Transtympanic Ringer's lactate application in the prevention of cisplatinum-induced ototoxicity in a chinchilla animal model

Objective

Ototoxicity is currently the most frequent dose-limiting side effect of cisplatinum chemotherapy. To date, there is no protocol to prevent dose-related ototoxicity, despite its prevalence and predictability. Previous animal studies have found lactate to be effective in the prevention of cisplatinum-induced ototoxicity. The objective of this study was to test the protective benefits of transtympanic Ringer's lactate in the prevention of cisplatinum-induced ototoxicity.

Study Design

A randomized prospective controlled trial was conducted in an animal model.

Setting

Animal care research facilities of The Montreal Children's Hospital Research Institute.

Subjects and Methods

A total of 44 chinchillas were exposed to systemic cisplatinum injected intraperitoneally in divided cycles to reach the targeted cumulative dosage of 16 mg/kg. Ototopical application of Ringer's lactate solution 0.2 mL twice per day during the chemotherapy cycles was performed. Each animal had one experimental (Ringer's) and one control ear. Distortion product otoacoustic emissions (DPOAEs) were collected for a wide range of frequencies (between 1 and 16 kHz), and scanning electron microscopy was performed to evaluate the protective effects of Ringer's lactate.

Results

Ototopical application of Ringer's lactate solution in our established chinchilla animal model did not provide an otoprotective effect as measured by the DPOAE response and electron microscopy.

Conclusion

In our study, the intratympanic application of Ringer's lactate solution through a tympanostomy ventilation tube did not provide an otoprotective effect. Further studies are needed to better assess the otoprotective or ototoxic effects of Ringer's lactate and other antioxidants on animal and human hearing.     

Rhinoscleroma causing severe bilateral nasal obstruction

Rhinoscleroma is a chronic, infectious and granulomatous disease of the respiratory tract. There is often a delay in diagnosis due to unfamiliarity with the disease and also because culture is not always positive. We report a case in a 26-year-old woman with granular mass obstructing bilateral nasal cavities and causing breathing difficulty. Histopathological examination showed characteristic Mikulicz histiocytes containing numerous Gram-negative intracellular rod-shaped bacilli consistent with the diagnosis of rhinoscleroma. The patient was treated with gemifloxacin and tetracycline and remains asymptomatic over a year follow-up period. It is important to consider rhinoscleroma in cases of chronic nasal obstruction. As culture is not always positive, histopathological examination may be crucial to the diagnosis.     

Liver fibrosis in women with chronic hepatitis C: evidence for the negative role of the menopause and steatosis and the potential benefit of hormone replacement therapy

BACKGROUND AND AIMS: The rates of fibrosis progression in chronic hepatitis C are significantly different between males and females. The antifibrogenic effect of oestrogen has been proposed, possibly via inhibition of stellate cells. The aim of this study was to evaluate the severity of chronic hepatitis C in women, in relation to the menopause, steatosis and hormone replacement therapy (HRT). METHODS: From November 2003 to October 2004, women with chronic hepatitis C were enrolled prospectively. A questionnaire was completed prospectively and a blood sample was obtained on the day of biopsy. We identified characteristics associated with moderate/severe fibrosis using univariate and multivariate analysis. RESULTS: 251 women were included in the study. 122 women (52%) were menopausal and 65 were receiving HRT. 61 (24%) women with moderate/severe fibrosis (F2-F4, Metavir score) had a longer known duration of infection (>15 years), a higher body mass index and presented with steatosis more frequently than 190 (76%) women with mild fibrosis (F0-F1). Women with F2-F4 were more often menopausal (67% v 47%). The probability of fibrosis F2-F4 was lower for menopausal women receiving HRT (p = 0.012). Steatosis was more frequent and more severe in menopausal women. CONCLUSIONS: Severity of fibrosis was associated with a longer duration of infection (>15 years), a higher body mass index, advanced steatosis and the menopause. Menopausal women receiving HRT presented with a lower stage fibrosis. These results reinforce the hypothesis of a protective role of oestrogens in the progression of fibrosis. Steatosis may be implicated in the progression of fibrosis after the menopause.     

Final results of a double-blind, placebo-controlled trial of the antifibrotic efficacy of interferon-gamma1b in chronic hepatitis C patients with advanced fibrosis or cirrhosis

Interferon-gamma1b (IFN-gamma1b) is a pleiotropic cytokine that displays antifibrotic, antiviral, and antiproliferative activity. A total of 502 patients with compensated liver disease and an Ishak fibrosis score of 4-6 were randomized in a double-blind, placebo-controlled study, and 488 of these patients received subcutaneous injections of IFN-gamma1b 100 microg (group 1, n=169), IFN-gamma1b 200 microg (group 2, n=157), or placebo (group 3, n=162) 3 times a week for 48 weeks. Most patients (83.6%) had cirrhosis at baseline (Ishak score=5 or 6). Posttreatment liver biopsies were assessed in a blinded fashion for a reduction of 1 or more Ishak points (primary endpoint). Four hundred twenty patients with pretreatment and posttreatment liver biopsies were evaluable and showed no improvement in Ishak score between the 3 treatment groups (12.1%, 12.4%, and 16% of patients in groups 1, 2, and 3, respectively; P>0.05). Analysis of IFN-gamma-inducible biomarkers revealed that interferon-inducible T cell-alpha chemoattractant (ITAC), an IFN-gamma-inducible CXCR3 chemokine was an independent predictor of stable or improving Ishak score. IFN-gamma1b was well tolerated. There were similar numbers of deaths in all 3 arms (5, 5, and 4, respectively), and most were related to complications of cirrhosis. CONCLUSION: IFN-gamma1b therapy was not able to reverse fibrosis in patients with advanced liver disease for 1 year. Subgroups of patients with elevated ITAC levels and perhaps less advanced disease may be considered for future studies with IFN-gamma1b.     

