Electrocardiogram Changes and Therapeutic Desipramine and 2-Hydroxy-Desipramine Concentrations in Elderly Depressives

1986 ◽  
Vol 148 (6) ◽  
pp. 676-679 ◽  
Author(s):  
S. P. Kutcher ◽  
K. Reid ◽  
J. D. Dubbin ◽  
K. I. Shulman

ECG parameters in elderly depressed in-patients were assessed during routine despramine treatment. Significant changes (prolonged PR and PRS intervals and a decreased QTc interval) were found, related only to steady state concentrations of desipramine's major metabolite—2-hydroxy-desipramine. Potentially clinically significant changes developed in 40% of the patients. All serum drug concentrations were within therapeutic limits. Previous assurances about despiramines's cardiac safety in the elderly may need to be re-evaluated.

2017 ◽  
Vol 89 (12) ◽  
pp. 34-42
Author(s):  
S V Ivanov ◽  
B A Volel ◽  
E A Syrkina ◽  
E S Ternovaya ◽  
D V Troshina ◽  
...  

Aim. To confirm the data available in the literature on the cardiac safety of antidepressants. Subjects and methods. The archival data of 146 case histories were retrospectively analyzed. A study sample consisted of 96 cardiac inpatients regularly taking an antidepressant for more than 3 days during treatment for the underlying cardiovascular disease. The safe use of antidepressants was evaluated in terms of initial electrocardiogram (ECG) QTc interval changes, systolic and diastolic blood pressures (BP) (SBP and DBP), heart rate (HR), and hemorrhagic complications. The data obtained over periods of 3- and 6-8 days were analyzed. Results. The sample showed no clinically significant ECG QTc interval changes when taking regularly antidepressants within 8 days. Analysis of the dynamics of BP and HR in patients receiving antidepressants revealed no statistically significant differences in these indicators before and 3 and 6-8 days after drug administration. No case of hemorrhagic complications was seen in the study group taking antidepressants. Conclusion. The investigation generally confirms the high cardiac safety of new-generation antidepressants within at least the first week of therapy. Noteworthy are the low daily drug dosages (relatively specified in the instructions) that are sufficient for most cardiac patients with depressive disorders and an additional factor for minimizing adverse reactions.


Author(s):  
Sudi Mungkasi

We consider the problem of drug diffusion in the dermal layer of human body. Two existing mathematical models of the drug diffusion problem are recalled. We obtain that the existing models lead to inconsistent equations for the steady state condition. We also obtain that solutions to the existing models are unrealistic for some cases of the unsteady state condition, because negative drug concentrations occur due to the inappropriate assumption of the model. Therefore, in this paper, we propose a modified mathematical model, so that the model is consistent, and the solution is nonnegative for both steady and unsteady state conditions of the drug diffusion problem in the dermal layer of human body. For the steady state condition, the exact solution to the proposed model is given. For unsteady state condition, we use a finite difference method for solving the models numerically, where the discretisation is centred in space and forward in time. Simulation results confirm that our proposed model and method preserve the non-negativity of the solution to the problem, so the solution is more realistic than that of the old model.


Author(s):  
Lori M. Newman ◽  
Martin Kankam ◽  
Aya Nakamura ◽  
Tom Conrad ◽  
John Mueller ◽  
...  

Zoliflodacin is a novel spiropyrimidinetrione antibiotic being developed as single oral dose treatment to address the growing global threat of Neisseria gonorrhoeae . To evaluate the cardiac safety of zoliflodacin, a thorough QT/QTc (TQT) study was performed in healthy subjects. In this randomized, double-blind, placebo-controlled, 4-period crossover study, 72 subjects in a fasted state received a single dose of zoliflodacin 2 g (therapeutic), zoliflodacin 4 g (supratherapeutic), placebo, and moxifloxacin 400 mg as a positive comparator. Cardiac repolarization was measured by duration of the corrected QT interval by Fridericia’s formula (QTcF). At each time point up to 24 hours after zoliflodacin administration, the upper limit of the one-sided 95% confidence interval (CI) for the placebo-corrected change from the pre-dose baseline in QTcF (ΔΔQTcF) was less than 10 ms, indicating an absence of a clinically meaningful increase in QT prolongation. The lower limit of the one-sided multiplicity-adjusted 95% CI of ΔΔQTcF for moxifloxacin was longer than 5 ms at four time points from 1-4 hours after dosing, demonstrating adequate sensitivity of the QTc measurement. There were no clinically significant effects on heart rate, PR and QRS intervals, ECG morphology, or laboratory values. Treatment-emergent adverse events (AEs) were mild or moderate in severity and transient. This was a negative TQT study according to regulatory guidelines (E14) and confirms that a single oral dose of zoliflodacin is safe and well-tolerated. These findings suggest zoliflodacin is not proarrhythmic and contribute to the favorable assessment of cardiac safety for a single oral dose of zoliflodacin.


