Signs Of Ototoxicity Research Articles

Plasminogen - safe for treatment of chronic tympanic membrane perforation: a phase 1 randomized, placebo-controlled study

Background There is a need for a simpler and accessible intervention to heal tympanic membrane perforations than myringoplasty that is todaýs golden standard. Experimental studies have identified plasminogen as a promising agent for medical treatment of chronic tympanic membrane perforation. Aims/Objectives This was a phase 1, prospective, randomized, placebo-controlled study with the main objective to evaluate the safety of injecting plasminogen in the vicinity of the tympanic membrane in subjects with chronic tympanic membrane perforation. Material and Methods Adults diagnosed with a dry chronic tympanic membrane perforation were recruited for an injection schedule with Human plasminogen 10. Adverse events, audiometry, VAS fluctuations and size of perforation, were monitored throughout the length of the study. Results It was possible to perform the injections according to schedule in all subjects. None of the subjects experienced any severe adverse events. Most common adverse event was ear pain. No signs of ototoxicity were reported. Conclusions and Significance This pilot study suggests that plasminogen injections close to the tympanic membrane as treatment for chronic tympanic membrane injections are safe and feasible, encouraging further dose-escalating studies.

OTOTOXICITY IN MULTIDRUG-RESISTANT TUBERCULOSIS: A SCOPING REVIEW OF THE INDONESIAN STUDIES

A wide variation in ototoxicity or hearing loss due to injectable anti-tubercular drugs in patients with multidrug-resistant tuberculosis (MDR-TB) has been reported globally and in Indonesia. This scoping review assesses the ototoxicity of second-line injectable anti-tubercular drugs in Indonesian patients with MDR-TB. This review was conducted under the recommended PRISMA extension for scoping review (PRISMA-ScR). The Google Scholar and PubMed database were used to search the articles on MDR-TB in the Indonesian population. Seven studies were identified based on the inclusion criteria reporting kanamycin and capreomycin in the management of MDR-TB. Ototoxicity was observed in 39.3% (116/295) MDR-TB patients. Ototoxicity was observed in kanamycin, 38.7% (105/271 patients); capreomycin, 36,8% (7/19 patients); and kanamycin plus capreomycin, 80% (4/5 patients). Only one study reported risk factors ototoxicity in MDR-TB patients. Ototoxicity was significantly associated with older age and the length of kanamycin therapy correlates with hearing loss. This review identified a high prevalence of ototoxicity in Indonesian patients with MDR-TB treated with second-line injectable drugs. Efforts were urgently needed to develop guidelines for monitoring ototoxicity, improving pharmacist and clinician awareness, and educating patients or caregivers to report hearing loss symptoms as a sign of ototoxicity.
 
 Keywords: MDR-TB; Ototoxicity, Second-line injectable
 

The Use of Nanoparticles in Otoprotection.

The inner ear can be insulted by various noxious stimuli, including drugs (cisplatin and aminoglycosides) and over-acoustic stimulation. These stimuli damage the hair cells giving rise to progressive hearing loss. Systemic drugs have attempted protection from ototoxicity. Most of these drugs poorly reach the inner ear with consequent ineffective action on hearing. The reason for these failures resides in the poor inner ear blood supply, the presence of the blood-labyrinthine barrier, and the low permeability of the round window membrane (RWM). This article presents a review of the use of nanoparticles (NPs) in otoprotection. NPs were recently used in many fields of medicine because of their ability to deliver drugs to the target organs or cells. The studies included in the review regarded the biocompatibility of the used NPs by in vitro and in vivo experiments. In most studies, NPs proved safe without a significant decrease in cell viability or signs of ototoxicity. Many nano-techniques were used to improve the drugs' kinetics and efficiency. These techniques included encapsulation, polymerization, surface functionalization, and enhanced drug release. In such a way, it improved drug transmission through the RWM with increased and prolonged intra-cochlear drug concentrations. In all studies, the fabricated drug-NPs effectively preserved the hair cells and the functioning hearing from exposure to different ototoxic stimuli, simulating the actual clinical circumstances. Most of these studies regarded cisplatin ototoxicity due to the wide use of this drug in clinical oncology. Dexamethasone (DEX) and antioxidants represent the most used drugs in most studies. These drugs effectively prevented apoptosis and reactive oxygen species (ROS) production caused by ototoxic stimuli. These various successful experiments confirmed the biocompatibility of different NPs and made it successfully to human clinical trials.

