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Raymond L Woosley - One of the best experts on this subject based on the ideXlab platform.
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summary of torsades de pointes tdp reports associated with intravenous drug formulations containing the preservative Chlorobutanol
Drug Safety, 2019Co-Authors: David R Woosley, Klaus Romero, Craig William Heise, Tyler Gallo, Jared Tate, Raymond L WoosleyAbstract:Drug-induced torsades de pointes (TdP) is a potentially lethal ventricular arrhythmia that is associated with drugs that prolong the QT interval on the electrocardiogram (ECG) due to their interference with the cardiac potassium current, IKR. Intravenous (IV) formulations of methadone have been associated with TdP and contain the preservative Chlorobutanol, which, like methadone, blocks IKR. The combinations of Chlorobutanol with methadone or terfenadine, another IKR blocker, produce synergistic IKR block. The aim of this study was to examine and summarize the evidence available to address the question: what other IV drug formulations contain Chlorobutanol and are they associated with TdP? IV drug products containing the preservative Chlorobutanol were identified by searching the websites DailyMed ( https://dailymed.nlm.nih.gov/dailymed/index.cfm ) and Drugs@FDA ( https://www.accessdata.fda.gov/scripts/cder/daf/ ). For each drug identified, PubMed and the FDA’s Adverse Event Reporting System (FAERS) were searched for reports of TdP and/or QT prolongation and FAERS data were analyzed for disproportionality of reports. The search found nine drugs (methadone, epinephrine, papaverine, oxytocin, vasopressin, testosterone, estradiol, isoniazid, and desmopressin) that contain Chlorobutanol 2.5 (n = 1) or 5.0 mg/mL. All nine drugs had reports of QT prolongation or TdP reported in FAERS and all but estradiol, testosterone, desmopressin, and isoniazid had reports of QT prolongation or TdP in PubMed. Two of the nine drugs (epinephrine and methadone) had positive signals (by disproportionality analysis) for TdP in FAERS (EB05 2.88 and 23.81, respectively) and four (methadone, epinephrine, papaverine, and vasopressin) were reported in published articles as the suspect drugs in cases of TdP. The pharmacologic profile of Chlorobutanol (synergistic IKR block) and its association with reports of TdP and QT prolongation suggest the need for a full evaluation of its cardiac safety when used as a preservative in IV drug and vitamin formulations.
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qtc interval prolongation associated with intravenous methadone
Pain, 2003Co-Authors: Craig A. Kornick, Michael J Kilborn, Juan Santiagopalma, Glenn Schulman, Deborah Keefe, Alexander N Katchman, Steven N Ebert, Howard T. Thaler, John C. Pezzullo, Raymond L WoosleyAbstract:Abstract Numerous medications prolong the rate-corrected QT (QTc) interval and induce arrhythmias by blocking ionic current through cardiac potassium channels composed of subunits expressed by the human ether-a-go-go-related gene (HERG). Recent reports suggest that high doses of methadone cause torsades de pointes. To date, no controlled study has described an association between methadone and QTc prolongation. The only commercial formulation of parenteral methadone available in the United States contains the preservative Chlorobutanol. The objectives of this study are to determine: (1) whether the administration of intravenous (i.v.) methadone causes QTc prolongation in humans; (2) whether methadone and/or Chlorobutanol block cardiac HERG potassium currents ( I HERG ) in vitro. Over 20 months, we identified every inpatient with at least one electrocardiogram (ECG) performed on i.v. methadone. For each patient, we measured QTc intervals for every available ECG performed on and off i.v. methadone. Concurrent methadone doses were also recorded. Similar data were collected for a separate group of inpatients treated with i.v. morphine. In a separate set of experiments I HERG was evaluated in transfected human embryonic kidney cells exposed to increasing concentrations of methadone, Chlorobutanol, and the two in combination. Mean difference (±standard error) per patient in QTc intervals on and off methadone was 41.7 (±7.8) ms, p p =0.15. The approximately linear relationship between QTc measurements and log-dose of methadone was significant ( p I HERG in a concentration-dependent manner with IC 50 values of 20±2 μM and 4.4±0.3 mM, respectively. Chlorobutanol potentiates methadone's ability to block I HERG . Methadone in combination with Chlorobutanol is associated with QTc interval prolongation. Our data strongly suggest that methadone in combination with Chlorobutanol is associated with QTc interval prolongation.
