Sexual side effects of serotonergic antidepressants: mediated by inhibition of serotonin on central dopamine release?

Antidepressant-induced sexual dysfunction adversely affects the quality of life of antidepressant users and reduces compliance with treatment. Animal models provide an instructive approach for examining potential sexual side effects of novel drugs. This review discusses the stability and reproducibility of our standardized test procedure that assesses the acute, subchronic and chronic effects of psychoactive compounds in a 30 minute mating test. In addition, we present an overview of the effects of several different (putative) antidepressants on male rat sexual behavior, as tested in our standardized test procedure. By comparing the effects of these mechanistically distinct antidepressants (paroxetine, venlafaxine, bupropion, buspirone, DOV 216,303 and S32006), this review discusses the putative mechanism underlying sexual side effects of antidepressants and their normalization. This review shows that sexual behavior is mainly inhibited by antidepressants that increase serotonin neurotransmission via blockade of serotonin transporters, while those that mainly increase the levels of dopamine and noradrenaline are devoid of sexual side effects. Those sexual disturbances cannot be normalized by simultaneously increasing noradrenaline neurotransmission, but are normalized by increasing both noradrenaline and dopamine neurotransmission. Therefore, it is hypothesized that the sexual side effects of selective serotonin reuptake inhibitors may be mediated by their inhibitory effects on dopamine signaling in sex brain circuits. Clinical development of novel antidepressants should therefore focus on compounds that simultaneously increase both serotonin and dopamine signaling.

Effects of probucol, a typical hERG expression inhibitor, on in vivo QT interval prolongation in conscious dogs.

The cholesterol-lowering drug, probucol, is known to induce QT interval prolongation and torsades de pointes in patients. Recent in vitro studies have indicated that probucol reduces hERG expression in the plasma membrane and does not directly block human ether-a-go-go-related gene (hERG) channels. The present study was performed to investigate the effects of probucol on in vivo QT interval prolongation. Epicardial electrocardiograms were recorded in conscious dogs given oral single or repeated (7 days) doses of probucol (100mg/kg), and in combination with moxifloxacin (20mg/kg). QTc intervals were analyzed by a probabilistic method with individual rate collection formulae. Values of change in QTc (QTc) interval and its integration from 1 to 21 h (AUC1-21h) were calculated to evaluate drug-induced QT prolongation. A single dose of probucol slightly but significantly increased the AUC1-21h QTc interval on days 2 and 3. The QT prolongation was markedly augmented by repeated doses of probucol in a time-dependent manner, despite the lack of increase in plasma concentration. The combination of probucol and moxifloxacin produced additive effects on QT interval prolongation. These results suggest that long-term exposure to the hERG expression inhibitor, probucol, is required to evaluate its maximal effects on in vivo QT interval prolongation. A combination of direct and indirect hERG inhibitors may produce simple additive effects on QT interval prolongation.

[Fluoroquinolone associated myasthenia gravis exacerbation: clinical analysis of 9 cases].

OBJECTIVE: To explore the characteristics of acute exacerbations of myasthenia gravis after fluoroquinolone exposure. METHODS: Gender, age, prior type, absolute score, concurrent disease, precipitated disease, use of antibiotic, onset/symptom/degree of exacerbation, therapeutic measures and prognosis at Month 1 were retrospectively analyzed for 9 patients after fluoroquinolone systemic exposure. RESULTS: Ciprofloxacin (n = 4), levofloxacin (n = 1) and moxifloxacin (n = 4) exposure resulted in myasthenia gravis exacerbation. Myasthenia gravis exacerbations developed at 15 minutes to 4 days post-exposure. And the clinical scores of quantitative myasthenia gravis (QMG) increased by an average of 10. The main syndromes included dyspnea, diplopia, ptosis and dysphagia. All patients improved upon the withdrawal of fluoroquinolone in conjunctions with other interventions. CONCLUSION: Fluoroquinolone exposure may result in myasthenia gravis exacerbations in patients with underlying diseases. Healthcare professionals should be aware of this serious drug-disease association.

Efficacy and safety of prophylactic intracameral moxifloxacin injection in Japan.

