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Background: Ciprofloxacin is an antibiotic used in osteoarticular infections owing to its very good bone penetration. Very few pharmacokinetic data are available in this population., Objectives: To investigate oral ciprofloxacin population pharmacokinetics in adult patients treated for osteoarticular infections and propose guidance for more effective dosing., Methods: A retrospective population-pharmacokinetic analysis was performed on 92 consecutive hospitalized patients in the orthopaedic department. Ciprofloxacin plasma samples were obtained on one or two occasions during treatment. Plasma concentration was measured using ultra-performance liquid chromatography system coupled with tandem mass spectrometry. Data analysis was performed using a non-linear mixed-effect approach via Monolix 2019R2., Results: A total of 397 plasma samples were obtained with 11.5% and 41.6% of patients being below the therapeutic target for Gram-negative and staphylococcal infections, respectively. Ciprofloxacin pharmacokinetics were best described by a two-compartment model with a first-order absorption. Ciprofloxacin apparent plasma clearances and volumes of distribution were dependent on patients' fat-free mass according to the allometric rule. Elimination clearance was also positively related to renal function through the modification of diet in renal disease equation (MDRD) and rifampicin co-administration. When patients are co-treated with rifampicin, ciprofloxacin dosage should be increased by 50% to 60%., Conclusions: This study showed that free-fat mass was a better size predictor than total body weight for ciprofloxacin clearance and volumes terms. Moreover, both MDRD and rifampicin status were significant predictors of individual ciprofloxacin clearance. Our study suggests that individual adjustment of ciprofloxacin dose in osteoarticular infections with less-susceptible bacteria might be indicated to reach required efficacy targets., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: With the explosion of anticancer drugs, an emerging concern is the risk for drug-induced sudden death (SD) via ventricular arrhythmias (VA)., Methods and Results: We used the international pharmacovigilance database VigiBase (n = 18 441 659 reports) to compare drug-induced long QT (diLQT, n = 18 123) and VA (n = 29 193) including torsade de pointes (TdP, n = 8163) reporting for 663 anticancer drugs vs. all other drugs until 01/01/2019. The analysis used the 95% lower-end credibility interval of the information component (IC025), an indicator for disproportionate Bayesian reporting; significant when IC025 >0. There were 2301 reports (13.8% fatal) for 40 anticancer drugs significantly associated with diLQT (with 27 also associated with VA or SD) and 9 drugs associated with VA without diLQT. Half of these (46.9%, 23/49) were associated with SD. Most (41%, 20/49) were kinase inhibitors, 8% (4/49) were hormonal therapies, 6% (3/49) were immunotherapies, 24% (12/49) were cytotoxics, and 20% (10/49) were miscellaneous. In VigiBase, reports of diLQT, TdP, or VA increased from 580 in the period 1967-83 to 15 070 in 2014-18 with the proportion related to anticancer drugs increasing from 0.9% (5/580) to 14.0% (2115/15 070) (P < 0.0001). Concordance between these VigiBase signals and data concerning diLQT and VA/TdP identified in CredibleMeds or US Food and Drug Administration (FDA) labels was moderate (κ = 0.47 and 0.40, P < 0.0001). Twenty-three drugs represent new signals, while 24 flagged by CredibleMeds or FDA had no signal in VigiBase. A three-level SD risk stratification relying on isolated long QT (low risk), associated with VA without SD (moderate risk), and VA with SD (high risk) is proposed., Conclusion: This list of liable anticancer drugs may prove useful for physicians and regulatory authorities to re-evaluate cardiac monitoring requirements., Clinical Trial Registration: NCT03530215., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Aims: Congenital long-QT syndromes (cLQTS) or drug-induced long-QT syndromes (diLQTS) can cause torsade de pointes (TdP), a life-threatening ventricular arrhythmia. The current strategy for the identification of drugs at the high risk of TdP relies on measuring the QT interval corrected for heart rate (QTc) on the electrocardiogram (ECG). However, QTc has a low positive predictive value., Methods and Results: We used convolutional neural network (CNN) models to quantify ECG alterations induced by sotalol, an IKr blocker associated with TdP, aiming to provide new tools (CNN models) to enhance the prediction of drug-induced TdP (diTdP) and diagnosis of cLQTS. Tested CNN models used single or multiple 10-s recordings/patient using 8 leads or single leads in various cohorts: 1029 healthy subjects before and after sotalol intake (n = 14 135 ECGs); 487 cLQTS patients (n = 1083 