Value of gated-SPECT in defining the post-revascularization prognosis of patients with ischemic cardiomyopathy

INTRODUCTION AND OBJECTIVES: Gated-SPECT simultaneously evaluates perfusion and ventricular function and could provide important prognostic information in ischemic cardiomyopathy. Our aim was to study the value of gated-SPECT performed before revascularization in a cardioischemic population to predict the outcome of revascularization. METHODS: One hundred and ten patients who had undergone percutaneous (n = 100) or surgical revascularization were included. Patients underwent sestamibi gated-SPECT before revascularization. After revascularization, they were followed-up for at least 12 months (mean 23.7 months, maximum 44 months). We recorded deaths and a combined clinical event of death, non-fatal infarction, and hospital re-admission for cardiac reasons. We analyzed the prognostic value of clinical, angiographic, and gated-SPECT variables. RESULTS: During follow-up, there were 14 deaths (6.4%/ year) and 36 cases of combined events (16.5%/year). Multivariate analysis showed that depressed gated-SPECT ejection fraction (threshold 0.30) was the only variable independently related to death (OR = 4.8; 95%CI, 1.6-14.6) and combined event (OR = 2.5; 95%CI, 1.2-4.8). Survival analysis showed that patients with ejection fraction < or = 0.30% had a significantly shorter period of time free of death (33 months [28-38] versus 42 months [40-44]; p = 0.002) and combined events (28 months [23-32] versus 36 months [33-39]; p = 0.007). CONCLUSIONS: Gated-SPECT, due to the information it provides about left ventricular function, predicts the prognosis of patients after coronary revascularization.     

Thyroid disorders in patients with chronic hepatitis C using interferon-alpha and ribavirin therapy

ObjectiveTo investigate the frequency of thyroid disorders (TD) in patients with chronic hepatitis C before and during interferon-alpha (IFN-α) and ribavirin (RIB) treatment.Study designProspective study.Patients and MethodsWe prospectively studied 65 anti-HCV and viral RNA positive patients. Free thyroxine, thyroid-stimulating hormone, and thyroid peroxidase antibodies (TPO-Ab) were systematically tested at entry (m0), week 12 (m3) and week 24 (m6) of treatment.ResultsMean age of the 65 patients (38 females and 27 males) was 49.61 ± 11.83 years. Seven (10.76%) patients presented baseline thyroid disorders (m0), three had thyroid dysfunction, and four were TPO-Ab positive. Thyroid disorders occurred in the first 12 weeks of treatment in 11 (16.92%) patients, four with thyroid dysfunction, and seven with TPO-Ab positive (m3). A total of 18 patients (27.69%) developed TD after 24 weeks of treatment, 7 with thyroid dysfunction, and 11 with TPO-Ab positive (m6). The relative risk of developing hypothyroidism found in this study was 1.3 (95% CI: 1.1 to 1.6), hyperthyroidism 1.2 (95% CI: 1.1 to 1.4), and TPO-Ab positivity 7.6 (95% CI: 3.9 to 14.5). The study showed a significant association between female sex and thyroid disease (p = 0.009).ConclusionThyroid dysfunction and autoimmune TD were observed during IFN-α and RIB therapy.     

Multiple ascending dose study of BMS-790052, a nonstructural protein 5A replication complex inhibitor, in patients infected with hepatitis C virus genotype 1

The antiviral activity, resistance profile, pharmacokinetics (PK), safety, and tolerability of BMS-790052, a nonstructural protein 5A (NS5A) replication complex inhibitor, were evaluated in a double-blind, placebo-controlled, sequential panel, multiple ascending dose study. Thirty patients with chronic hepatitis C virus (HCV) genotype 1 infection were randomized to receive a 14-day course of BMS-790052 (1, 10, 30, 60, or 100 mg once daily or 30 mg twice daily) or placebo in a ratio of 4:1. The mean maximum decline from baseline in HCV RNA ranged from 2.8 to 4.1 log(10) IU/mL; the placebo group showed no evidence of antiviral activity. Most patients experienced viral rebound on or before day 7 of treatment with BMS-790052 monotherapy; viral rebound was associated with viral variants that had been previously implicated in resistance development in the in vitro replicon system. The PK profile was supportive of once-daily dosing with median peak plasma concentrations at 1-2 hours postdose and mean terminal half-life of 12-15 hours. Steady state was achieved following 3-4 days of daily dosing. BMS-790052 was well tolerated in all dose groups, with adverse events occurring with a similar frequency in BMS-790052- and placebo-treated groups. There were no clinically relevant changes in vital signs, laboratory, or electrocardiogram parameters. Conclusion: BMS-7590052 is the first NS5A replication complex inhibitor with multiple dose proof-of-concept in clinic. At doses of 1-100 mg daily, BMS-790052 was well tolerated, had a PK profile supportive of once-daily dosing, and produced a rapid and substantial decrease in HCV-RNA levels in patients chronically infected with HCV genotype 1.