Pharmacokinetics, pharmacodynamics, and metabolism of triethylenetetramine in healthy human participants: an open-label trial.

The selective Cu(II)-chelator, triethylenetetramine (TETA), is undergoing clinical trials for the treatment of heart failure in patients with diabetes. Recently, the authors showed that 2 acetylated metabolites, N(1)-acetyltriethylenetetramine (MAT) and N(1),N(10)-diacetyltriethylenetetramine (DAT), are formed in humans following oral TETA administration. Thus, it became necessary to determine whether the N-acetyltransferase (NAT) 2 phenotype has any effects on the pharmacological properties and safety profile of TETA. Twelve fast and 12 slow NAT2-phenotype healthy participants were recruited. After oral drug administration, the authors collected plasma and urine samples, measured plasma concentrations of TETA and its 2 metabolites along with concomitant urinary copper concentrations, and performed safety tests. They present, for the first time, the complete 24-hour pharmacokinetic profiles of TETA, MAT, and DAT in humans. There was no evidence for clear-cut differences in pharmacokinetic profiles between fast and slow acetylators. Pharmacodynamic analysis showed no significant differences in cupruresis between the 2 NAT2 phenotypes. Safety results were consistent with TETA being well tolerated, and no significant differences in safety profiles were observed between the 2 phenotypes. Based on these data, NAT2 phenotype does not affect TETA's pharmacokinetic, pharmacodynamic, or safety profiles. TETA may be acetylated via an alternative mechanism, such as that catalyzed by spermidine/spermine N(1)-acetyltranferase.

Multicenter, double-blind, randomized comparison of wood creosote, the principal active ingredient of Seirogan, an herbal antidiarrheal medication, and loperamide in adults with acute nonspecific diarrhea.

BACKGROUND: Seirogan, an herbal medication containing wood creosote, a mixture of simple phenolic (single-ring)compounds, has been marketed in Asia for the past century as an antidiarrheal and antispasmodic medication. This was the first randomized, double-blind study of this herbal medication in patients with acute, nonspecific diarrhea. OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of wood creosote with those of loperamide hydrochloride in patients with acute, nonspecific diarrhea. METHODS: This double-blind, randomized, active-controlled study was conducted at 12 centers across the United States and Mexico. Patients aged >or=18 years with acute, nonspecific diarrhea, defined as a history of diarrhea for or=3 unformed stools in the 24 hours before the study, accompanied by >or=1 associated symptom (ie, nausea, vomiting, abdominal cramping, and/or fever [

Wood creosote, the principal active ingredient of seirogan, an herbal antidiarrheal medicine: a single-dose, dose-escalation safety and pharmacokinetic study.

STUDY OBJECTIVE: To assess the safety, tolerability and pharmacokinetics of escalating single doses of wood creosote, an herbal antidiarrheal and antispasmodic agent. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Clinical research center. SUBJECTS: Forty (32 men, 8 women) healthy volunteers aged 19-42 years. INTERVENTION: By random assignment, 22 men and 8 women received escalating single doses of wood creosote (45, 90, 135, 180, and 225 mg) and 10 men received placebo (for each of the five dose levels, 6 subjects received active substance and 2 subjects received placebo). MEASUREMENTS AND MAIN RESULTS: Vital signs, laboratory tests, and electrocardiograms were assessed; no dose-related or clinically significant changes were noted. Serial blood samples were obtained to determine the pharmacokinetics of four major active components of wood creosote: total (conjugated plus free) guaiacol, creosol, o-cresol, and 4-ethylguaiacol. The most common adverse events were mild headache and dizziness, with no dose-related trends being apparent. Area under the concentration-time curve from time zero to infinity increased in a dose-proportional manner for total guaiacol, creosol, and o-cresol and was not assessed for total 4-ethylguaiacol owing to lack of data at the low dose level. No apparent differences by sex were noted for any of the four active components. All four components were rapidly eliminated. CONCLUSION: Single oral doses of wood creosote up to 225 mg were safe and well tolerated in healthy men and women. Also, the doses of wood creosote were rapidly absorbed, conjugated, and eliminated. Such a rapid onset and short duration of action would appear desirable in the treatment of acute nonspecific diarrhea.