PURPOSE: To report endophthalmitis rates after cataract surgery and the incidence of complications after intracameral moxifloxacin injection. SETTING: Nineteen clinics in Japanese institutions. DESIGN: Retrospective survey cohort study. METHODS: The number of surgeries and endophthalmitis cases in the past 4 years before and after the introduction of intracameral moxifloxacin was evaluated. The survey was performed by mail or interview in February 2013. RESULTS: All institutions used total-replacement administration rather than small-volume injection. At 3 institutions, 50 to 100 µg/mL moxifloxacin; at 9 institutions, 100 to 300 µg/mL moxifloxacin; and at 7 institutions, 500 µg/mL moxifloxacin was administered. The highest concentration (500 µg/mL) was administered in 14,124 cases. Endophthalmitis cases occurred 1 month or sooner postoperatively in 8 of 15,958 cases (ie, 1 in 1955) without intracameral moxifloxacin administration and in 3 of 18,794 cases (ie, 1 in 6265) with intracameral moxifloxacin administration. CONCLUSIONS: Intracameral moxifloxacin (50 to 500 µg/mL) administration decreased the risk for endophthalmitis by 3-fold. In more than 18,000 cases, moxifloxacin administration of 500 µg/mL or less did not result in severe complications, such as toxic anterior segment syndrome or corneal endothelial cell loss.

Electrocardiographic safety of cangrelor, a new intravenous antiplatelet agent: a randomized, double-blind, placebo- and moxifloxacin-controlled thorough QT study.

Cangrelor is an intravenous P2Y12 inhibitor under investigation as an antiplatelet drug in the setting of acute coronary syndromes. To determine the electrophysiologic safety of parenteral cangrelor, cardiac repolarization effects were measured in 67 healthy volunteers (aged 18-45 years) in a randomized crossover design, including 4 treatment sequences of therapeutic cangrelor, supratherapeutic cangrelor, placebo, and moxifloxacin (positive control). Triplicate electrocardiogram measurements and pharmacokinetic samples were collected at baseline and 9 time points postdose on day 1. For both cangrelor and moxifloxacin, time-matched, placebo-adjusted change in QT from baseline was evaluated using an individual (QTcI) heart rate correction. After cangrelor dosing, change in QTcI was <5 ms at all times points and all corresponding upper 2-sided 90% confidence intervals (CIs) were <10 ms. Although moxifloxacin failed to show a lower CI >5 ms, expected time trends and lower CI >4.0 ms demonstrate assay sensitivity. QTcI was not affected by plasma concentrations of cangrelor metabolites, and cangrelor had no other adverse effects on electrocardiographic parameters. Clinically, cangrelor exposure was well tolerated. Thus, this thorough QT study demonstrated that therapeutic and supratherapeutic cangrelor doses do not adversely affect cardiac repolarization in normal volunteers (clinicaltrials.gov; identifier NCT00699504).

Preladenant, a selective adenosine A2A receptor antagonist, is not associated with QT/QTc prolongation.

PURPOSE: Preladenant is an orally administered adenosine2A (A2A) receptor antagonist in phase III development for Parkinson's disease treatment. This thorough QT/QTc study evaluated its potential effects on cardiac repolarization. METHODS: This was a randomized, double-blind, positive- and placebo-controlled, four-period crossover study performed under steady-state exposure of clinical and supratherapeutic doses of preladenant (10 mg BID and 100 mg BID, respectively, for 5 days), moxifloxacin (400 mg on day 5), or placebo in 60 healthy adult volunteers. The potential effect on QTcF was measured by the largest upper bound of 95 % one-sided CIs for the mean changes from time-matched baseline ECG recordings compared with placebo. Plasma preladenant concentrations were also determined on day 5. RESULTS: The QTcF difference for moxifloxacin compared with placebo exceeded 5 ms from 1 to 12 h postdose, establishing assay sensitivity. The QTcF interval was similar between the preladenant and placebo treatment groups: the upper bound of the 95 % one-sided CI for the mean difference in QTcF between preladenant and placebo was less than 10 ms at all time points for the supratherapeutic treatment group (1.3 to 5.7 ms, mean difference: -1.3 to 2.7 ms) and the therapeutic treatment group (0.4 to 4.3 ms, mean difference: -2.1 to 1.5 ms), substantially below the threshold of regulatory concern. The supratherapeutic dose (100 mg BID) provided a Cmax margin of 6.1-fold and AUC margin of 6.9-fold, respectively, compared with 10 mg BID. CONCLUSIONS: At clinical and supratherapeutic doses, preladenant is not associated with QTc prolongation.