Benefits of Using an Early Palliative Care Intervention in Pediatric Oncology

Early palliative care (PC) interventions can foster effective symptom management during oncology treatments. Children with cancer are an appropriate population to receive early PC interventions to minimize suffering and foster quality of life during oncology treatments. Delivery of cisplatin along with posthydration (PH) intravenous fluids (IVFs) is an example of an early PC intervention for children diagnosed with standard risk medulloblastoma. In this study, we performed a retrospective chart review to evaluate the impact of outpatient delivery of cisplatin and PH IVF on target outcomes (renal function, ototoxicity, and health care costs) for 45 pediatric patients with standard risk medulloblastoma. Evaluation of physical outcomes revealed (a) no significant changes in serum creatinine, (b) no signs of hemorrhagic cystitis or renal insufficiency, and (c) no significant increase in signs of ototoxicity. Evaluation of health care costs revealed a reduction in the number of required hospital admissions for pediatric patients receiving outpatient cisplatin and PH IVF. In summary, PH IVF after delivery of cisplatin seems to be a potentially effective early PC intervention that may benefit the pediatric oncology patient by preserving renal function, reducing the risk of ototoxicity, and reducing health care costs because of the decreased number of hospital admissions related to outpatient delivery of cisplatin treatments.

107 Sputum flora among teenage cystic fibrosis patients using inhaled TOBI therapy for 5 and more years from Sofia CF center

Objectives To assess the diversity of the sputum flora among teenaged cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa (PA) colonization treated for 5 years and more with inhaled TOBI (TIS), as well as the safety of inhaled drug. Methods Microbiological investigations of sputum flora from 22 CF patients (13 boys and 9 girls), aged 12–18 y (mean age 15.7 y) receiving 5 years and more of inhaled TOBI were done together with a main blood biochemical assessment of liver condition (ALAT, ASAT, LDH), renal function (creatinine, urea, ureic acid), lung functional tests (FEV1) and ototoxicity (audiometric testing). Results PA in sputum was permanently established in 6 patients (27.27%), in two of them in combination with other pathogens; Candida sp. was found in 3 (13.63%), methicillin resistant Staphylococcus aureus in 6 patients, Burkholderia cepacia in one. Stenotrophomonas maltophilia , Achromobacter xylosoxidans, Aspergillus sp. and non-tuberculous mycobacteria were not found. 7 patients (31.81%) were free of sputum pathogens. FEV1 less than 40% of predicted showed 5 patients (22.73%). Out of a slight elevation of ureic acid level in 1 patient none of the others revealed liver and renal dysfunction, neither signs of ototoxicity. Conclusion 5 years and more of inhaled TOBI therapy is safe, shows effective results in more than 75% of chronically PA infected teenaged CF patients and leads to permanent full sputum pathogen eradication in at least 1/3 of them. New drug inhaled formulae are needed for each fourth teenaged CF patients with chronic PA colonization.

Repeated treatment of recurrent uncomplicated Plasmodium falciparum malaria in Senegal with fixed-dose artesunate plus amodiaquine versus fixed-dose artemether plus lumefantrine: a randomized, open-label trial

