectiveness, to safeguard all treatment options after recurrence, and to prevent the spread of resistant TB. Studies on all-oral regimens should also assess the effect of regimen composition on resistance acquisition. Until evidence shows that other drugs can assure at least the same strong resistance preventing activity of the injectables, it seems wise to continue using this group of drugs, and adapt the regimen if any ototoxicity is detected.
Assuntos
Farmacorresistência Bacteriana/efeitos dos fármacos , Rifampina/farmacologia , Tuberculose/tratamento farmacológico , Adolescente , Adulto , Estudos de Coortes , Feminino , Humanos , Injeções , Canamicina/administração & dosagem , Canamicina/farmacologia , Canamicina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Infection with Shiga toxin-producing Escherichia coli (STEC) results in hemorrhagic colitis and can lead to life-threatening sequelae including hemolytic uremic syndrome (HUS). Conventional treatment is intravenous fluid volume expansion. Antibiotic treatment is contraindicated, due in part to the elevated risk of HUS related to increased Shiga toxin (Stx) release associated with some antibiotics. Given the lack of effective strategies and the increasing number of STEC outbreaks, new treatment approaches are critically needed. In this study, we used an antimicrobial peptide wrwycr, previously shown to enhance STEC killing without increasing Stx production, in combination with antibiotic treatments. Checkerboard and time-kill assays were used to assess peptide wrwycr-antibiotic combinations for synergistic STEC killing. Cytotoxicity and real-time PCR were used to evaluate Stx production and stx expression, respectively, associated with these combinations. The synergistic combinations that showed rapid killing, no growth recovery and minimal Stx production were peptide wrwycr-kanamycin/gentamicin. Transmission electron microscopy revealed striking differences in bacterial cell morphology associated with various treatments. This study provides proof of principle for the design of an antibiotic-peptide wrwycr combination effective in killing STEC without enhancing release of Shiga toxins. It also offers a strategy for the repurposing of antibiotics for treatment of STEC infection.
Assuntos
Antibacterianos/farmacologia , Escherichia coli O157/efeitos dos fármacos , Proteínas Citotóxicas Formadoras de Poros/farmacologia , Antibacterianos/administração & dosagem , Cloranfenicol/administração & dosagem , Cloranfenicol/farmacologia , Ciprofloxacina/administração & dosagem , Ciprofloxacina/farmacologia , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Gentamicinas/administração & dosagem , Gentamicinas/farmacologia , Humanos , Canamicina/administração & dosagem , Canamicina/farmacologia , Meropeném/administração & dosagem , Meropeném/farmacologia , Testes de Sensibilidade Microbiana , Proteínas Citotóxicas Formadoras de Poros/administração & dosagem , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Ototoxic drugs may induce auditory sensory hair cell loss and permanent deafness; however, there is still no effective treatments or prevention strategies for this side effect. A recent study found that microRNA182 (miR-182) protected cochlear hair cells from ototoxic drug-induced apoptosis in vitro. However, it remains unclear whether miR-182 can protect drug-induced deafness in vivo. In this study, we overexpressed cochlear miR-182 in Sprague-Dawley rats by trans-round window niche delivery of miR-182 mimics. The rats subsequently received intraperitoneal injections of kanamycin and furosemide to induce acute cochlear outer hair cell death and permanent deafness. Auditory brainstem response tests showed that miR-182 attenuated permanent threshold shifts. Consistent with this result, miR-182 reduced the loss of outer hair cells and missing stereocilia. miR-182 treatment also increased the level of phosphoinositide-3 kinase regulatory subunit p85α in the outer hair cells after co-administration of kanamycin and furosemide. Our findings suggest that miR-182â¯has powerful protective potential against ototoxic drug-induced acute auditory sensory hair cell loss and permanent deafness.