Effects of injectable HPßCD-diclofenac on the human delayed rectifier potassium channel current in vitro and on proarrhythmic QTc in vivo.

BACKGROUND: Novel formulations and administration routes of established drugs may result in higher maximum concentrations or total exposures and potentially cause previously unrecognized adverse events. OBJECTIVE: This study evaluated the proarrhythmic potential of hydroxypropyl-ß-cyclodextrin (HPßCD)-diclofenac, a novel injectable diclofenac formulation solubilized with hydroxypropyl-ß-cyclodextrin (HPßCD), on ventricular electrical conduction in preclinical and clinical models. METHODS: We assessed the effects of diclofenac, HPßCD, and HPßCD-diclofenac on the human delayed rectifier potassium channel (IKr) using human embryonic kidney (HEK) 293 cells transfected with a human ether-à-go-go-related gene (hERG) using whole-cell patch-clamp. In a single-dose, active- and placebo-controlled, 4-period crossover, thorough QT in vivo study, 70 healthy volunteers (mean age, 23.3 years; range, 18-49 years; 55.75% male) received HPßCD-diclofenac at 37.5- and 75-mg doses, inactive vehicle (placebo), and an active control (moxifloxacin). RESULTS: In vitro, diclofenac produced no statistically significant effect on IKr. Significant, non-dose-dependent effects were observed in the presence of HPßCD or HPßCD-diclofenac of similar magnitude across the 300-fold dose range of concentrations tested, suggesting an artifact due to the detergent effect of HPßCD in this in vitro model. In vivo, neither HPßCD-diclofenac dose resulted in QTc prolongation ≥2 ms (≥5 ms is the threshold of clinical concern). No correlation was evident between changes in QTc and plasma concentrations of diclofenac or HPßCD. Confirming study sensitivity, moxifloxacin produced a mean QTc prolongation >10 ms. CONCLUSIONS: The findings from the present study suggest that HPßCD-diclofenac does not have a dose-dependent effect in the in vitro hERG assay system and does not produce proarrhythmic QTc prolongation in vivo. ClinicalTrials.gov identifier: NCT01812538.

Oral antibiotics for fever in low-risk neutropenic patients with cancer: a double-blind, randomized, multicenter trial comparing single daily moxifloxacin with twice daily ciprofloxacin plus amoxicillin/clavulanic acid combination therapy--EORTC infectious diseases group trial XV.

PURPOSE: This double-blind, multicenter trial compared the efficacy and safety of a single daily oral dose of moxifloxacin with oral combination therapy in low-risk febrile neutropenic patients with cancer. PATIENTS AND METHODS: Inclusion criteria were cancer, febrile neutropenia, low risk of complications as predicted by a Multinational Association for Supportive Care in Cancer (MASCC) score > 20, ability to swallow, and ≤ one single intravenous dose of empiric antibiotic therapy before study drug treatment initiation. Early discharge was encouraged when a set of predefined criteria was met. Patients received either moxifloxacin (400 mg once daily) monotherapy or oral ciprofloxacin (750 mg twice daily) plus amoxicillin/clavulanic acid (1,000 mg twice daily). The trial was designed to show equivalence of the two drug regimens in terms of therapy success, defined as defervescence and improvement in clinical status during study drug treatment (< 10% difference). RESULTS: Among the 333 patients evaluated in an intention-to-treat analysis, therapy success was observed in 80% of the patients administered moxifloxacin and in 82% of the patients administered combination therapy (95% CI for the difference, -10% to 8%, consistent with equivalence). Minor differences in tolerability, safety, and reasons for failure were observed. More than 50% of the patients in the two arms were discharged on protocol therapy, with 5% readmissions among those in either arm. Survival was similar (99%) in both arms. CONCLUSION: Monotherapy with once daily oral moxifloxacin is efficacious and safe in low-risk febrile neutropenic patients identified with the help of the MASCC scoring system, discharged early, and observed as outpatients.

