A new rapid titration protocol for lamotrigine that reduces the risk of skin rash

Abstract Trimethoprim (TMP)-induced skin rash and liver injury are likely to involve the formation of reactive metabolites. Analogous to nevirapine-induced skin rash, one possible reactive metabolite is the sulfate conjugate of α-hydroxyTMP, a metabolite of TMP. We synthesized this sulfate and found that it reacts with proteins in vitro. We produced a TMP-antiserum and found covalent binding of TMP in the liver of TMP-treated rats. However, we found that α-hydroxyTMP is not a substrate for human sulfotransferases, and we did not detect covalent binding in the skin of TMP-treated rats. Although less reactive than the sulfate, α-hydroxyTMP was found to covalently bind to liver and skin proteins in vitro. Even though there was covalent binding to liver proteins, TMP did not cause liver injury in rats or in our impaired immune tolerance mouse model that has been able to unmask the ability of other drugs to cause immune-mediated liver injury. This is likely because there was much less covalent binding of TMP in the livers of TMP-treated mice than TMP-treated rats. It is possible that some patients have a sulfotransferase that can produce the reactive benzylic sulfate; however, α-hydroxyTMP, itself, has sufficient reactivity to covalently bind to proteins in the skin and may be responsible for TMP-induced skin rash. Interspecies and interindividual differences in TMP metabolism may be one factor that determines the risk of TMP-induced skin rash. This study provides important data required to understand the mechanism of TMP-induced skin rash and drug-induced skin rash in general.

Download Full-text

17. Comparative Safety of Antibiotic Therapy for Outpatient Treatment of Uncomplicated Urinary Tract Infections

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa417.016 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S9-S10

Author(s):

Anne M Butler ◽

Michael Durkin ◽

Matthew R Keller ◽

Yinjiao Ma ◽

William Powderly ◽

...

Keyword(s):

Renal Failure ◽

Acute Renal Failure ◽

Abdominal Pain ◽

Urinary Tract ◽

Skin Rash ◽

Adverse Drug Events ◽

Vulvovaginal Candidiasis ◽

First Line ◽

Research Support ◽

Comparative Safety

Abstract Background Urinary tract infection (UTI) is one of the most common indications for outpatient antibiotic prescriptions in otherwise healthy women, yet the comparative safety of antibiotics for empirical therapy is not well established. We compared the risk of adverse drug events by antibiotic treatment regimen among premenopausal women with uncomplicated UTI. Methods Using the IBM MarketScan Commercial Database (2006–2015), we identified healthy, non-pregnant women aged 18–44 who were diagnosed with UTI and prescribed a same-day antibiotic with activity against common uropathogens. Patients were followed for outcomes with varying follow-up periods: 3 days (anaphylaxis), 14 days (acute renal failure, skin rash, urticaria/hives, nausea/vomiting, abdominal pain), 30 days (vaginitis/vulvovaginal candidiasis, non-C. difficile diarrhea) and 90 days (C. difficile diarrhea, pneumonia, tendinopathy, retinal detachment). We estimated propensity score-weighted hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models. Results Of 1,140,602 eligible women, the distribution of antibiotic receipt was fluoroquinolones (44%), trimethoprim-sulfamethoxazole (TMP/SMX) (28%), nitrofurantoin (24%), narrow-spectrum β-Lactam / β-Lactamase inhibitor combinations (“β-Lactams”) (3%), broad-spectrum β-Lactams (1%) and amoxicillin/ampicillin (1%). Of two first-line agents, we observed higher risk of outcomes among TMP/SMX vs. nitrofurantoin initiators: acute renal failure (HR 2.46, 95% CI 1.46–4.14), skin rash (HR 2.43, 95% CI 2.13–2.77), urticaria (HR 1.35, 95% CI 1.18–1.56), nausea/vomiting (HR 1.19, 95% CI 1.10–1.29) and abdominal pain (HR 1.14, 95% CI 1.09–1.19). Compared to nitrofurantoin, non-first-line agents (fluoroquinolones, broad-, and/or narrow-spectrum β-Lactams) were associated with higher risk of acute renal failure, skin rash, nausea/vomiting, abdominal pain, vaginitis/vulvovaginal candidiasis, diarrhea (C. difficile & non-C. difficile), pneumonia and tendinopathy. Conclusion The risk of adverse drug events differs widely by antibiotic agent, with substantial differences in first-line agents. Understanding antibiotic safety is critical to prevent suboptimal antibiotic prescribing and reduce adverse events. Disclosures Margaret A. Olsen, PhD, MPH, Merck (Grant/Research Support)Pfizer (Consultant, Grant/Research Support)

Download Full-text

Analysis of risk factors for lenalidomide-associated skin rash in patients with multiple myeloma