Multiple-dose escalation, safety, and tolerability study of wood creosote, the principal active ingredient of seirogan, an herbal antidiarrheal medication, in healthy subjects.

Seirogan, an herbal medicine containing wood creosote (CAS 8021-39-4), a mixture of simple phenolic compounds, has been marketed for the past century in Asia for the treatment of acute diarrhea and associated symptoms, such as abdominal discomfort and cramping. The present study was designed to assess the safety and tolerability of an anticipated acute antidiarrheal dosing regimen. Sixty healthy males were randomized into five groups of 12 subjects each (9 wood creosote; 3 placebo) to receive 45-, 90-, 135-, 180-, and 225-mg tablets every 2 hours for five doses. Serial sitting and standing vital signs, ECG rhythm strips, and continuous telemetry monitoring were obtained predose and for 24 hours after the first dose. Clinical laboratory tests and 12-lead resting ECGs were obtained predose and 24 hours postdose. Of the subjects, 27% (12/45) receiving wood creosote and 27% (4/15) receiving placebo reported adverse events. The most common adverse events were altered taste and somnolence, reported more often with 180- and 225-mg doses. Wood creosote had no clinically significant effects on vital signs, ECG intervals or interpretations, or clinical laboratory tests. No clinically significant or serious dysrhythmias were reported on continuous telemetry monitoring. It was concluded that oral doses of wood creosote 45 to 225 mg every 2 hours for up to five doses were safe and well tolerated in 45 healthy subjects. Wood creosote doses ranging from 45 to 135 mg per dose, which are commonly administered antidiarrheal doses in Asia, were associated with minimal side effects.

A Comparison of the Cough Profile of Fosinopril and Enalapril in Hypertensive Patients with a History of ACE Inhibitor-Associated Cough.

OBJECTIVE: Cough frequency and severity with fosinopril and enalapril were assessed in hypertensive patients with previous angiotensin-converting enzyme inhibitor (ACEI)-associated cough. DESIGN: Prospective, multicenter, randomized, 8-week double-blind treatment. PATIENTS: One hundred seventy-nine patients (mild-to-moderate hypertension, nonsmokers, mean age 58 years; 55% females; 72% Caucasian, 6% black, 19% Hispanic) were studied. Patients with other cough etiologies, significant co-morbidity, or confounding medications were excluded. INTERVENTIONS: Patients were randomized to fosinopril 10 mg (n = 85) or enalapril 5 mg (n = 94) once daily. Dosage could be doubled for blood pressure control after 4 weeks. Outcome measurements: The primary end point was all-cough frequency based on patient daily diary ratings; a cumulative cough frequency score was calculated. Secondary end points included cough severity, nonproductive cough frequency, night awakenings, cough time of day, and spontaneously reported cough. RESULTS: Fosinopril and enalapril demonstrated similar blood pressure control. Significant cough profile differences were observed in favor of fosinopril: all-cough frequency was 40.6 plus minus 3.8 (mean plus minus SE) versus 52.8 plus minus 3.6 (p = 0.02); nonproductive cough frequency was 26.7 plus minus 3.5 versus 40.3 plus minus 3.4 (p less-than-or-equal 0.01); and cough time of day was 49.2 plus minus 5.2 versus 66.0 plus minus 5.0 (p = 0.02), for fosinopril and enalapril, respectively. Subgroup analysis revealed all-cough frequency was 33.5 plus minus 6.3 versus 56.6 plus minus 5.3 (p = 0.006) for fosinopril and enalapril, respectively, in patients who previously had cough on one of these two ACEI (predominantly enalapril). Ten (12%) fosinopril and 25 (27%) enelapril patients spontaneously reported cough (p = 0.01). CONCLUSIONS: Hypertensive patients with previous ACEI-associated cough reported less frequent cough with fosinopril compared to enalapril, based on cumulative patient diary scores and spontaneously reported cough. This difference was most apparent in the subgroup of patients who previously experienced cough associated with enalapril therapy. Patients with prior ACEI-associated cough may experience less frequent with fosinopril.