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qtc interval prolongation associated with intravenous methadone
Pain, 2003Co-Authors: Craig A. Kornick, Michael J Kilborn, Juan Santiagopalma, Glenn Schulman, Alexander N Katchman, Steven N Ebert, Howard T. Thaler, John C. Pezzullo, Deborah L Keefe, Raymond L WoosleyAbstract:Abstract Numerous medications prolong the rate-corrected QT (QTc) interval and induce arrhythmias by blocking ionic current through cardiac potassium channels composed of subunits expressed by the human ether-a-go-go-related gene (HERG). Recent reports suggest that high doses of methadone cause torsades de pointes. To date, no controlled study has described an association between methadone and QTc prolongation. The only commercial formulation of parenteral methadone available in the United States contains the preservative Chlorobutanol. The objectives of this study are to determine: (1) whether the administration of intravenous (i.v.) methadone causes QTc prolongation in humans; (2) whether methadone and/or Chlorobutanol block cardiac HERG potassium currents (IHERG) in vitro. Over 20 months, we identified every inpatient with at least one electrocardiogram (ECG) performed on i.v. methadone. For each patient, we measured QTc intervals for every available ECG performed on and off i.v. methadone. Concurrent methadone doses were also recorded. Similar data were collected for a separate group of inpatients treated with i.v. morphine. In a separate set of experiments IHERG was evaluated in transfected human embryonic kidney cells exposed to increasing concentrations of methadone, Chlorobutanol, and the two in combination. Mean difference (±standard error) per patient in QTc intervals on and off methadone was 41.7 (±7.8) ms, p
Hassan M Badawi - One of the best experts on this subject based on the ideXlab platform.
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a study of the molecular structure and vibrational spectra of 1 3 dichloro 2 propanol and 1 1 1 trichloro 2 methyl 2 propanol Chlorobutanol
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 2012Co-Authors: Hassan M BadawiAbstract:Abstract The conformational stability of 1,3-dichloro-2-propanol and 1,1,1-trichloro-2-methyl-2-propanol (Chlorobutanol) was investigated by the DFT-B3LYP/6-311+G**, MP2/6-311+G** and MP4(SDQ)/6-311+G** levels of theory. From the calculations Chlorobutanol was predicted to exist in a non-planar gauche structure. The planar cis and trans structures of Chlorobutanol were calculated to be about 3 kcal/mol higher in energy than the gauche structure. From the calculations 1,3-dichloro-2-propanol was predicted to exist in a Ggg1 and Ggg conformational mixture at ambient temperature. In the low energy structures of both alcohols the non-bonded Cl⋯H(O) distance was calculated to be of about 2.6–2.7 A. The observation of a broad and very intense band at about 3400 cm−1 in the infrared spectra of the two alcohols supports the presence of strong intermolecular Cl⋯H(O) dipolar interactions in their condensed phases. The analysis of the Raman spectra of 1,3-dichloro-2-propanol suggests the presence of a second high energy Ggg structure of the dichloride at room temperature. The vibrational frequencies of 1,3-dichloro-2-propanol and Chlorobutanol in their low energy structures were computed at the B3LYP level and tentative vibrational assignments were made for their normal modes on the basis of combined calculated and experimental data.
Michael J Doughty - One of the best experts on this subject based on the ideXlab platform.