Exenatide at therapeutic and supratherapeutic concentrations does not prolong the QTc interval in healthy subjects.

AIMS: Exenatide has been demonstrated to improve glycaemic control in patients with type 2 diabetes, with no effect on heart rate corrected QT (QTc ) at therapeutic concentrations. This randomized, placebo- and positive-controlled, crossover, thorough QT study evaluated the effects of therapeutic and supratherapeutic exenatide concentrations on QTc . METHODS: Intravenous infusion was employed to achieve steady-state supratherapeutic concentrations in healthy subjects within a reasonable duration (i.e. days). Subjects received exenatide, placebo and moxifloxacin, with ECGs recorded pre-therapy and during treatment. Intravenous exenatide was expected to increase heart rate to a greater extent than subcutaneous twice daily or once weekly formulations. To assure proper heart rate correction, a wide range of baseline heart rates was assessed and prospectively defined methodology was applied to determine the optimal QT correction. RESULTS: Targeted steady-state plasma exenatide concentrations were exceeded (geometric mean ± SEM 253 ± 8.5 pg ml(-1) , 399 ± 11.9 pg ml(-1) and 627 ± 21.2 pg ml(-1) ). QTc P, a population-based method, was identified as the most appropriate heart rate correction and was prespecified for primary analysis. The upper bound of the two-sided 90% confidence interval for placebo-corrected, baseline-adjusted QTc P (ΔΔQTc P) was <10 ms at all time points and exenatide concentrations. The mean of three measures assessed at the highest steady-state plasma exenatide concentration of ∼500 pg ml(-1) (ΔΔQTc P(avg) ) was -1.13 [-2.11, -0.15). No correlation was observed between ΔΔQTc P and exenatide concentration. Assay sensitivity was confirmed with moxifloxacin. CONCLUSIONS: These results demonstrated that exenatide, at supratherapeutic concentrations, does not prolong QTc and provide an example of methodology for QT assessment of drugs with an inherent heart rate effect.

Randomised clinical trial of moxifloxacin versus ertapenem in complicated intra-abdominal infections: results of the PROMISE study.

Antibiotic therapy for complicated intra-abdominal infections (cIAIs) should provide broad-spectrum coverage both Gram-positive and Gram-negative microorganisms. The PROMISE study compared the clinical and bacteriological efficacy and safety of moxifloxacin versus ertapenem for the treatment of cIAIs. This randomised, prospective, double-dummy, double-blind, multicentre trial was designed as a non-inferiority study. The safety and efficacy of 5-14 days of daily intravenous moxifloxacin (400mg) or ertapenem (1g) were compared in patients with cIAIs requiring surgery and parenteral antibiotic therapy. The primary and secondary endpoints included clinical and bacteriological responses at 21-28 days after the end of treatment (TOC), respectively. Of 830 enrolled patients, 699 were efficacy valid. Moxifloxacin was non-inferior to ertapenem regarding clinical success [89.5% (315/352) versus 93.4% (324/347); 95% confidence interval (CI) -7.9%, 0.4%]. There were no significant differences between groups for any of the primary causes or types of cIAI regarding clinical response. Bacteriological success was achieved in 86.5% (257/297) of moxifloxacin-treated patients and 90.2% (249/276) of ertapenem-treated patients (95% CI -9.0%, 1.5%). There were no major differences between groups regarding the frequency or types of organisms eradicated. The incidence of adverse events (AEs) was higher with moxifloxacin than ertapenem (P=0.039), however a similar number of drug-related AEs was seen in each group (P=1.000). Wound infections, nausea and increased lipase were the most commonly reported AEs with both agents. The results show that moxifloxacin is a valuable treatment option for a range of community-acquired cIAIs with mild-to-moderate severity.

