Bioequivalence study of two perindopril tert-butylamine tablet formulations in healthy Chinese subjects under fasting and fed conditions: A randomized, open-label, single-dose, crossover trial.

BACKGROUND: To evaluate the bioequivalence between test and reference formulations of perindopril tert-butylamine under fasting and fed conditions and to assess their pharmacokinetic (PK) and safety profiles. METHOD: A randomized, open-label, single-dose, crossover trial was conducted in healthy Chinese subjects. Test or reference perindopril tert-butylamine tablets (4 mg) were randomly given to subjects under fasting (2-period crossover, with an administration sequence of test tablet (T), reference tablet (R) or RT) and fed (4-period crossover, with an administration sequence of TRTR or RTRT) conditions, while each single administration was followed by a 14-day washout period. The plasma concentrations and corresponding non-compartmental PK parameters of perindopril and perindoprilat were determined. The two formulations were considered to be bioequivalent if the 90 % confidence intervals (CIs) of the geometric mean (GM) ratio (test/reference) for Cmax, AUC0-t, and AUC0-∞ (perindopril) was both within the range of 80-125 %. Safety assessments including vital signs, physical examination, laboratory examination, 12-lead ECG and reports of treatment emergent adverse events (TEAEs) were carefully documented. RESULTS: A total of 64 subjects (32 in each trial) were randomized and all completed the trials. Regardless of fasting or fed trials, the PK characteristics of perindopril and perindoprilat for the test formulation were similar to those of the reference formulation (all P > 0.05). The 90 % CIs of the geometric mean (GM) ratio for Cmax, AUC0-t, and AUC0-∞, respectively, were 92.86-106.81 %, 98.44-102.88 % and 98.48-103.02 % under the fasting condition and 90.64-110.04 %, 96.95-101.90 % and 96.83-101.78 % under the fed condition, which were both within the pre-specified range of 80-125 %. A total of 10 (31.3 %) fasted subjects and 11 (34.4 %) fed subjects experienced 11 and 24 TEAEs, respectively, all of which were within the severity of grade 1. The incidence of TEAEs and drug-related TEAEs were similar between test and reference formulations (all P > 0.05) and no serious TEAEs or deaths occurred during the trials. CONCLUSIONS: The test and reference formulations of perindopril tert-butylamine tablets (4 mg) were bioequivalent and well tolerated in healthy Chinese subjects under fasting and fed conditions.

Results of a phase 2 trial of an oral CXCR4 antagonist, mavorixafor, for treatment of WHIM syndrome.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare primary immunodeficiency caused by gain-of-function mutations in the CXCR4 gene. We report the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mavorixafor from a phase 2 open-label dose-escalation and extension study in 8 adult patients with genetically confirmed WHIM syndrome. Mavorixafor is an oral small molecule selective antagonist of the CXCR4 receptor that increases mobilization and trafficking of white blood cells from the bone marrow. Patients received escalating doses of mavorixafor, up to 400 mg once daily. Five patients continued on the extension study for up to 28.6 months. Mavorixafor was well tolerated with no treatment-related serious adverse events. At a median follow-up of 16.5 months, we observed dose-dependent increases in absolute neutrophil count (ANC) and absolute lymphocyte count (ALC). At doses ≥300 mg/d, ANC was maintained at >500 cells per microliter for a median of 12.6 hours, and ALC was maintained at >1000 cells per microliter for up to 16.9 hours. Continued follow-up on the extension study resulted in a yearly infection rate that decreased from 4.63 events (95% confidence interval, 3.3-6.3) in the 12 months prior to the trial to 2.27 events (95% confidence interval, 1.4-3.5) for patients on effective doses. We observed an average 75% reduction in the number of cutaneous warts. This study demonstrates that mavorixafor, 400 mg once daily, mobilizes neutrophil and lymphocytes in adult patients with WHIM syndrome and provides preliminary evidence of clinical benefit for patients on long-term therapy. The trial was registered at www.clinicaltrials.gov as #NCT03005327.

Cardiac Arrest Due to Benzonatate Overdose.