2013 ◽  
Vol 3 (3) ◽  
pp. 205 ◽  
Author(s):  
Sandeep Mistry ◽  
Wesley Mayer ◽  
Rose Khavari ◽  
Gustavo Ayala ◽  
Brian Miles

Introduction: Prostate cancer is the most common nonskin malignancyaffecting men and is the second leading cause of cancerrelateddeath in North America. The incidence of prostate cancerincreases dramatically with age. However, many healthauthorities advocate the cessation of routine prostate cancer testingin men older than 75 because of the belief that most patientswill have a clinically insignificant cancer and will not benefit fromtherapy. The true prevalence of clinically significant prostate cancerin elderly men is not known.Methods: We analyzed 1446 needle biopsies of the prostate inmen aged 75 or older. All pathological reviews were conductedby the pathology department at the Methodist Hospital in Houston,Tex. Data were collected from pathology reports, hospital andclinic databases, and medical records when available. Dataobtained included age at biopsy, serum prostate-specific antigen(PSA) levels, number of positive core biopsies and Gleasongrade. Statistical analysis was performed using Stata. Clinicallysignificant cancer was defined by the pathological presence ofGleason grade 6 adenocarcinoma in more than 1 biopsy coreor the presence of any Gleason 4 or 5 component in the biopsy.Results: The median age of the patients included in the studywas 78.8 and 95% of the patients were between the ages of 75and 85. The mean serum PSA level for patients biopsied was10.4 μg/L. Of all biopsies reviewed, 53% were positive for prostatecancer and 78% of these would be defined as clinically significantcancer. Regression analysis revealed age to be a significant(p < 0.05) factor for increased Gleason grade in positive biopsies.Logistic regression revealed age as a significant factor (p <0.05) for clinically significant prostate cancer even when controllingfor PSA. A serum PSA threshold value of 6.5 μg/L would havemissed 38% of significant cancers and a threshold of 4.0 μg/Lwould have missed 8% of significant cancers.Conclusion: Our findings suggest that the prevalence of clinicallysignificant prostate cancer in the elderly population may be higherthan previously thought. As the population continues to livelonger and healthier lives, it will become more common to confrontprostate cancer morbidity in the eldery population. Usinghigher serum PSA thresholds to eliminate unnecessary biopsies inolder men does not appear to help identify patients at greaterrisk of having clinically significant prostate cancer. Patients withprostate cancer having aggressive clinical features may benefitfrom treatment of their prostate cancer well into their eighth andninth decades of life. Testing and diagnostic recommendationsshould reflect the potential benefit of identifying patients withaggressive prostate cancer even after age 75.Introduction : Le cancer de la prostate est le type de cancer noncutané le plus fréquent chez les hommes et la seconde causede décès lié au cancer en importance en Amérique du Nord.L’incidence du cancer de la prostate augmente grandement avecl’âge. Néanmoins, de nombreuses autorités en matière de santéavancent l’idée de mettre fin au dépistage systématique du cancerde la prostate chez les hommes de plus de 75 ans en raisonde la croyance selon laquelle la plupart des patients présenterontun cancer non significatif sur le plan clinique et ne bénéficierontpas d’un traitement. La véritable prévalence des cas decancer de la prostate cliniquement significatif chez les hommesâgés n’est pas établie.Méthodes : Nous avons analysé 1446 échantillons de biopsie àl’aiguille prélevés au niveau de la prostate chez des patients de75 ans ou plus. Toutes les analyses de pathologie ont été effectuéespar le service de pathologie du Methodist Hospital deHouston, au Texas. Les données ont été tirées des rapports depathologie, des bases de données des hôpitaux et des cliniques,et des dossiers médicaux lorsque possible. Les données obtenuesincluaient l’âge au moment de la biopsie, les valeurs d’antigèneprostatique spécifique (APS), le nombre de microbiopsies positiveset le score de Gleason. Les analyses statistiques ont été effectuéesà l’aide du système Stata. Le cancer cliniquement significatifest défini comme la présence d’un adénocarcinome avec un scorede Gleason de 6 dans plus d’une zone de biopsie ou un scorede Gleason de 4 ou 5 dans toute partie de l’échantillon.Résultats : L’âge moyen des patients inclus était de 78,8 ans et95 % des patients avaient entre 75 et 85 ans. La valeur moyennede l’APS chez les patients ayant subi une biopsie était de 10,4 μg/L.De tous les échantillons examinés, 53 % confirmaient la présenced’un cancer de la prostate, et le cancer était défini comme étantcliniquement significatif dans 78 % de ces cas. Une analyse derégression a révélé que l’âge était un facteur significatif (p <0,05) lié à un score de Gleason plus élevé dans les biopsies positives.Une analyse de régression logistique a révélé que l’âge étaitaussi un facteur significatif (p < 0,05) lié à un cancer de la prostatecliniquement significatif même en tenant compte du taux d’APS.Une valeur seuil d’APS de 6,5 μg/L serait passée à côté de 38 %des cas de cancer significatif, alors qu’une valeur seuil d’APSde 4,0 μg/L serait passée à côté de 8 % des cancers significatifs.Conclusion : Nos observations portent à croire que la prévalencedu cancer de la prostate significatif sur le plan clinique chezles patients âgés pourrait être plus élevée qu’on le croit. Avecl’augmentation de l’espérance de vie, l’incidence de la morbiditéliée au cancer de la prostate augmentera. Le recours àdes valeurs seuils d’APS plus élevées pour éliminer les cas debiopsies non nécessaires chez les hommes âgés ne semble pasaider à cerner les patients présentant un risque plus élevé de cancerde la prostate cliniquement significatif. Les patients atteintsde cancer de la prostate cliniquement agressif peuvent bénéficierd’un traitement contre le cancer même lorsqu’ils dépassentlargement les 80 ou les 90 ans. Les recommandations concernantle dépistage et le diagnostic devraient refléter les avantages potentielsliés au dépistage d’un cancer de la prostate agressif, mêmeaprès 75 ans.