BackgroundThe use of artemisinin-based combination therapy (ACT) is currently recommended for treating uncomplicated malaria. The objective was to assess the efficacy and safety of repeated administrations of two fixed-dose presentations of ACT - artesunate plus amodiaquine (ASAQ) and artemether-lumefantrine (AL) - in subsequent episodes of Plasmodium falciparum malaria.MethodsA randomized comparative study was conducted in a rural community of central Senegal from August 2007 to January 2009. Children and adults with uncomplicated P. falciparum malaria were randomized to receive open-label ASAQ once daily or AL twice daily for three days. Drug doses were given according to body weight. Treatments for first episodes were supervised. For subsequent episodes, only the first intake of study drug was supervised. ECGs and audiograms were performed in patients ≥12 years of age. Primary outcome was adequate clinical and parasitological response rate (ACPR) after polymerase chain reaction (PCR) correction on day 28 for the first episode.ResultsA total of 366 patients were enrolled in the two groups (ASAQ 184, AL 182) and followed up during two malaria transmission seasons. In the intent-to-treat population, PCR-corrected ACPRs at day 28 for the first episode were 98.4% and 96.2%, respectively, in the ASAQ and AL groups. For the per-protocol population (ASAQ 183, AL 182), PCR-corrected ACPRs at day 28 for the first episode were 98.9% and 96.7%, respectively. A 100% ACPR rate was obtained at day 28 in the 60 and four patients, respectively, who experienced second and third episodes. Treatment-related adverse events were reported in 11.7% of the patients, without significant differences between the two groups. A better improvement of haemoglobin at day 28 was noted in the ASAQ versus the AL group (12.2 versus 11.8 g/dL; p = 0.03). No sign of ototoxicity was demonstrated. A prolongation of the QTc interval was observed in both groups during treatment with no clinical consequence.ConclusionsStudy results confirmed the satisfactory efficacy and safety profile of ASAQ and AL. Moreover, in patients who were treated at least twice, repeated administration of ASAQ or AL did not identify any major safety issues.Trial registrationClinicalTrials.gov identifier NCT00540410.

Organic Cation Transporter 2 Mediates Cisplatin-Induced Oto- and Nephrotoxicity and Is a Target for Protective Interventions

The use of the effective antineoplastic agent cisplatin is limited by its serious side effects, such as oto- and nephrotoxicity. Ototoxicity is a problem of special importance in children, because deafness hampers their language and psychosocial development. Recently, organic cation transporters (OCTs) were identified in vitro as cellular uptake mechanisms for cisplatin. In the present study, we investigated in an in vivo model the role of OCTs in the development of cisplatin oto- and nephrotoxicity. The functional effects of cisplatin treatment on kidney (24 hours excretion of glucose, water, and protein) and hearing (auditory brainstem response) were studied in wild-type and OCT1/2 double-knockout (KO) mice. No sign of ototoxicity and only mild nephrotoxicity were observed after cisplatin treatment of knockout mice. Comedication of wild-type mice with cisplatin and the organic cation cimetidine protected from ototoxicity and partly from nephrotoxicity. For the first time we showed that OCT2 is expressed in hair cells of the cochlea. Furthermore, cisplatin-sensitive cell lines from pediatric tumors showed no expression of mRNA for OCTs, indicating the feasibility of therapeutic approaches aimed to reduce cisplatin toxicities by competing OCT2-mediated cisplatin uptake in renal proximal tubular and cochlear hair cells. These findings are very important to establish chemotherapeutical protocols aimed to maximize the antineoplastic effect of cisplatin while reducing the risk of toxicities.

Efficacy and safety of artemether-lumefantrine dispersible tablets compared with crushed commercial tablets in African infants and children with uncomplicated malaria: a randomised, single-blind, multicentre trial

Combination treatments, preferably containing an artemisinin derivative, are recommended to improve efficacy and prevent Plasmodium falciparum drug resistance. Our aim was to show non-inferiority of a new dispersible formulation of artemether-lumefantrine to the conventional crushed tablet in the treatment of young children with uncomplicated malaria. We did a randomised non-inferiority study on children weighing 5-35 kg with uncomplicated P falciparum malaria in Benin, Kenya, Mali, Mozambique, and Tanzania. The primary outcome measure was PCR-corrected 28-day parasitological cure rate. We aimed to show non-inferiority (with a margin of -5%) of dispersible versus crushed tablet. We constructed an asymptotic one-sided 97.5% CI on the difference in cure rates. A computer-generated randomisation list was kept centrally and investigators were unaware of the study medication administered. We used a modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00386763. 899 children aged 12 years or younger were randomly assigned to either dispersible (n=447) or crushed tablets (n=452). More than 85% of patients in each treatment group completed the study. 812 children qualified for the modified intention-to-treat analysis (n=403 vs n=409). The PCR-corrected day-28 cure rate was 97.8% (95% CI 96.3-99.2) in the group on dispersible formulation and 98.5% (97.4-99.7) in the group on crushed formulation. The lower bound of the one-sided 97.5% CI was -2.7%. The most common drug-related adverse event was vomiting (n=33 [7%] and n=42 [9%], respectively). No signs of ototoxicity or relevant cardiotoxicity were seen. A six-dose regimen of artemether-lumefantrine with the new dispersible formulation is as efficacious as the currently used crushed tablet in infants and children, and has a similar safety profile.