ECGs: 560 type 1, 456 type 2, 67 type 3); and 48 patients with diTdP (n = 1105 ECGs, with 147 obtained within 48 h of a diTdP episode). CNN models outperformed models using QTc to identify exposure to sotalol [area under the receiver operating characteristic curve (ROC-AUC) = 0.98 vs. 0.72, P ≤ 0.001]. CNN models had higher ROC-AUC using multiple vs. single 10-s ECG (P ≤ 0.001). Performances were comparable for 8-lead vs. single-lead models. CNN models predicting sotalol exposure also accurately detected the presence and type of cLQTS vs. healthy controls, particularly for cLQT2 (AUC-ROC = 0.9) and were greatest shortly after a diTdP event and declining over time (P ≤ 0.001), after controlling for QTc and intake of culprit drugs. ECG segment analysis identified the J-Tpeak interval as the best discriminator of sotalol intake., Conclusion: CNN models applied to ECGs outperform QTc measurements to identify exposure to drugs altering the QT interval, congenital LQTS, and are greatest shortly after a diTdP episode., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Aims: The explosion of novel anticancer therapies has meant emergence of cardiotoxicity signals including atrial fibrillation (AF). Reliable data concerning the liability of anticancer drugs in inducing AF are scarce. Using the World Health Organization individual case safety report database, VigiBase®, we aimed to determine the association between anticancer drugs and AF., Methods and Results: A disproportionality analysis evaluating the multivariable-adjusted reporting odds ratios for AF with their 99.97% confidence intervals was performed for 176 U.S. Food and Drug Administration (FDA)- or European Medicines Agency (EMA)-labelled anticancer drugs in VigiBase®, followed by a descriptive analysis of AF cases for the anticancer drugs identified in VigiBase®. ClinicalTrial registration number: NCT03530215. A total of 11 757 AF cases associated with at least one anticancer drug were identified in VigiBase® of which 95.8% were deemed serious. Nineteen anticancer drugs were significantly associated with AF of which 14 (74%) are used in haematologic malignancies and 9 (45%) represented new AF associations not previously confirmed in literature including immunomodulating agents (lenalidomide, pomalidomide), several kinase inhibitors (nilotinib, ponatinib, midostaurin), antimetabolites (azacytidine, clofarabine), docetaxel (taxane), and obinutuzumab, an anti-CD20 monoclonal antibody., Conclusion: Although cancer malignancy itself may generate AF, we identified 19 anticancer drugs significantly associated with a significant increase in AF over-reporting. This pharmacovigilance study provides evidence that anticancer drugs themselves could represent independent risk factors for AF development. Dedicated prospective clinical trials are now required to confirm these 19 associations. This list of suspected anticancer drugs should be known by physicians when confronted to AF in cancer patients, particularly in case of haematologic malignancies., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: HLA-G is an immune checkpoint molecule, naturally expressed during pregnancy, playing a critical role in the tolerance of the fetal semi-allograft from the maternal immune system. While HLA-G expression levels are associated with progesterone, the influence of other hormones is still unclear. Congenital adrenal hyperplasia (CAH) represents an adequate model to study the hormonal influence on biomarkers as it leads to impaired cortisol biosynthesis and increased progesterone and androgens production due to 21-hydroxylase enzyme deficiency., Methods: In a cross-sectional study of CAH patients matched on sex and age with healthy control, the association between circulating levels of soluble HLA-G and hormones was assessed by use of non-parametric analyses tests. Multivariable linear regressions were performed on normalized data., Results: Overall, 83 CAH patients and 69 healthy controls were included. Among CAH patients, all were under glucocorticoid and 52 (62.6%) were under mineralocorticoid supplementation. Compared to controls, CAH patients had increased HLA-G levels (15 vs 8 ng/mL, P = 0.02). In controls, HLA-G level was independently associated with progesterone and estradiol (β = 0.44 (0.35-1.27) and -0.44 (-0.94, -0.26) respectively, both P values = 0.001). In CAH patients, HLA-G level was independently associated with mineralocorticoid supplementation dosage (β = 0.25 (0.04-0.41), P = 0.001) and estradiol (β = -0.22 (-0.57, -0.02), P < 0.001)., Conclusion: CAH patients had higher HLA-G levels than healthy controls. HLA-G level was positively associated with progesterone and corticosteroid supplementation, and negatively with estradiol. The association between mineralocorticoid, renin and HLA-G levels may suggest a role of the renin-angiotensin system in the expression of soluble HLA-G.