BACKGROUND Benzonatate is one of the most widely prescribed nonnarcotic antitussives to relieve cough symptoms. As a structurally similar agent to other local anesthetics, including tetracaine and procaine, the risk to the public is not fully appreciated. CASE REPORT A 37-year-old female presented to the Emergency Department (ED) status post cardiac arrest. Advanced cardiac life support (ACLS) protocol was performed, and return of spontaneous circulation (ROSC) was achieved. Total downtime was 30 minutes. The patient was intubated, sedated, and hypothermia protocol was initiated. The patient developed bradyarrhythmia and mild coagulopathy suspicious for disseminated intravascular coagulation (DIC), thus hypothermia protocol was terminated later. A review of laboratory data showed acidosis with pH of 6.87, mixed acidosis secondary to high anion gap metabolic and respiratory acidosis with elevated liver enzymes. It was reported that approximately 2 hours prior to her presentation; the patient had ingested less than 30 pills of benzonatate 200 mg capsules with alcohol. CONCLUSIONS Ingestion of benzonatate, a widely prescribed antitussive, may pose a risk to patients due to the potential for rapid development of life-threatening adverse events and limited treatment options in the overdose setting, not only in children but also in adults. Rational prescribing and patient education are needed.

Endoplasmic Reticulum Stress Is Involved in Nucleus Pulposus Degeneration and Attenuates Low pH-Induced Apoptosis of Rat Nucleus Pulposus Cells.

The microenvironment of degenerative intervertebral disk (IVD) is characteristic of a high concentration of lactic acid and low pH levels, whereas the underlying mechanism has not been clearly defined. Endoplasmic reticulum (ER) is the hub of interactions between environmental signals and cellular biological functions, the malfunction of which is closely involved in the pathogenesis of multiple disorders, including IVD degeneration (IVDD). This research mainly aims at exploring what role ER stress plays in the natural process of IVDD and pH-induced apoptosis of rat nucleus pulposus (NP) cells (NPCs). The IVD of Sprague-Dawley rats at different ages was stained by Hematoxylin-Eosin staining to visualize the histocytological changes during the nature process of IVDD. Immunohistochemical staining was performed to evaluate the expression of ER stress markers within normal and degenerated NP. The ER stress markers were also quantified by quantitative real-time-polymerase chain reaction (PCR) and Western blotting analysis, respectively. NPCs were exposed to the culturing media with acidity of pH 7.4, 7.0, 6.5, or 6.0 for 24-72 h, with or without the supplement of 4-phenylbutyrayte (4-PBA, the blocker of ER stress pathways). Changes in cell viability were evaluated by CCK-8 assay and neutral red assay, whereas apoptosis was stained by Annexin-V/PI staining and quantified by flow cytometry analysis. The acidity-induced changes in the expression of ER stress markers were studied by immunofluorescent staining, qRT-PCR, and Western blotting analysis. In vivo, the expression of GRP78 and XBP1 was downregulated whereas CHOP and Caspase12 were upregulated in natural degeneration. In vitro, low pH induced apoptosis of rat NPCs; prolonged exposure of acid reduced cell viability and caused upregulation of ER stress markers. 4-PBA was used to alleviate ER stress, and it promoted acid-induced apoptosis of NPCs. ER stress is involved in NP natural degeneration and attenuates low-pH-induced apoptosis of NPCs.

Inhibition of monoamine oxidase (MAO) by α-ethylphenethylamine and N,α-diethylphenethylamine, two compounds related to dietary supplements.

Phenethylamines can interact with the metabolic enzyme monoamine oxidase (MAO), which can cause neurochemical dysfunction or changes in drug potency. A methamphetamine analog, N,α-diethylphenethylamine (N,α-DEPEA), was recently discovered in athletic performance-enhancing supplements, along with discovery of its metabolite, α-ethylphenethylamine (AEPEA). In vitro inhibition of human recombinant MAO by AEPEA and N,α-DEPEA was evaluated by measuring the fluorescence of 4-hydroxyquinoline produced from MAO substrate, kynuramine. AEPEA competitively inhibited human recombinant MAO A (Ki = 14.0 µM), which was 17-fold stronger compared to MAO B (Ki = 234 µM). Furthermore, N,α-DEPEA was a weak inhibitor of both MAO A (Ki = 251 µM) and MAO B (Ki = 159 µM). Trends regarding MAO A inhibition were explored among structural analogs, yielding the following ranking: amphetamine (Ki = 5.3 µM), AEPEA (Ki = 14.0 µM), methamphetamine (Ki = 17.2 µM), phentermine (Ki = 196 µM), and N,α-DEPEA (Ki = 251 µM). This study provides important data relating chemical structures and biochemical effects for two emerging compounds associated with dietary supplements.