Safety of prophylactic intracameral moxifloxacin use in cataract surgery.

PURPOSE: To evaluate posterior and anterior segment safety of an intracameral injection of moxifloxacin as prophylaxis for endophthalmitis in cataract surgery. METHODS: In this study, 60 eyes of 60 patients were included. In the first group, only 5% povidine iodine drop was administrated to 30 patients at the end of the surgery, while 30 patients were treated with intracameral moxifloxacin (250 µg/0.050 mL) additionally in the second group. Visual acuity, intraocular pressure, corneal pachymetry, corneal clarity, and edema and retinal thickness were evaluated preoperatively and for day 3 postoperatively for each group and were compared. RESULTS: Mean preoperative visual acuity was 0.7 ± 0.9 LogMAR in both groups 1 and 2, while mean postoperative visual acuity was 0.05 ± 1.00 LogMAR in both groups. Preoperative and postoperative intraocular pressure averaged 13.2 ± 2.0 and 13.2 ± 2.1 mmHg, respectively, in the first group, while preoperative and postoperative intraocular pressure was 14.9 ± 2.1 and 14.3 ± 2.0, respectively, in the second group. Preoperative and postoperative visual acuity changes and intraocular pressure changes were not significantly different between 2 groups. There was no single case of corneal edema. In the first group, preoperative pachymetry was 523 ± 44 and postoperative pachmetry was 536 ± 45 µm, while in the second group preoperative pachymetry was 527 ± 43 and postoperative pachymetry was 543 ± 42 µm. Preoperative and postoperative pachymetry changes were not significantly different between 2 groups. Mean preoperative macular thickness in the first group was 188 ± 7.73 µm, while it was measured as 189 ± 7.75 µm postoperatively. In the second group, mean preoperative macular thickness was 188 ± 8.89 µm, while it was 189 ± 9.61 µm postoperatively. Preoperative and postoperative optical coherence tomography (OCT) measure changes were not significantly different between the 2 groups. No study-related adverse events were noted. CONCLUSION: There was no increased safety risk associated with a 250 µm/0.050 mL intracameral injection of moxifloxacin, which appears to be safe in the prophylaxis of endophthalmitis after cataract surgery.

Midostaurin does not prolong cardiac repolarization defined in a thorough electrocardiogram trial in healthy volunteers.

PURPOSE: Midostaurin (PKC412) is a multitargeted tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 receptor (FLT3), c-KIT, and other receptors. Midostaurin is active in patients with acute myeloid leukemia and systemic mastocytosis. Although no substantive risk for cardiac abnormalities has been observed with midostaurin in clinical studies thus far, some TKIs have been shown to affect cardiac repolarization. Here we evaluated midostaurin's effect on cardiac repolarization. METHODS: This phase I study evaluated the effect of midostaurin (75 mg twice daily for 2 days; 75 mg once on day 3) on the heart rate-corrected QT (QTc) interval in a parallel design with active (moxifloxacin) and placebo control arms in healthy volunteers. RESULTS: The maximum mean QTc change from baseline corrected using Fridericia's correction (QTcF) for midostaurin compared with placebo was 0.7 ms at 24 h post dose on day 3. The highest upper bound of the 1-sided 95% CI was 4.7 ms, which excluded 10 ms, demonstrating a lack of QTcF prolongation effect. Assay sensitivity was demonstrated by modeling the moxifloxacin plasma concentration versus QTcF change from baseline, which showed a clear positive increase in QTcF with increasing moxifloxacin plasma concentrations, as expected based on previous studies. In the 4-day evaluation period, a minority of participants (34.6%) experienced an adverse event; 97.0% were grade 1. No grade 3 or 4 adverse events were reported. CONCLUSION: Midostaurin demonstrated a good safety profile in healthy volunteers, with no prolonged cardiac repolarization or other changes on the electrocardiogram.

[Maculo-papular exanthem with acute renal failure. Drug-induced hypersensitivity syndrome]. / Makulopapulöses Exanthem mit akuter Niereninsuffizienz. Arzneimittelinduziertes Hypersensitivitätssyndrom.