Context: QT interval duration is longer in women than in men. Sex steroid hormones have inconsistently been suggested to explain this difference. The implication of gonadotropins has never been studied., Objective: We report here the combined influence of sex steroid hormones and gonadotropins on QT interval duration in healthy subjects and patients with congenital adrenal hyperplasia (CAH) as a model of T and progesterone overexpression., Design and Patients: Eighty-four CAH patients (58 women) and 84 healthy subjects matched and paired for sex and age were prospectively included. Circulating concentrations of 17-OH-progesterone, progesterone, T, estradiol, FSH, and LH were measured concomitantly to the recording of a digitized electrocardiogram., Results: QTcFridericia (QTcF) was shorter in women with CAH than in control women (404 ± 2 vs 413 ± 2.1 milliseconds; P ≤ .001). 17-OH-progesterone, progesterone, the progesterone/estradiol ratio, and total T were higher in women with CAH than in female controls (P < .05), whereas FSH was lower (P ≤ .05). According to multivariable analysis in all women, the progesterone/estradiol ratio (β = -0.33) and FSH levels (β = 0.34) were related to QTcF (r = 0.5; P < .0001), with no influence of CAH or healthy status. QTcF was not different between CAH (404.7 ± 3.7 milliseconds) or healthy men (396 ± 2.8 milliseconds). For men, QTcF (r = 0.48; P < .01) was negatively related to free T (β = -0.29) and positively to FSH levels (β = 0.34)., Conclusion: Cardiac repolarization is influenced by complex interactions between sex steroid hormones and gonadotropins, depending on gender. Our results indicate that the progesterone/estradiol ratio in women, T in men, and FSH in both genders are major determinants of ventricular repolarization with opposite effects on QTc interval.

Aims: Natural history and prognosis of acute coronary syndrome (ACS) in HIV-infected patients remain to be determined. We sought to compare coronary risk factors, angiographic features, acute results of percutaneous coronary intervention, in-hospital outcomes, and pre-specified 1 year prognosis of HIV-infected and HIV-uninfected patients with ACS., Methods and Results: HIV-infected and HIV-uninfected patients with a first episode of ACS were matched for age (±5 years), sex, and type of ACS. The primary endpoint was the rate of major adverse cardiac and cerebral events (MACCE), comprising cardiac death, recurrent ACS, recurrent coronary revascularization, and stroke. Overall, 103 HIV-infected and 195 HIV-uninfected patients were enrolled (mean age 49.0 ± 9.4 years, 94% men). Coronary risk factors were well balanced, but HIV-infected patients more frequently used illicit drugs (23 vs. 6%, P = 0.001) and had higher triglyceride concentrations (246 ± 189 vs. 170 ± 139 mg/dL, P = 0.002) compared with HIV-uninfected patients. Angiographic features of coronary artery disease were similar (multivessel disease 41 vs. 39%, P = 0.96; ACC/AHA type culprit lesion ≥B2, both 77%, P = 0.83). At 1 year, the rate of occurrence of first MACCE did not differ between groups [hazard ratio (HR) 1.4, 95% CI 0.6-3.0]. Recurrent ACS was more frequent in HIV-infected patients (HR 6.5, 95% CI 1.7-23.9) with no difference in the rate of clinical restenosis., Conclusions: These results suggest that the acute management of ACS in HIV-infected patients can routinely be the same as that of HIV-uninfected patients, but that specific secondary prevention measures are needed to alleviate the increased risk of recurrent ACS.