Analysis of benzonatate overdoses among adults and children from 1969-2010 by the United States Food and Drug Administration.

STUDY OBJECTIVE: To augment the December 2010 United States Food and Drug Administration (FDA) Drug Safety Communication on accidental ingestion of benzonatate in children less than 10 years old by summarizing data on emergency department visits, benzonatate exposure, and reports of benzonatate overdoses from several data sources. DESIGN: Retrospective review of adverse-event reports and drug utilization data of benzonatate. DATA SOURCES: The FDA Adverse Event Reporting System (AERS) database (1969-2010), the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance Project (NEISS-CADES, 2004-2009), and the IMS commercial data vendor (2004-2009). PATIENTS: Any patient who reported an adverse event with benzonatate captured in the AERS or NEISS-CADES database or received a prescription for benzonatate according to the IMS commercial data vendor. MEASUREMENTS AND MAIN RESULTS: Postmarketing adverse events with benzonatate were collected from the AERS database, emergency department visits due to adverse events with benzonatate were collected from the NEISS-CADES database, and outpatient drug utilization data were collected from the IMS commercial data vendor. Of 31 overdose cases involving benzonatate reported in the AERS database, 20 had a fatal outcome, and five of these fatalities occurred from accidental ingestions in children 2 years of age and younger. The NEISS-CADES database captured emergency department visits involving 12 cases of overdose from accidental benzonatate ingestions in children aged 1-3 years. Signs and symptoms of overdose included seizures, cardiac arrest, coma, brain edema or anoxic encephalopathy, apnea, tachycardia, and respiratory arrest and occurred in some patients within 15 minutes of ingestion. Dispensed benzonatate prescriptions increased by approximately 52% from 2004 to 2009. CONCLUSION: Although benzonatate has a long history of safe use, accumulating cases of fatal overdose, especially in children, prompted the FDA to notify health care professionals about the risks of benzonatate overdose. Pharmacists may have a role in preventing benzonatate overdoses by counseling patients on signs and symptoms of benzonatate overdose, the need for immediate medical care, and safe storage and disposal of benzonatate.

PD0084430: a non-nucleoside inhibitor of human cytomegalovirus replication in vitro.

Human cytomegalovirus (HCMV) is a major opportunistic pathogen in immunocompromised individuals. Current therapies target viral DNA replication and accumulate mutations that yield cross-resistance among the approved drugs. A novel, non-nucleoside inhibitor of HCMV replication, PD0084430, was identified in a screening assay using the HCMV beta-galactosidase recombinant RC256. The EC(50) for PD0084430 by inhibition of beta-galactosidase production is 1+/-0.7 microM. This antiviral activity was confirmed by yield reduction and plaque reduction assays using HCMV strain AD169. The TC(50) of PD0084430 as measured by (4C)thymidine incorporation is approximately 30 microM and by XTT is approximately 90 microM. The TC(50) for inhibition of cellular proliferation is approximately 20 microM. Time of addition experiments displayed a similar drop in efficacy for both PD0084430 and GCV when added after the onset of viral DNA replication. The transcomplementation assay for viral DNA replication, using a transfected ori(Lyt) containing plasmid, confirmed that viral DNA synthesis was inhibited at the same concentrations that showed antiviral activity. Western blots showed no apparent block of immediate early or early gene expression. Two ganciclovir (GCV) resistant isolates of HCMV tested showed no cross-resistance to PD0084430. These data suggested a potentially promising novel compound that inhibited HCMV at or before viral DNA replication. However, in vivo testing in mice dosed either orally or intraperitoneally showed rapid glucuronidation on the -OH group. SAR studies on this backbone showed that the -OH group was essential for the antiviral activity in vitro.

CYP2D6 and CYP2C19 genotypes of patients with terodiline cardiotoxicity identified through the yellow card system.