Acute renal failure caused by interstitial nephritis as part of a drug hypersensitivity syndrome constitutes a rare, but potentially life-threatening adverse drug reaction. We describe a patient with a mild maculo-papular rash accompanied by eosinophilia after prolonged treatment with meropenem, vancomycin, and moxifloxacin. Subsequently, a rapidly progressing renal failure developed which dominated the clinical picture. Upon cessation of all suspected drugs and therapy with high-dose steroids for 6 weeks, the renal function slowly returned to normal.

Efficacy and safety of moxifloxacin as antibacterial prophylaxis for patients receiving autologous haematopoietic stem cell transplantation: a randomised trial.

Patients receiving high-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) are at high risk of infections, especially bacteraemia. A prospective, double-blind, randomised, placebo-controlled, single-centre, pilot study was performed on oral moxifloxacin 400mg versus placebo for preventing bacteraemia in PBSCT recipients. Patients received moxifloxacin or placebo for the duration of neutropenia or until emergence of fever or other infections necessitating intravenous antibiotic treatment. Of 68 patients included in the trial, 2 were excluded from the trial before taking their first dose. The remaining 66 patients were eligible for evaluation in the intention-to-treat analysis set. Neutropenia with an absolute neutrophil count of <500cells/µL developed in 30 moxifloxacin-treated patients (88.2%) and 21 patients in the placebo group (65.6%) (P<0.03). Nine patients (26.5%) and eight patients (25.0%), respectively, were prematurely discontinued from study treatment. Breakthrough bacteraemia occurred in 3 moxifloxacin-treated patients (8.8%) and 9 patients in the placebo group (28.1%) (P=0.042). The time period until fever was 9.5 days [95% confidence interval (CI) 8.06-10.94 days) and 7.69 days (95% CI 6.51-8.85 days), respectively (P=0.0499). There was no difference in adverse events or toxicities between the groups. Moxifloxacin prevented bacteraemia and shortened febrile episodes in patients receiving autologous PBSCT. No significant increase of adverse events in the moxifloxacin arm was observed, possibly due to the rather small sample size.

Moxifloxacin-Gelrite in situ ophthalmic gelling system against photodynamic therapy for treatment of bacterial corneal inflammation.

In this study, six in situ gelling formulations based on Gelrite were prepared and evaluated for the retained ophthalmic delivery of Moxifloxacin (Mox). The effectiveness of the best developed formula G5 was compared with photodynamic therapy (PDT), the recent expanding approach for the treatment of ophthalmologic disorders after the assessment of optimum photodynamic inactivation parameters that permit efficient pathogens eradication. It was found that, Staphylococcus aureus (S. aureus) (Gram-positive) was more susceptible to effective lethal photosensitization that reaches 93.5% reduction in viable count than Escherichia coli (E. coli) (Gramnegative) of 76.1% using 3 mg/mL Hematoporphyrin (HP), illuminated by 630 nm Light Emitting Diode (LED) at 9 J/cm(2) and incubated for 15 min. Following topical instillation of G5 to rabbits corneas, higher amount of Mox was retained in the aqueous humor up to 24 h with significant 6-fold increase in the C(max) and AUC((0-∞)) compared to vigamox commercial eye drops. After post corneal infection with S. aureus, both approaches were effectively treating the infection without causing ocular irritation or collateral damage to corneal tissue where G5 showed remarkable improvement after four days compared to seven days of PDT treatment.

Moxifloxacin-acetaminophen-warfarin interaction during bacille Calmette-Guerin treatment for bladder cancer.