Objective: The antimalarial agents chloroquine (CQ) and hydroxychloroquine (HCQ) are used in long-term treatment of connective tissue diseases (CTDs). A high incidence of heart conduction disorders, including bundle-branch block and incomplete or complete atrioventricular block, has been observed among patients treated with CQ. Since no data were available for HCQ, we studied electrocardiograms (ECGs) in 85 unselected patients with CTD treated with HCQ as the sole antimalarial., Methods: Eighty-five unselected out-patients treated with HCQ for a minimum of 1 yr, and without established cardiac diseases had standard 12-lead ECGs., Results: Two incomplete right bundle-branch blocks and one left bundle-branch block were observed. No atrioventricular block was observed. The mean PR interval was 137 +/- 20 ms (range 99-188). The mean QTc interval was 410 ms (range 349-464). The mean heart rate was 73 beats/min (range 53-102)., Conclusion: PR interval, QTc interval and heart rate were not different from normal values. The rate of heart conduction disorders was similar to what is expected in the general population, and contrasted with prior results in CQ-treated patients. Our results add further evidence on the safety of HCQ compared with CQ.

Aims: Women have a longer QT interval and a greater incidence of torsades de pointes than men. It has been suggested that oestrogens may influence the duration of cardiac repolarization. We thus investigated the influence of oestradiol (E2) on ventricular repolarization within the physiological concentration range of this hormone., Methods and Results: We studied QT interval duration in 21 healthy women aged 18 to 35 years with regular menstrual cycle (mean duration: 29+/-1 days) during two periods associated with a wide range of oestradiol plasma levels: low level during menses (105+/-34 pmol/l) and high level during the pre-ovulatory phase (750+/-277 pmol/l). We used heart rate-independent assessment of QT. QT-RR pairs were measured over a wide range of RR intervals obtained at rest and during a sub-maximal exercise test. Using a monoexponential nonlinear curve fitting for the QT-RR relation, the QT(1000 ms)during nadir and peak oestradiol periods was then determined for each subject. QT(1000 ms)interval was not different between both study periods: 382.1+/-18.4 ms at peak versus 382.2+/-19.4 ms at nadir oestradiol level (P=0.98)., Conclusion: No significant change in QT interval duration was observed within the large range of physiological E2 variations found during the menstrual cycle.

Aims: Whether all patients with congestive heart failure (CHF) need to reach the target dose of beta-blocker to obtain a benefit in terms of survival remains uncertain., Methods and Results: We classified by tertile the 2647 patients enrolled in CIBIS II according to the last tolerated dose: low dose (LD: 1.25, 2.5 or 3.75mg/day, n=434), moderate dose (MD: 5 or 7.5mg/day, n=328) and high dose (HD: 10mg/day, n=565) of bisoprolol or placebo (LD=234, MD=278 and HD=808). In both groups, patients tolerating only low doses were significantly older with more severe New York Heart Association (NYHA) functional class and higher frequency of co-morbidities. Treatment withdrawal was associated with a significant increase of mortality in the bisoprolol group (relative hazard (RH)=2.13, 95% confidence interval (CI)=1.43-3.17, p=0.0002). After adjustment, all-cause mortality was significantly reduced in the bisoprolol group compared to placebo regardless of the dose level considered: LD (RH=0.66, 95% CI=0.48-0.92), MD (RH=0.33, 95% CI=0.21-0.51) or HD (RH=0.59, 95% CI=0.40-0.89)., Conclusions: Bisoprolol reduces mortality in CHF patients at all tolerated dose levels and its withdrawal increases the risk of mortality. Efforts should be made to maintain bisoprolol therapy based on the individual patient's tolerability.