Assuntos
Surdez/metabolismo , Furosemida/toxicidade , Canamicina/toxicidade , MicroRNAs/biossíntese , Ototoxicidade/metabolismo , Animais , Antibacterianos/administração & dosagem , Antibacterianos/toxicidade , Surdez/induzido quimicamente , Surdez/prevenção & controle , Combinação de Medicamentos , Feminino , Furosemida/administração & dosagem , Canamicina/administração & dosagem , Ototoxicidade/prevenção & controle , Ratos , Ratos Sprague-Dawley , Inibidores de Simportadores de Cloreto de Sódio e Potássio/administração & dosagem , Inibidores de Simportadores de Cloreto de Sódio e Potássio/toxicidadeRESUMO
BACKGROUND: The sites of mycobacterial infection in the lungs of tuberculosis (TB) patients have complex structures and poor vascularization, which obstructs drug distribution to these hard-to-reach and hard-to-treat disease sites, further leading to suboptimal drug concentrations, resulting in compromised TB treatment response and resistance development. Quantifying lesion-specific drug uptake and pharmacokinetics (PKs) in TB patients is necessary to optimize treatment regimens at all infection sites, to identify patients at risk, to improve existing regimens, and to advance development of novel regimens. Using drug-level data in plasma and from 9 distinct pulmonary lesion types (vascular, avascular, and mixed) obtained from 15 hard-to-treat TB patients who failed TB treatments and therefore underwent lung resection surgery, we quantified the distribution and the penetration of 7 major TB drugs at these sites, and we provide novel tools for treatment optimization. METHODS AND FINDINGS: A total of 329 plasma- and 1,362 tissue-specific drug concentrations from 9 distinct lung lesion types were obtained according to optimal PK sampling schema from 15 patients (10 men, 5 women, aged 23 to 58) undergoing lung resection surgery (clinical study NCT00816426 performed in South Korea between 9 June 2010 and 24 June 2014). Seven major TB drugs (rifampin [RIF], isoniazid [INH], linezolid [LZD], moxifloxacin [MFX], clofazimine [CFZ], pyrazinamide [PZA], and kanamycin [KAN]) were quantified. We developed and evaluated a site-of-action mechanistic PK model using nonlinear mixed effects methodology. We quantified population- and patient-specific lesion/plasma ratios (RPLs), dynamics, and variability of drug uptake into each lesion for each drug. CFZ and MFX had higher drug exposures in lesions compared to plasma (median RPL 2.37, range across lesions 1.26-22.03); RIF, PZA, and LZD showed moderate yet suboptimal lesion penetration (median RPL 0.61, range 0.21-2.4), while INH and KAN showed poor tissue penetration (median RPL 0.4, range 0.03-0.73). Stochastic PK/pharmacodynamic (PD) simulations were carried out to evaluate current regimen combinations and dosing guidelines in distinct patient strata. Patients receiving standard doses of RIF and INH, who are of the lower range of exposure distribution, spent substantial periods (>12 h/d) below effective concentrations in hard-to-treat lesions, such as caseous lesions and cavities. Standard doses of INH (300 mg) and KAN (1,000 mg) did not reach therapeutic thresholds in most lesions for a majority of the population. Drugs and doses that did reach target exposure in most subjects include 400 mg MFX and 100 mg CFZ. Patients with cavitary lesions, irrespective of drug choice, have an increased likelihood of subtherapeutic concentrations, leading to a higher risk of resistance acquisition while on treatment. A limitation of this study was the small sample size of 15 patients, performed in a unique study population of TB patients who failed treatment and underwent lung resection surgery. These results still need further exploration and validation in larger and more diverse cohorts. CONCLUSIONS: Our results suggest that the ability to reach and maintain therapeutic concentrations is both lesion and drug specific, indicating that stratifying patients based on disease extent, lesion types, and individual drug-susceptibility profiles may eventually be useful for guiding the selection of patient-tailored drug regimens and may lead to improved TB treatment outcomes. We provide a web-based tool to further explore this model and results at http://saviclab.org/tb-lesion/.