Leukemia & Lymphoma ◽

10.1080/10428194.2021.1876867 ◽

2021 ◽

pp. 1-12

Author(s):

Tomiyuki Sugi ◽

Yasuo Nishigami ◽

Hirohisa Saigo ◽

Homare Hanai ◽

Keisuke Takabatake ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Skin Rash

Download Full-text

Neonatal Toxic Shock Syndrome–Like Exanthematous Disease in North America

Journal of the Pediatric Infectious Diseases Society ◽

10.1093/jpids/piz060 ◽

2019 ◽

Author(s):

Megan Culler Freeman ◽

Stephanie Mitchell ◽

John Ibrahim ◽

John V Williams

Keyword(s):

North America ◽

Diagnostic Criteria ◽

Skin Rash ◽

Toxic Shock Syndrome ◽

Disease Process ◽

Toxic Shock ◽

C Reactive Protein ◽

Reactive Protein ◽

First Case

Abstract Neonatal toxic shock syndrome (TSS)-like exanthematous disease (NTED) is a syndrome first reported in Japan. Neonates develop systemic exanthema, thrombocytopenia, and fever usually during the first week of life. The disease is distinguished from frank TSS because affected infants are not severely ill and do not meet TSS criteria. Most infants are confirmed to be colonized with TSST-1 producing strains of S. aureus. Suggested diagnostic criteria for NTED include a skin rash with generalized macular erythema and one of the following symptoms: fever >38.0°C, thrombocytopenia <150 x103uL, or low positive C-reactive protein (1-5 mg/dL) in the absence of another known disease process. NTED is common in Japanese NICUs, but outside Japan, only one case has been reported in France. We describe the first case of NTED reported in North America.

Download Full-text

Radiation-Induced Prevention of Erlotinib-Induced Skin Rash Is Transient: A New Aspect Toward the Understanding of Epidermal Growth Factor Receptor Inhibitor–Associated Cutaneous Adverse Effects

Journal of Clinical Oncology ◽

10.1200/jco.2007.12.8330 ◽

2007 ◽

Vol 25 (29) ◽

pp. 4697-4698 ◽

Cited By ~ 13

Author(s):

Peter Arne Gerber ◽

Elaine Enderlein ◽

Bernhard Homey ◽

Anja Muller ◽

Edwin Boelke ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Adverse Effects ◽

Skin Rash ◽

Growth Factor Receptor ◽

Radiation Induced ◽

Epidermal Growth ◽

Receptor Inhibitor

Download Full-text

Formulation and Stability of Naltrexone Oral Liquid for Rapid Withdrawal from Methadone

Annals of Pharmacotherapy ◽

10.1177/106002809703101102 ◽

1997 ◽

Vol 31 (11) ◽

pp. 1291-1295 ◽

Cited By ~ 4

Author(s):

J Paul Fawcett ◽

Nicola C Morgan ◽

David J Woods

Keyword(s):

Methadone Maintenance Treatment ◽

Methadone Maintenance ◽

Withdrawal Symptoms ◽

Dose Titration ◽

Oral Liquid ◽

Naltrexone Treatment ◽

Flexible Dosing ◽

Drug Dependent ◽

The Stability ◽

Titration Protocol

OBJECTIVE: To assess the stability of naltrexone oral liquid prepared from tablets and powder, and to evaluate its use in precipitating rapid withdrawal from methadone. DESIGN: Naltrexone 1 mg/mL oral liquids were prepared from tablets and powder and stored in the dark at 4, 25, and 70 °C. Similar formulations containing 5 mg/mL were stored at 70 °C. The 1-mg/mL formulation prepared from tablets was clinically evaluated in inducing rapid withdrawal in two drug-dependent individuals receiving methadone maintenance treatment using a naltrexone dose titration protocol. SETTING: A university pharmacy school and affiliated urban teaching hospital. MAIN OUTCOME MEASURES: Samples removed at six time points were analyzed for naltrexone concentration to assess decomposition over 90 days. An opioid withdrawal symptom checklist was used to assess the severity of the withdrawal symptoms prior to, and 30 minutes after, each dose of naltrexone. RESULTS: Decomposition of naltrexone in all formulations stored at 4 and 25 °C was not significant over 90 days. Both patients tolerated naltrexone 1 mg/mL oral liquid, but found it bitter and gritty. Withdrawal symptoms were experienced immediately after the first dose, but were resolving by the end of day 3 of naltrexone treatment, at which stage both patients were able to tolerate a 50-mg tablet of naltrexone as maintenance. CONCLUSIONS: Naltrexone 1 mg/mL oral liquids prepared from tablets or powder are stable when stored in the dark for 60 days at 4 °C and for 30 days at 25 °C. The formulation prepared from tablets provides flexible dosing in patients undergoing rapid withdrawal from methadone.

Download Full-text