d,l-Sotalol is a racemic drug composed of equimolar amounts of d-(+)-sotalol and l-(-)-sotalol. The l-(-)-enantiomer has both beta-blocking (class II) activity and potassium-channel-blocking (class III) properties. The d-(+)-enantiomer has class III properties similar to those of l-sotalol. However, the affinity of d-sotalol for beta-adrenergic receptors is 30 to 60 times lower than the affinity of l-sotalol. The pharmacokinetics of d,l-sotalol are linear. Following oral administration, absorption and bioavailability are almost complete; apparent elimination half-life ranges from 7 to 18 hours. More than 80% of racemic sotalol elimination occurs by renal excretion of unchanged drug. Sotalol is not metabolized, nor is it significantly bound to plasma proteins. Thus, steady-state plasma concentration is reached within 3 days of treatment onset in patients without renal insufficiency. Dosage of sotalol should be adjusted to creatinine clearance. The pharmacokinetic profile of d-sotalol is similar to that of the racemate. Plasma concentrations of racemic sotalol associated with beta-adrenergic blockade are similar to those associated with its class III actions. QT interval prolongation with d,l-sotalol is dose- and concentration-dependent and decreases at rapid heart rates. Also, QT interval prolongation at a given plasma concentration during repeated dosing tends to be less pronounced than QT prolongation at the same plasma concentration during single dosing. The class III actions of d-sotalol in the sinus node are associated with slowing of sinus heart rate, whereas additional beta blockade contributes to the decrease in heart rate observed with l- or d,l sotalol.(ABSTRACT TRUNCATED AT 250 WORDS)

The arrhythmogenic effects of exercise tests are often unpredictable, sometimes paradoxical, and usually poorly reproducible. This explains why they are rather neglected by rhythmologists in studying the mechanisms of arrhythmias and the effects of antiarrhythmic drugs and why their prognostic value is a matter of controversy. At the same time the induced, supposedly ischaemia-related arrhythmias are usually not prevented by revascularization procedures. All these discrepancies are probably explained by the complex interactions between the time-limited stimulation of the sympathetic drive and the arrhythmia mechanisms. During the exercise test the sympathetic drive is increased via the neurogenic and humoral routes, and the post-exercise period is characterized by a vagally-induced deceleration of the heart rate which intervenes in the setting of a persistent high level of sympathetic activity. The arrhythmia components formed by potential triggers (isolated premature beats) and substrates (repetitive activity) do not react in the same way to those different phases. Extrasystoles are mainly rate-dependent, so that they often tend to disappear as the sinus rate accelerates. The repetitive ventricular activity directly depends on the sympathetic drive, but necessitates the presence of the trigger to become manifest. Conceivably, many different situations may result from the complex interplay between these distinct parameters, so that the apparent clinical effect of exercise may be either arrhythmogenic or antiarrhythmic in apparently identical diseases, or even in the same patients.

Drug interactions involving macrolides have been mainly reported in subjects receiving troleandomycin and in a few receiving erythromycin derivatives. In rats and in humans, troleandomycin, erythromycin and erythromycin derivatives induce microsomal enzymes; the induced isozymes of cytochrome P-450 have a high activity for these macrolides but a poor activity with several other substrates. These isozymes actively demethylate and oxidize these macrolides into nitrosoalkanes which form stable, inactive complexes with the iron of cytochrome P-450. Eventually, the oxidative metabolism of other drugs may be decreased. These effects are marked after administration of troleandomycin, moderate after administration of erythromycin derivatives and absent (or negligible) after administration of spiramycin, josamycin or midecamycin. A second adverse effect of the administration of troleandomycin or erythromycin derivatives is the possible occurrence of hepatitis. Mild hepatic dysfunction is fairly frequent and may be toxic in type. In contrast, jaundice is common, is frequently associated with hypersensitivity, and promptly recurs when the drug is readministered. Troleandomycin and erythromycin derivatives, which form nitrosoalkanes, produce hepatitis, whereas josamycin, midecamycin and spiramycin, which do not form cytochrome P-450-nitrosoalkane complexes, rarely, if ever, produce hepatitis. Nitrosoalkanes are unstable intermediates which react with glutathione but also with cysteine and might covalently bind to the SH-groups of proteins. The following mechanism might be proposed as a hypothetical attempt to link up these various observations. The macrolide (or its reactive metabolite) may have discrete toxicity; in several subjects, this may produce minor liver lesions and a mildly raised aminotransferase activity. Necrosis of a few hepatocytes may release into the circulation plasma membrane proteins altered by the covalent binding of metabolites. Such modified liver antigens may be recognized as foreign and may trigger, in an exceptional subject, an immunoallergic type of clinical hepatitis.