Assuntos
Antituberculosos/administração & dosagem , Antituberculosos/farmacocinética , Pulmão/metabolismo , Tuberculose Resistente a Múltiplos Medicamentos/etiologia , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Técnicas de Apoio para a Decisão , Progressão da Doença , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Farmacorresistência Bacteriana Múltipla , Quimioterapia Combinada , Feminino , Humanos , Isoniazida/administração & dosagem , Isoniazida/farmacocinética , Canamicina/administração & dosagem , Canamicina/farmacocinética , Linezolida/administração & dosagem , Linezolida/farmacocinética , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Pirazinamida/administração & dosagem , Pirazinamida/farmacocinética , Estudos Retrospectivos , Rifampina/administração & dosagem , Rifampina/farmacocinética , Distribuição Tecidual , Falha de Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/metabolismo , Tuberculose Resistente a Múltiplos Medicamentos/patologia , Tuberculose Pulmonar/metabolismo , Tuberculose Pulmonar/patologia , Adulto JovemRESUMO
SETTING: Reducing pain from intramuscular injection of kanamycin (KM) could improve the tolerability of multidrug-resistant tuberculosis (MDR-TB) treatment. Lidocaine has been shown to be an effective anaesthetic diluent for some intramuscular injections, but has not been investigated with KM in the treatment of adult patients with MDR-TB. OBJECTIVE AND DESIGN: We performed a randomised single-blinded crossover study to determine if lidocaine reduces KM injection-site pain. We recruited patients aged î¶18 years on MDR-TB treatment at two TB hospitals in Cape Town, South Africa. KM pharmacokinetic parameters and a validated numeric pain scale were used at intervals over 10 h following the injection of KM with and without lidocaine on two separate occasions. RESULTS: Twenty participants completed the study: 11 were males, the median age was 36 years, 11 were HIV-infected, and the median body mass index was 17.5 kg/m2. The highest pain scores occurred early, and the median pain score was 0 by 30 min. The use of lidocaine with KM significantly reduced pain at the time of injection and 15 min post-dose. On multiple regression analysis, lidocaine halved pain scores (adjusted OR 0.5, 95%CI 0.3-0.9). The area under the curve at 0-10 h of KM with and without lidocaine was respectively 147.7 and 143.6 µg·h/ml. CONCLUSION: Lidocaine significantly reduces early injection-site pain and has no effect on KM pharmacokinetics.
Assuntos
Anestésicos Locais/administração & dosagem , Canamicina/farmacocinética , Lidocaína/administração & dosagem , Dor Processual/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Estudos Cross-Over , Feminino , Infecções por HIV/complicações , Humanos , Injeções Intramusculares/efeitos adversos , Canamicina/administração & dosagem , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Método Simples-Cego , África do Sul , Tuberculose Resistente a Múltiplos Medicamentos/complicaçõesRESUMO
Antimicrobial resistance is a major threat the world is currently facing. Development of new antibiotics and the assessment of their toxicity represent important challenges. Current methods for addressing antibiotic toxicity rely on measuring mitochondrial damage using ATP and/or membrane potential as a readout. In this study, we propose an alternative readout looking at changes in the lipidome on intact and unprocessed cells by matrix-assisted laser desorption ionization mass spectrometry. As a proof of principle, we evaluated the impact of known antibiotics (levofloxacin, ethambutol, and kanamycin) on the lipidome of HeLa cells and mouse bone marrow-derived macrophages. Our methodology revealed that clinically relevant concentrations of kanamycin alter the ratio of cardiolipins to phosphatidylinositols. Unexpectedly, only kanamycin had this effect even though all antibiotics used in this study led to a decrease in the maximal mitochondrial respiratory capacity. Altogether, we report that intact cell-targeted lipidomics can be used as a qualitative method to rapidly assess the toxicity of aminoglycosides in HeLa and primary cells. Moreover, these results demonstrate there is no direct correlation between the ratio of cardiolipins to phosphatidylinositols and the maximal mitochondrial respiratory capacity.
Assuntos
Antibacterianos/farmacologia , Cardiolipinas/metabolismo , Canamicina/farmacologia , Fosfatidilinositóis/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Antibacterianos/administração & dosagem , Relação Dose-Resposta a Droga , Etambutol/farmacologia , Células HeLa , Humanos , Canamicina/administração & dosagem , Levofloxacino/farmacologia , Metabolismo dos Lipídeos , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
INTRODUCTION: Cycloserine and Kanamycin are approved for treatment of multidrug-resistant tuberculosis with good tolerability in Tuberculosis patients and have various labeled adverse reactions but the neuropsychiatric adverse drug reactions with cycloserine are rarely explained. CASE REPORT: We present a case report on Cycloserine induced Suicidal tendencies and Kanamycin induced decrease in hearing sensation in Indian MDR-TB patient. A 55-year-old male patient who was diagnosed with MDR-TB was prescribed with category IV anti-tubercular therapy. Within one month of initiation of therapy, he developed repeated suicidal thoughts, joint pain, restlessness, depression, constipation, insomnia, tinnitus and a decrease in hearing sensation. RESULTS AND DISCUSSION: Cycloserine and kanamycin were closely associated with suicidal tendency and tinnitus followed by a decrease in hearing sensations respectively. On causality assessment using WHO-UMC Causality assessment scale, Adverse Drug Reaction with Cycloserine was found to be certain and for kanamycin, ADR was found to be possible. CONCLUSION: Early management of such fatal ADR can improve the compliance, thus preventing the relapse of infection as well as improving therapeutic outcome in Tuberculosis patients.