Aminoglycoside ototoxicity and the medial efferent system: I. Comparison of acute and chronic gentamicin treatments.

Recently our laboratory has demonstrated, in the guinea pig (GP), that an intramuscular (i.m.) injection of a high dose of gentamicin (GM) (150 mg/kg), can reversibly block the contralateral efferent suppression of ipsilateral cochlear activity. The aims of the present study were: (1) to investigate this effect with lower doses of GM; and (2) to find out whether this effect could constitute an anticipatory sign of ototoxicity during a chronic GM treatment (60 mg/kg i.m., 10 days). The function of the medial olivocochlear efferent system (MOES) was tested by recording the VIIIth nerve ensemble background activity (EBA) without and with contralateral low level (55 dB SPL) broadband noise stimulation. The results show a dose-dependent effect of GM on contralateral suppression, as the dose of 120 mg/kg induced a smaller blockade of the MOES, compared to 150 mg/kg, and no blockade was observed with lower doses. During the ten-day treatment no significant changes in the EBA without acoustic stimulation, nor in contralateral efferent suppression were detected. GPs monitored over several weeks after the treatment showed progressive reduction of the EBA without contralateral stimulation parallel to reduced suppression coefficients of the EBA, and CAP threshold elevations, denoting impaired cochlear function. Thus, this study demonstrated that a chronic treatment with 60 mg/kg of GM, although ototoxic, does not affect the contralateral efferent suppression, at least before the development of ototoxicity.

Tolerance of once-daily dosing of netilmicin and teicoplanin, alone or in combination, in healthy volunteers

The purposes of this study were to test the pharmacokinetics and renal and otologic tolerances of a once-daily regimen of netilmicin and teicoplanin administered intramuscularly, alone or in combination (4.5 and 6 mg/kg, respectively), for 7 days in 30 healthy male volunteers. Teicoplanin induced only a mild increase in enzymuria. Nephrotoxicity was moderate and reversible with netilmicin; there was increased enzymuria and alteration in diluting ability, without significant changes in urinary beta 2-microglobulin levels, concentrating ability, and glomerular filtration rate. Ototoxicity was not detected in any of the subjects. Our results suggest that (1) teicoplanin and netilmicin given once daily induced only slight, reversible tubular damage, without any sign of ototoxicity; (2) their combination was not more toxic; and (3) clinical studies can be envisaged to evaluate the efficacy and tolerance of once-daily regimens in long-term treatment.

When the Weeping Stopped: An Otologist Views Otorrhea and Gentamicin

Gentamicin sulfate ophthalmic solution, 0.3%, was used ototopically in the treatment of 300 patients with otorrhea associated with acute and chronic ear conditions and to obtain a preoperative "dry state" in 93 cases in which surgical operation was indicated. Bacterial cultures, antibiograms, and audiometric tests were conducted before, during, and after ototopical therapy. Gentamicin-susceptible pathogens were isolated in all cases. A totally "dry state", after three weeks of therapy, was considered evidence of clinical success. Administration of gentamicin was by means of a wick or at the rate of 0.3 to 0.4 ml twice daily. Clinical success was observed in 271 cases. There were no signs of ototoxicity and only one reported instance of skin reaction. This simple, inexpensive treatment is particularly adaptable to situations in which specialized bacteriological testing facilities are unavailable and a broad-spectrum antibiotic is indicated.