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acute effects of Chlorobutanol or benzalkonium chloride containing artificial tears on the surface features of rabbit corneal epithelial cells
Optometry and Vision Science, 1994Co-Authors: Michael J DoughtyAbstract:I examined the epithelial surface, by high resolution scanning electron microscopy, after its recovery from the instillation of artificial tears containing Chlorobutanol or benzalkonium chloride. Is the mild epithelial surface compromise observed after occasional use of a Chlorobutanol-containing artificial tear more substantial after use of a benzalkonium-containing artificial tear? Two drops of a Chlorobutanol- or benzalkonium chloride-containing artificial tear were instilled into the right eye of 6 female gray rabbits (2 kg) at 9:00 p.m. and 9:00 a.m. At the same time six control animals received no eyedrops. All animals were euthanized at 3:00 p.m. and the central region of the corneal epithelium quantitatively assessed using a digitizer pad/computer system. There were up to 5% exfoliating cells evident at the ocular surface in treated rabbits but with no difference between the two products. Controls had no cell exfoliation (< 0.5%). The distribution of surface areas of the squamous cells in the treated eyes was shifted to slightly larger values than in the controls after use of the Chlorobutanol-containing product but the number of epithelial cell craters/cell was unchanged from that of the controls. Cell surface areas were shifted to significantly smaller values than controls after use of the benzalkonium chloride-containing product and there were much fewer epithelial cell craters/cell. The results reveal differences in the effects of preservative-containing artificial tears on the squamous cells of the corneal epithelium in a clinically relevant situation.
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twice daily use of a Chlorobutanol preserved artificial tear on rabbit corneal epithelium assessed by scanning electron microscopy
Ophthalmic and Physiological Optics, 1992Co-Authors: Michael J DoughtyAbstract:Female pigmented rabbits received two drops of a Chlorobutanol 0.5%-preserved, polyvinyl alcohol-based artificial tear at 21.00 h and 09.00 h for 1, 2, 3, 6 or 12 consecutive days. The animals were killed at 15.00, 6 h after the last treatment. Scanning electron microscopy of the corneal epithelial surface at x 200 magnification revealed only occasional cell exfoliation averaging < 8% of the surface analysed at central, mid-peripheral and peripheral sites, showing minimal cytotoxic effects. The level of exfoliation was maximal after 2 to 3 days treatment and then returned to close to zero, so the eye adapts to repeated use of the artificial tears. Evaluation of the surface microplicae of the cells at x 15,000 indicated subtle, but distinct, changes in what might be the mucus material associated with the cell surface, especially after 2 and 3 days treatment.
Craig A. Kornick - One of the best experts on this subject based on the ideXlab platform.
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qtc interval prolongation associated with intravenous methadone
Pain, 2003Co-Authors: Craig A. Kornick, Michael J Kilborn, Juan Santiagopalma, Glenn Schulman, Deborah Keefe, Alexander N Katchman, Steven N Ebert, Howard T. Thaler, John C. Pezzullo, Raymond L WoosleyAbstract:Abstract Numerous medications prolong the rate-corrected QT (QTc) interval and induce arrhythmias by blocking ionic current through cardiac potassium channels composed of subunits expressed by the human ether-a-go-go-related gene (HERG). Recent reports suggest that high doses of methadone cause torsades de pointes. To date, no controlled study has described an association between methadone and QTc prolongation. The only commercial formulation of parenteral methadone available in the United States contains the preservative Chlorobutanol. The objectives of this study are to determine: (1) whether the administration of intravenous (i.v.) methadone causes QTc prolongation in humans; (2) whether methadone and/or Chlorobutanol block cardiac HERG potassium currents ( I HERG ) in vitro. Over 20 months, we identified every inpatient with at least one electrocardiogram (ECG) performed on i.v. methadone. For each patient, we measured QTc intervals for every available ECG performed on and off i.v. methadone. Concurrent methadone doses were also recorded. Similar data were collected for a separate group of inpatients treated with i.v. morphine. In a separate set of experiments I HERG was evaluated in transfected human embryonic kidney cells exposed to increasing concentrations of methadone, Chlorobutanol, and the two in combination. Mean difference (±standard error) per patient in QTc intervals on and off methadone was 41.7 (±7.8) ms, p p =0.15. The approximately linear relationship between QTc measurements and log-dose of methadone was significant ( p I HERG in a concentration-dependent manner with IC 50 values of 20±2 μM and 4.4±0.3 mM, respectively. Chlorobutanol potentiates methadone's ability to block I HERG . Methadone in combination with Chlorobutanol is associated with QTc interval prolongation. Our data strongly suggest that methadone in combination with Chlorobutanol is associated with QTc interval prolongation.