Assuntos
Ciclosserina/efeitos adversos , Transtornos da Audição/induzido quimicamente , Canamicina/efeitos adversos , Ideação Suicida , Antituberculosos/administração & dosagem , Antituberculosos/efeitos adversos , Ciclosserina/administração & dosagem , Quimioterapia Combinada , Humanos , Índia , Canamicina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoRESUMO
The objective of the present study was to evaluate the effectiveness of enrofloxacin (ERFX) as a second-line antibiotic for treatment of acute Escherichia coli (E. coli) mastitis. Forty-two cows with naturally occurring acute E. coli mastitis were enrolled. On the first day of treatment (day 0), empirically selected antibiotics (oxytetracycline: n = 32, kanamycin: n = 10) were administered. Although systemic signs improved in 10 cows (first-line group), the signs remained unchanged or worsened in 32 cows on day 1, including two cows that were found dead. The 30 surviving cows were randomly assigned to second-line groups constituting an ERFX group (n = 19) or a control group (n = 11) that was treated with other antibiotics. Response to each treatment was evaluated by measuring clinical signs from day 0 to day 3, subsequent quarter milk recovery, and the 60-day survival rate. Appetite on day 3 was significantly better in the ERFX group compared to the control group. No significant differences were observed in the 60-day survival rate or the subsequent milk recovery between the ERFX group and the control group. Thus, the use of ERFX as a second-line antibiotic for the treatment of acute E. coli mastitis could induce a rapid appetite recovery.
Assuntos
Antibacterianos/administração & dosagem , Doenças dos Bovinos/tratamento farmacológico , Infecções por Escherichia coli , Fluoroquinolonas/administração & dosagem , Mastite/tratamento farmacológico , Mastite/microbiologia , Mastite/veterinária , Retratamento/métodos , Doença Aguda , Animais , Apetite , Bovinos , Doenças dos Bovinos/fisiopatologia , Progressão da Doença , Quimioterapia Combinada , Enrofloxacina , Feminino , Canamicina/administração & dosagem , Mastite/fisiopatologia , Oxitetraciclina/administração & dosagem , Fatores de Tempo , Falha de Tratamento , Resultado do TratamentoRESUMO
BACKGROUND: The intersection of HIV and drug-resistant (DR) tuberculosis (TB) presents the challenge of managing convergent drug toxicities. METHODS: We conducted a retrospective study of adult patients with DR-TB treated with a kanamycin/capreomycin-based (KM) regimen, with or without concomitant antiretroviral therapy (ART). We estimated the incidence of nephrotoxicity (defined as an increase in serum creatinine greater than 26.5 µmol, or an increase in serum creatinine to 1.5 times the baseline value, or a decline in glomerular filtration rate to less than 60 mL/min/1.73 m), and evaluated the association between reported drug use and nephrotoxicity using Kaplan-Meier plots. RESULTS: A total of 215 patients with DR-TB were treated with a kanamycin/capreomycin-based regimen, with or without concomitant ART. The incidence rate of nephrotoxicity was 3.6 [95% confidence interval (CI): 1.4 to 7.3], 6.9 (95% CI: 5.2 to 9.0), and 12 (95% CI: 3.3 to 30.9) cases per 100 person-months of follow-up in the KM only group (n = 42), the KM + TDF (tenofovir disoproxil fumarate) group (n = 163), and the KM + Other ART group (n = 10), respectively. Using the KM only group as a reference, the hazard ratio was 2.06 (95% CI: 0.92 to 4.63) in the KM + TDF group, and 4.09 (95% CI: 1.17 to 14.25) in the KM + Other ART group. Advancing age was an independent predictor of nephrotoxicity (adjusted hazard ratio 1.29, 95% CI: 1.14 to 1.46). CONCLUSIONS: Our findings provide evidence of a significant risk of nephrotoxicity during treatment with a kanamycin/capreomycin-based DR-TB regimen, with or without concurrent treatment with ART. This study lends further support to calls for the substitution of TDF during the intensive phase of DR-TB treatment and for close monitoring of renal function during DR-TB treatment, especially in settings where the use of kanamycin/capreomycin is unavoidable.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Antituberculosos/efeitos adversos , Capreomicina/efeitos adversos , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Canamicina/efeitos adversos , Rim/efeitos dos fármacos , Tenofovir/efeitos adversos , Tuberculose Resistente a Múltiplos Medicamentos/complicações , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Antituberculosos/administração & dosagem , Antituberculosos/uso terapêutico , Capreomicina/administração & dosagem , Capreomicina/uso terapêutico , Creatinina/sangue , Quimioterapia Combinada , Feminino , Taxa de Filtração Glomerular , Humanos , Canamicina/administração & dosagem , Canamicina/uso terapêutico , Rim/fisiopatologia , Masculino , Estudos Retrospectivos , Tenofovir/administração & dosagem , Tenofovir/uso terapêuticoRESUMO