2012 ◽  
Vol 56 (10) ◽  
pp. 5076-5081 ◽  
Author(s):  
Keith A. Rodvold ◽  
Mark H. Gotfried ◽  
J. Gordon Still ◽  
Kay Clark ◽  
Prabhavathi Fernandes

ABSTRACTThe steady-state concentrations of solithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from intrapulmonary samples during bronchoscopy and bronchoalveolar lavage (BAL) in 30 healthy adult subjects. Subjects received oral solithromycin at 400 mg once daily for five consecutive days. Bronchoscopy and BAL were carried out once in each subject at either 3, 6, 9, 12, or 24 h after the last administered dose of solithromycin. Drug concentrations in plasma, ELF, and AM were assayed by a high-performance liquid chromatography-tandem mass spectrometry method. Solithromycin was concentrated extensively in ELF (range of mean [± standard deviation] concentrations, 1.02 ± 0.83 to 7.58 ± 6.69 mg/liter) and AM (25.9 ± 20.3 to 101.7 ± 52.6 mg/liter) in comparison with simultaneous plasma concentrations (0.086 ± 0.070 to 0.730 ± 0.692 mg/liter). The values for the area under the concentration-time curve from 0 to 24 h (AUC0–24values) based on mean and median ELF concentrations were 80.3 and 63.2 mg · h/liter, respectively. The ratio of ELF to plasma concentrations based on the mean and median AUC0–24values were 10.3 and 10.0, respectively. The AUC0–24values based on mean and median concentrations in AM were 1,498 and 1,282 mg · h/L, respectively. The ratio of AM to plasma concentrations based on the mean and median AUC0–24values were 193 and 202, respectively. Once-daily oral dosing of solithromycin at 400 mg produced steady-state concentrations that were significantly (P< 0.05) higher in ELF (2.4 to 28.6 times) and AM (44 to 515 times) than simultaneous plasma concentrations throughout the 24-h period after 5 days of solithromycin administration.


2012 ◽  
Vol 56 (5) ◽  
pp. 2408-2413 ◽  
Author(s):  
Manoli Vourvahis ◽  
Rong Wang ◽  
Marie-Noella Ndongo ◽  
Melissa O'Gorman ◽  
Margaret Tawadrous