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qtc interval prolongation associated with intravenous methadone
Pain, 2003Co-Authors: Craig A. Kornick, Michael J Kilborn, Juan Santiagopalma, Glenn Schulman, Alexander N Katchman, Steven N Ebert, Howard T. Thaler, John C. Pezzullo, Deborah L Keefe, Raymond L WoosleyAbstract:Abstract Numerous medications prolong the rate-corrected QT (QTc) interval and induce arrhythmias by blocking ionic current through cardiac potassium channels composed of subunits expressed by the human ether-a-go-go-related gene (HERG). Recent reports suggest that high doses of methadone cause torsades de pointes. To date, no controlled study has described an association between methadone and QTc prolongation. The only commercial formulation of parenteral methadone available in the United States contains the preservative Chlorobutanol. The objectives of this study are to determine: (1) whether the administration of intravenous (i.v.) methadone causes QTc prolongation in humans; (2) whether methadone and/or Chlorobutanol block cardiac HERG potassium currents (IHERG) in vitro. Over 20 months, we identified every inpatient with at least one electrocardiogram (ECG) performed on i.v. methadone. For each patient, we measured QTc intervals for every available ECG performed on and off i.v. methadone. Concurrent methadone doses were also recorded. Similar data were collected for a separate group of inpatients treated with i.v. morphine. In a separate set of experiments IHERG was evaluated in transfected human embryonic kidney cells exposed to increasing concentrations of methadone, Chlorobutanol, and the two in combination. Mean difference (±standard error) per patient in QTc intervals on and off methadone was 41.7 (±7.8) ms, p
Anthony Tommasello - One of the best experts on this subject based on the ideXlab platform.
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methadone associated q t interval prolongation and torsades de pointes
American Journal of Health-system Pharmacy, 2009Co-Authors: John Stringer, Christopher Welsh, Anthony TommaselloAbstract:Purpose. The association of methadone with Q-T interval prolongation and torsades de pointes (TdP) is reviewed, and recommendations for preventing Q-T interval prolongation in methadone users are provided. Summary. Abnormalities in voltage-gated potassium channels have been shown to lead to prolonged action potentials that are expressed as long Q-T intervals, and methadone has been found to interact with the voltage-gated potassium channels of the myocardium. While cardiac arrhythmias in methadone users have been reported for several decades, specific reports of methadone-associated Q-T interval prolongation and TdP did not appear in the literature until the early part of the 21st century. Because not every patient experiences Q-T interval prolongation with methadone, recent research has elucidated risk factors that predispose patients to this adverse effect, including female sex, hypokalemia, high-dose methadone, drug interactions, underlying cardiac conditions, unrecognized congenital long Q-T interval syndrome, and predisposing DNA polymorphisms. Given the high mortality rates seen in untreated illicit opioid users and the clear efficacy of methadone in treating opioid addiction, the risk of using methadone, even in a patient with other risk factors for Q-T interval prolongation, may outweigh the alternative of no pharmacologic treatment. A baseline electrocardiogram (ECG), personal and family history of syncope, and a complete medication history should be obtained before a patient begins treatment with methadone. Given the apparent synergistic effects of parenteral methadone and Chlorobutanol, oral methadone should be used whenever possible. Conclusion. Q-T interval prolongation and TdP associated with the use of methadone are potentially fatal adverse effects. A thorough patient history and ECG monitoring are essential for patients treated with this agent, and alterations in treatment options may be necessary.