High dose delivery of drugs to the lung using a dry powder inhaler (DPI) is an emerging approach to combat drug-resistant local infections. To achieve this, highly aerosolizable powders are required. We hypothesized that co-spray-drying kanamycin, a hydrophilic hygroscopic antibiotic, with rifampicin, a hydrophobic antibiotic, would produce inhalable particles with surfaces enriched in rifampicin. Such particles would have higher aerosolization than kanamycin alone, and minimise the mass of powder for inhalation avoiding use of non-active excipients. Kanamycin was co-spray-dried with rifampicin using a Buchi Mini Spray-dryer. All powders were inhalable in size (1.1-5.9⯵m) and noncrystalline. X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) showed the surface of the combination powder was enriched with rifampicin. In vitro aerosolization (fine particle fraction) determined by next generation impactor (NGI), dramatically improved from 29.5⯱â¯0.2% (kanamycin-only) to 78.2⯱â¯1.3% (kanamycin-rifampicin combination). The combination powder was flake-shaped in morphology, stable at 15% and 53% RH and 25⯱â¯2⯰C during one-month storage in an open Petri dish, and non-toxic (up to 50⯵g/mL) to human alveolar and bronchial cell-lines. Surface enrichment of kanamycin by hydrophobic rifampicin improves aerosolization, which may help to combat drug-resistant local infections by facilitating high dose delivery to deep lung.
Assuntos
Antibacterianos/administração & dosagem , Composição de Medicamentos/métodos , Canamicina/administração & dosagem , Infecções Respiratórias/tratamento farmacológico , Rifampina/administração & dosagem , Administração por Inalação , Aerossóis , Antibacterianos/química , Antibacterianos/uso terapêutico , Química Farmacêutica , Dessecação , Combinação de Medicamentos , Inaladores de Pó Seco , Humanos , Interações Hidrofóbicas e Hidrofílicas , Canamicina/química , Canamicina/uso terapêutico , Tamanho da Partícula , Pós , Rifampina/química , Rifampina/uso terapêutico , Propriedades de Superfície , MolhabilidadeRESUMO
INTRODUCTION: Sexually transmitted infections (STIs) are managed syndromically in most developing countries. In Zimbabwe, men presenting with urethral discharge are treated with a single intramuscular dose of kanamycin or ceftriaxone in combination with a week's course of oral doxycycline. This study was designed to assess the current etiology of urethral discharge and other STIs to inform current syndromic management regimens. METHODS: We conducted a study among 200 men with urethral discharge presenting at 6 regionally diverse STI clinics in Zimbabwe. Urethral specimens were tested by multiplex polymerase chain reaction testing for Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, and Trichomonas vaginalis. In addition, serologic testing for syphilis and HIV was performed. RESULTS: Among the 200 studied men, one or more pathogens were identified in 163 (81.5%) men, including N. gonorrhoeae in 147 (73.5%), C. trachomatis in 45 (22.5%), T. vaginalis in 8 (4.0%), and M. genitalium in 7 (3.5%). Among all men, 121 (60%) had a single infection, 40 (20%) had dual infections, and 2 (1%) had 3 infections. Among the 45 men with C. trachomatis, 36 (80%) were coinfected with N. gonorrhoeae. Overall, 156 (78%) men had either N. gonorrhoeae or C. trachomatis identified. Of 151 men who consented to HIV testing, 43 (28.5%) tested positive. There were no differences in HIV status by study site or by urethral pathogen detected. CONCLUSIONS: Among men presenting at Zimbabwe STI clinics with urethral discharge, N. gonorrhoeae and C. trachomatis are the most commonly associated pathogens. Current syndromic management guidelines seem to be adequate for the treatment for symptomatic men, but future guidelines must be informed by ongoing monitoring of gonococcal resistance.