PURPOSE: The case of a patient receiving long-term anticoagulation with warfarin who had supratherapeutic International Normalized Ratios (INRs) after receiving concomitant acetaminophen and moxifloxacin as prophylaxis with bacille Calmette-Guérin (BCG) therapy for bladder cancer is reported. SUMMARY: An 89-year-old man receiving long-term anticoagulation with warfarin sodium (total weekly dosage of 19 mg) arrived at the anticoagulation clinic for his monthly visit. On the day before this visit, he had received the third of six serial weekly BCG bladder instillations for the treatment of bladder cancer. He did not report that acetaminophen 1000 mg four times daily and one dose of moxifloxacin 400 mg had been prescribed before these instillations. An INR check revealed a value of 6.7. He was instructed to take 2.5 mg of oral phytonadione and to withhold his warfarin dose that night. On the next day, his INR was 3.2. Each time he arrived at the anticoagulation clinic after his BCG therapy, his INR was supratherapeutic, except after his fourth treatment (INR of 2.5), which can be explained by residual effects from the phytonadione he received a week earlier. After completion of his BCG therapy, he was instructed to resume his usual warfarin sodium dosage of 19 mg weekly, and his INR remained in the desired therapeutic range. According to the Drug Interaction Probability Scale, the development of supratherapeutic INRs was probably associated with concomitant acetaminophen and moxifloxacin use. CONCLUSION: An 89-year-old man receiving long-term anticoagulation with warfarin had supratherapeutic INRs after receiving acetaminophen and moxifloxacin as prophylaxis during BCG therapy for bladder cancer.

Torticollis in mice intravenously infected with Mycobacterium tuberculosis.

Female BALB/cAnNCrl (n = 170; age, 6 to 9 wk) mice were infected by intravenous inoculation of 5 × 10(6) cfu Mycobacterium tuberculosis strain Erdman (ATCC 35801). Between day 52 and 5 mo after infection, 10 of the 170 mice infected according to this protocol developed torticollis, including mice in treatment groups that received combination antibiotic therapy of rifampin-pyrazinamide or moxifloxacin-rifampin-pyrazinamide. Torticollis did not develop in mice receiving isoniazid- rifampin-pyrazinamide therapy, nor was it present in the cohort of aerogenically infected mice. Affected mice were euthanized, and complete necropsy evaluation was performed on 4 mice. Gross necropsy evaluation revealed typical tuberculosis lesions in lungs of infected mice. Histologic evaluation of tissues revealed granulomatous otitis media with intralesional acid-fast bacilli consistent with Mycobacterium tuberculosis. These cases represent an unusual finding specific to the intravenous mouse model of Mycobacterium tuberculosis and may represent a model of a similar condition in humans that is known as tuberculous otitis media.

T-wave morphology abnormalities in benign, potent, and arrhythmogenic I(kr) inhibition.

BACKGROUND: There is a consensus on the limited value of the QTc interval prolongation as a surrogate marker of drug cardiotoxicity and as a risk stratifier in inherited long QT syndrome (LQTS) patients. OBJECTIVE: We investigated the interest of repolarization morphology in the acquired and the inherited LQTS. METHODS: We analyzed 2 retrospective electrocardiographic (ECG) datasets from healthy on/off moxifloxacin and from genotyped KCNH2 patients. We measured QT, RR, and T-peak to T-end intervals, early repolarization duration (ERD) and late repolarization duration, T-roundness, T-amplitude, left (αL) and right slopes of T-waves. We designed multivariate logistic models to predict the presence of the KCNH2 mutation or moxifloxacin while adjusting for the level of QTc prolongation and the level of heart rate in LQT2 patients. Independent learning and validation sets were used. A list of 4,874 ECGs from 411 healthy individuals, 293 from 143 LQT2 carriers and 150 noncarrier family members were analyzed. RESULTS: In the moxifloxacin model, ERD was associated with the presence of the drug (odds ratio = 1.15 per ms increase, confidence interval 1.04 to 1.26, P = .0001) after adjustment for QTc. The model for the LQT2 revealed that left slope was associated with the presence of the KCNH2 mutation (odds ratio = 0.38 per 1.5 µV/ms decrease, confidence interval 0.23 to 0.64, P = .0002). Only T-roundness complemented QTc in the model investigating cardiac events in LQT2. CONCLUSIONS: These observations demonstrate that the phenotypic expression of KCNH2 mutations and the effect of IKr-inhibitory drug on the surface electrocardiogram are specific. Future research should investigate whether this phenomenon is linked to different level/form of loss functions of Ikr channels, and whether they could result in different arrhythmogenic mechanisms.