ABSTRACTThe objective of this study was to investigate the effect of a supratherapeutic dose of lersivirine (LRV) on corrected QT (QTc) interval using Fridericia's equation (QTcF) in healthy subjects. In this randomized, single-dose, placebo- and active-controlled 3-way crossover study, healthy adult males (n= 48) were randomized to receive LRV (2,400 mg), moxifloxacin (400 mg), or placebo for each treatment period. Triplicate 12-lead electrocardiogram measurements were performed, PK samples were collected, and vital signs were measured. Adverse event monitoring and safety laboratory testing were performed. All subjects were white (mean age, 39 years; body mass index [BMI], 25.6 kg/m2) and completed the study. Following LRV administration, the upper bound of the 90% confidence interval (CI) for time-matched adjusted mean differences to placebo QTcF at each time point postdose was below the regulatory threshold of 10 ms, satisfying the criteria for a negative thorough QT/QTc study. The highest upper bound of QTcF 90% CI occurred at 6 h for LRV (3.32 ms; 90% CI, 1.47 to 5.17 ms). The study was deemed adequately sensitive as the lower bound of the 90% CI for the adjusted mean QTcF differences between moxifloxacin and placebo at the moxifloxacin historicalTmaxof 3 h was >5 ms (15.29 ms; 90% CI, 13.44 to 17.14 ms). There was no statistically significant relationship between LRV exposure and placebo-adjusted change from baseline QTcF or clinically significant changes in QRS complex, pulse rate (PR) interval, heart rate, or blood pressure. LRV (2,400 mg) did not prolong the QTcF interval, and no clinically relevant electrocardiogram or vital sign changes were observed in healthy subjects.


PEDIATRICS ◽  
1983 ◽  
Vol 71 (1) ◽  
pp. 139-139
Author(s):  
J. M. WRIGHT

To the Editor.— The case report of carbamazepine intoxication secondary to isoniazid administration recently described in this journal1 is a clinically significant interaction. I have previously presented2 a similar case in which a patient receiving carbamazepine, valproate, and nitrazepam developed severe carbamazepine intoxication when isoniazid was added to the drug regimen. The patient was determined to have inherited the slow acetylator phenotype. On careful rechallenge, 300 mg of isoniazid increased carbamazepine steady-state serum concentrations by 85% and decreased carbamazepine clearance by 45%.


2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S311-S311
Author(s):  
Borje Darpo ◽  
Anita F Das ◽  
Daniel Stein ◽  
Jennifer Schranz ◽  
Steven P Gelone

Abstract Background Preclinical data suggest potential effects of LEF on cardiac interval parameters. We therefore assessed LEF cardiac safety from the LEAP 1/2 trials. Methods In LEAP 1, PORT III–V patients received LEF 150mg IV q12h for 5–7 days or MOX 400mg IV q24h for 7 days, with optional IV-to-oral switch (600mg LEF q12h or 400 mg MOX q24h). In LEAP 2, PORT II–IV patients received oral LEF 600mg q12h for 5 days or oral MOX 400mg q24h for 7 days. Patients with known QT prolongation or on medication with potential to prolong the QT interval were excluded as per MOX label. After 5 minutes of rest in the supine position, triplicate 12-lead ECGs were obtained within a 5-minute interval at Screening in both studies, on Days 1/3 in LEAP 1 (predose and ≤15 minutes after first IV dose), and on Days 1/4 in LEAP 2 (predose and 1–3 hours after first oral dose), and sent to a central ECG reader for adjudication. Results Of 1,282 randomized/treated patients (n = 641/group), 1,274 had baseline (BL) and post-BL ECG data (n = 636 LEF, n = 638 MOX). Consistent with the resolution of infection, ECGs revealed mean reductions of 7–8 beats/minute for both groups in both studies. The largest mean change in QTcF from BL to post-BL was on Day 3 in LEAP 1 (13.6 and 16.4 msec with IV LEF and MOX, respectively) and on Day 4 in LEAP 2 (9.3 and 11.6 msec with oral LEF and MOX, respectively). The proportion of patients meeting potentially important post-BL QTcF values/changes was comparable between treatment groups (table). In the standardized MedDRA query of Torsade de pointes/QT prolongation (broad), the most common treatment-emergent adverse event was ECG QT prolonged (n = 4 LEF, n = 5 MOX). All events were nonserious and mild or moderate in severity. 6 events were considered study drug related (n = 4 LEF, n = 2 MOX). 5 events led to study drug discontinuation (n = 2 LEF, n = 3 MOX). In 2 patients with cardiovascular disease, 1 had ventricular arrhythmia on Day 20 (18 days after last LEF dose) and 1 had cardiac arrest on Day 18 (9 days after last MOX dose); both events were fatal and considered unrelated to study drug by investigator. Conclusion Mild prolongation of the QTcF interval was seen with LEF and MOX, with somewhat smaller effects seen with LEF. Given the small effect, LEF is unlikely to pose a clinically significant risk of ventricular proarrhythmia with appropriate precautions and use. Disclosures All authors: No reported disclosures.


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