Assuntos
Antibacterianos/administração & dosagem , Infecções Sexualmente Transmissíveis/microbiologia , Supuração/microbiologia , Uretrite/microbiologia , Adulto , Ceftriaxona/administração & dosagem , Doxiciclina/administração & dosagem , Inquéritos Epidemiológicos , Humanos , Canamicina/administração & dosagem , Masculino , Reação em Cadeia da Polimerase Multiplex , Técnicas de Amplificação de Ácido Nucleico , Comportamento Sexual , Infecções Sexualmente Transmissíveis/complicações , Infecções Sexualmente Transmissíveis/tratamento farmacológico , Uretrite/tratamento farmacológico , Uretrite/etiologia , Zimbábue/epidemiologiaRESUMO
BACKGROUND: Kanamycin, an injectable agent, is currently used to treat drug-resistant tuberculosis (TB). Parenteral kanamycin causes high systemic toxicity which could be avoided by direct delivery to the lungs. This study focused on producing a highly aerosolizable dry-powder of hygroscopic kanamycin by spray-drying with l-leucine. METHODS: Kanamycin powders were prepared with different concentrations (0, 5, 10, 15 and 20% w/w) of l-leucine using the Buchi B-290 Mini Spray-Dryer. In vitro aerosolization efficiency, particle size, morphology, crystallinity, surface composition, drug-excipient interaction and moisture content of the powders were characterized by a Next Generation Impactor (NGI), laser diffraction, scanning electron microscopy, X-ray diffractometry, XPS, ATR-FTIR and thermogravimetric analysis. The physicochemical and aerosolization stability of the powders were investigated after one-month storage at 25±2°C/15% RH and 25±2°C/75% RH. The cytotoxicity on Calu-3 and A549 cells of the kanamycin powders was evaluated by MTT assay. RESULTS: The spray-dried powder particles were in the inhalable size range (<6.1µm). The powders with l-leucine were wrinkled in shape, amorphous in nature and had low moisture content (<5.0%). Kanamycin with 5% (w/w) of l-leucine showed the best aerosolization efficiency of 73.0±2.5%. The powders remained stable during storage at 25±2°C/15% RH and tolerated by respiratory cell lines. CONCLUSION: l-leucine improved the aerosolization of kanamycin by surface modification, which may be helpful for the effective treatment of drug-resistant tuberculosis.
Assuntos
Inaladores de Pó Seco , Canamicina/administração & dosagem , Pós , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Administração por Inalação , Aerossóis , Linhagem Celular Tumoral , Humanos , Tamanho da PartículaRESUMO
Low transfection efficiency and high cytotoxicity of polymeric gene carriers have hampered the application of numerous polycations for gene therapy. To overcome this barrier, a cationic glycoconjugate of kanamycin and di(ethylene glycol) diacrylate was prepared via a facile approach. Nuclear magnetic resonance, Fourier transform infrared spectroscopy, and size exclusion chromatography were employed to investigate the resulting materials. Agarose gel electrophoresis, atomic force microscopy, and circular dichroism spectroscopy were used to record the interaction of the cationic oligomer and plasmid DNA. Finally, the cytotoxicity and transfection efficiency were evaluated by using COS-7 cells. The results indicated that cationic oligomers had been obtained and plasmid DNA was condensed into nanocomplexes, with a high transfection efficiency of the oligomer and a low toxicity in COS-7 cell line. It provided a novel perspective to develop gene carrier, with better safety and greater transfection efficiency, compared to traditional high molecular weight polymers.
Assuntos
Acrilatos/administração & dosagem , Técnicas de Transferência de Genes , Glicoconjugados/administração & dosagem , Canamicina/administração & dosagem , Acrilatos/química , Animais , Células COS , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , DNA/administração & dosagem , Glicoconjugados/química , Canamicina/química , Luciferases/genética , PlasmídeosRESUMO
Listeria monocytogenes is well known to cause prosthetic joint infections in immunocompromised patients. In this study, polyethylene oxide (PEO) nanofibers, containing kanamycin and hyaluronic acid (HA), were prepared by electrospinning at a constant electric field of 10kV. PEO nanofibers spun with 0.2% (w/v) HA and 1% (w/v) kanamycin had a smooth, bead-free structure at 30-35% relative humidity. The average diameter of the nanofibers was 83±20nm. Attenuated total reflectance (ATR)-Fourier transform infrared (FTIR) spectroscopy indicated that kanamycin was successfully incorporated into PEO/HA matrix. The presence of kanamycin affects the thermal properties of PEO/HA nanofibers, as shown by differential scanning calorimetry (DSC) and thermogravimetric analyses (TGA). The kanamycin-PEO-HA nanofibers (1mg; 47±3µg kanamycin) inhibited the growth of L. monocytogenes EDGe by 62%, as compared with PEO-HA nanofibers, suggesting that it may be used to coat prosthetic implants to prevent secondary infections.
Assuntos
Antibacterianos/administração & dosagem , Ácido Hialurônico/administração & dosagem , Canamicina/administração & dosagem , Listeria monocytogenes/efeitos dos fármacos , Nanofibras/administração & dosagem , Polietilenoglicóis/administração & dosagem , Antibacterianos/química , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Humanos , Ácido Hialurônico/química , Canamicina/química , Listeria monocytogenes/crescimento & desenvolvimento , Nanofibras/química , Polietilenoglicóis/químicaRESUMO
OBJECTIVE: The study objectives were to determine the incidence of aminoglycoside-induced ototoxicity in institutionalized patients on intensive phase of therapy for drug-resistant Tuberculosis (DR Tb) and also to assess clinical factors which could predict the ototoxicity. METHODS: The study was a prospective analytical study among consecutive DR Tb patients who were admitted for intensive phase of therapy (of 4 months) at the DR-Tb center over a 12-month period. Patients were diagnosed as DR Tb using the Gene Xpert machine to confirm Rifampicin resistance. All eligible 70 out of 87 consenting patients were consecutively recruited into the study. Patients had baseline (admission) and serial pure tone audiometries (PTAs) performed at 4 weekly intervals until discharge after 4 months of admission. Audiometric confirmation of aminoglycoside-induced ototoxicity was done by comparing serial with baseline PTA. RESULTS: Among the 70 patients the male:female ratio was 1.7:1. Nine patients (12.9%) were retroviral-positive, and 16 patients (22.9%) were confirmed to have ototoxicity by audiometric criteria. The duration of treatment when ototoxicity was detected in the patients ranged 4-17 (Mean±SD; 9.4±3.4) weeks. Ototoxicity was detected in the audiometric low frequency ranges in 7 (43.8%) and at the high frequencies in 4 (25.0%) of the patients. Univariate analyses of clinical parameters found that age, underlying diabetes mellitus, deranged baseline PTAv >25dB HL, BMI on admission and retroviral status were significantly associated, while sex and previous drug regimen failure were not associated with ototoxicity. Multivariate adjusted logistic regression analyses, controlling for sex, revealed age (OR=1.068, p=0.018), BMI on admission (OR=0.673, p=0.012) and retroviral positivity (OR=8.822, p=0.014) of patients could significantly predict aminoglycoside-induced ototoxicity. CONCLUSION: Incidence of aminoglycoside-induced ototoxicity in DR Tb patients was 22.9%. The clinical predictors for ototoxicity were age, BMI on admission, and co-existing retroviral infection in the patients. Clinicians should consider these factors in making choices of aminoglycosides to be used during intensive phase of treatment with second line anti-Tuberculous therapy.
Assuntos
Antituberculosos/uso terapêutico , Perda Auditiva/induzido quimicamente , Canamicina/efeitos adversos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adulto , Fatores Etários , Aminoglicosídeos/administração & dosagem , Aminoglicosídeos/efeitos adversos , Audiometria de Tons Puros , Índice de Massa Corporal , Coinfecção , Comorbidade , Ciclosserina/uso terapêutico , Diabetes Mellitus/epidemiologia , Feminino , Infecções por HIV/epidemiologia , Perda Auditiva/epidemiologia , Humanos , Canamicina/administração & dosagem , Levofloxacino/uso terapêutico , Masculino , Pessoa de Meia-Idade , Nigéria/epidemiologia , Estudos Prospectivos , Protionamida/uso terapêutico , Pirazinamida/uso terapêutico , Fatores de Risco , Fatores de Tempo , Adulto JovemRESUMO
OBJECTIVES: As a homing factor of stem cell, stromal derived factor-1 (SDF-1) is important for the regenerative research in ototoxicity. Mice models with aminoglycoside ototoxicity have been widely used to study the regeneration capacity of MSCs in repair of cochlear injury. We developed a mouse model with maximal increase in SDF-1 levels in the inner ear, according to the "one-shot" doses of kanamycin and furosemide. METHODS: C57BL/6 mice had kanamycin (420, 550, and 600 mg/kg) dissolved in PBS, followed by an intraperitoneal injection of furosemide (130 mg/kg). The injuries of inner ear were measured with hearing thresholds, histology, and outer hair cell counts at 0, 3, 5, 7, 10, and 14 days before the sacrifice. The levels of SDF-1 in the inner ear were tested by real-time RT-PCR and immunohistochemistry. RESULTS: There were a significant reduction in hearing thresholds and a maximal increase of SDF-1 levels in the furosemide 130 mg/kg + kanamycin 550 mg/kg group, but severe hearing deterioration over time was observed in the furosemide 130 mg/kg + kanamycin 600 mg/kg group and four mice were dead. SDF-1 was detected mostly in the stria vascularis and organ of Corti showing the highest increase in expression. CONCLUSION: We observed optimal induction of the stem cell homing factor in the newly generated aminoglycoside-induced ototoxicity mouse model using a "one-shot" protocol. This study regarding high SDF-1 levels in our mouse model of ototoxicity would play a major role in the development of therapeutic agents using MSC homing.
Assuntos
Aminoglicosídeos/administração & dosagem , Quimiocina CXCL12/genética , Audição/genética , Células-Tronco Mesenquimais/metabolismo , Aminoglicosídeos/efeitos adversos , Animais , Cóclea/efeitos dos fármacos , Cóclea/metabolismo , Modelos Animais de Doenças , Orelha Interna/efeitos dos fármacos , Orelha Interna/lesões , Orelha Interna/metabolismo , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Furosemida/administração & dosagem , Furosemida/efeitos adversos , Células Ciliadas Auditivas Externas/efeitos dos fármacos , Células Ciliadas Auditivas Externas/metabolismo , Audição/efeitos dos fármacos , Humanos , Canamicina/administração & dosagem , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BLRESUMO
SETTING: To compare renal insufficiency among multidrug-resistant tuberculosis (MDR-TB) patients treated with kanamycin (KM) based regimens and those treated concomitantly with tenofovir disoproxil fumarate (TDF) or other antiretroviral therapy (ART) regimens in Namibia. DESIGN: Retrospective review of the treatment records and laboratory tests of patients initiated on MDR-TB treatment (January-December 2014). The glomerular filtration rates (eGFR) estimated pre- and post-treatment were compared using the analysis of variance test. Renal insufficiency was defined as an eGFR of <60 ml/min/1.73 m2. Use of KM or TDF and association with renal insufficiency was assessed using Kaplan-Meier plots and Cox proportional hazards analysis. RESULTS: The baseline mean eGFR for the three groups was similar (P = 0.24): 139.3 ± 25.6 ml/min for the KM group (n = 68), 131.1 ± 25.7 ml/min for the KM+TDF group (n = 44) and 134.2±34.4 ml/min for the KM+Other group (n = 23). After 8 months, the values had declined significantly to respectively 104.8 ± 37.5 ml/min (P < 0.001), 101.5 ± 38.3 ml/min (P < 0.001) and 111.5 ± 41.7 ml/min (P = 0.01). Co-treatment with KM+ART was associated with an increased risk of renal insufficiency (hazard ratio [HR] 1.8, 95%CI 0.7-4.1, P = 0.20 for KM+TDF, and HR 3.5, 95%CI 1.4-8.2, P = 0.005 for KM+Other ART). CONCLUSION: Renal function declined at a similar rate in MDR-TB patients treated with KM-based regimens compared with patients treated concomitantly with TDF-based or other ART. The risk of renal insufficiency was greater for patients on ART.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Antituberculosos/administração & dosagem , Canamicina/administração & dosagem , Insuficiência Renal/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adulto , Fármacos Anti-HIV/efeitos adversos , Antituberculosos/efeitos adversos , Feminino , Seguimentos , Taxa de Filtração Glomerular , Infecções por HIV/tratamento farmacológico , Humanos , Canamicina/efeitos adversos , Estimativa de Kaplan-Meier , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Namíbia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Tenofovir/administração & dosagem , Tenofovir/efeitos adversos , Adulto JovemRESUMO
A 22 year-old lady with multi-drug-resistant pulmonary tuberculosis was on Kanamycin, Cycloserine, Ethionamide, Pyrazinamide and Moxifloxacin since more than two months. She presented with muscle cramps and carpopedal spasm. Investigation revealed hypokalemia and metabolic alkalosis. She also had hypomagnesemia, hypochloremia and hypocalciuria. Serum urea and creatinine levels were normal. Patient was treated with intravenous and oral potassium chloride. Kanamycin was stopped. Metabolic alkalosis and hypokalemia improved gradually over one month. Biochemical parameters were like Gitelman's syndrome but it reversed with stoppage of Kanamycin. Gitelman-like syndrome with Kanamycin toxicity has not been reported in literature previously.