AIMS: Terodiline has concentration dependent QT prolonging effects and thus the potential for cardiotoxicity. Pharmacogenetic variation in terodiline metabolism could be responsible for cardiotoxicity. We sought to determine whether CYP2D6 (debrisoquine hydroxylase) or CYP2C19 (S-mephenytoin hydroxylase) status is a risk factor for terodiline cardiotoxicity. METHODS: Using the UK Yellow Card scheme to identify patients, blood samples were obtained from eight patients who survived ventricular tachycardia or torsades de pointes suspected to be due to terodiline, for determination of CYP2D6 and CYP2C19 genotypes. Genotype prevalence was compared with that in published general population groups. RESULTS: One patient was a CYP2D6 poor metaboliser (CYP2D6*4 homozygous) and a second was heterozygous for CYP2D6*4, a slightly lower frequency for these genotypes compared with the general population (P = 0.31). In the case of CYP2C19, one patient was a poor metaboliser and four were heterozygous for the variant CYP2C19*2 allele, compared with general population frequencies of 2% and 23%, respectively (P = 0.035). CONCLUSIONS: These findings suggest that debrisoquine poor metaboliser status is not primarily responsible for terodiline cardiotoxicity. However, possession of the CYP2C19*2 allele appears to contribute to adverse cardiac reactions to terodiline. The present study demonstrates the feasibility of using spontaneous adverse drug reaction reporting schemes to determine the contribution of genotype for metabolizing enzymes to uncommon adverse drug reactions.

Pharmacokinetics and pharmacodynamics of the monoamine oxidase B inhibitor mofegiline assessed during a phase I dose tolerance trial.

The safety, pharmacokinetics, and pharmacodynamics of single oral doses of up to 48 mg and daily (for 28 days) doses of up 24 mg mofegiline were investigated in healthy male volunteers. Plasma pharmacokinetics indicated rapid absorption and elimination: time to reach maximum concentration occurred at about 1 hour; half-life ranged from 1 to 3 hours. Maximal plasma concentration and area under the plasma concentration-time curve increased and oral clearance decreased disproportionately with dose. Mofegiline rapidly and markedly inhibited platelet monoamine oxidase B (MAOB) activity, which returned to baseline within 14 days. Urinary excretion of phenylethylamine increased proportionately with doses up to 24 mg. No changes in urinary elimination of catecholamines, blood pressure, heart rate, or ECG were observed. A classic maximum tolerated dose was not achieved in these studies. However, the 48 mg single dose and the 24 mg multiple daily dose far exceeded the dose (1 mg) that was associated with > 90% platelet MAOB inhibition.

Concentration dependent cardiotoxicity of terodiline in patients treated for urinary incontinence.

OBJECTIVE: Terodiline, an antimuscarinic and calcium antagonist drug, was used to treat detrusor instability but was withdrawn in 1991 after provoking serious ventricular arrhythmias associated with increases in the corrected QT interval (QTc). This research was performed to relate drug induced electrocardiographic changes in asymptomatic recipients to plasma concentrations of the R(+) and S(-) terodiline enantiomers. SETTING: Urological and geriatric clinics and wards. SUBJECTS: Asymptomatic patients taking terodiline in stable dose. METHODS: Electrocardiograms (50 mm/s) were collected from patients while they were taking terodiline and compared with ECGs obtained before or after terodiline. QT interval, heart rate corrected QT interval (QTc), and QT dispersion (QTd) were measured. Drug induced electrocardiographic changes were related to plasma concentrations of R(+) and S(-) terodiline. RESULTS: During terodiline treatment mean QTc and QTd were prolonged (491(43) and 84 (35) ms 1/2) compared with measurements made off therapy (443 (33) and 42 (17) ms 1/2, paired t tests, P < 0.002 and P < 0.01 respectively) in the 12 patients in sinus rhythm. The mean (95% confidence interval) drug induced increases were 48 (23 to 74) ms 1/2 for QTc and 42 (13 to 70) ms 1/2 for QTd. These increases correlated with total plasma terodiline (QTc: r = 0.77, P < 0.006, QTd: r = 0.68, P < 0.025) and with plasma concentrations of both terodiline enantiomers. CONCLUSIONS: Terodiline increases QTc and QTd in a concentration dependent manner. It is not clear whether this is a stereoselective effect and, if so, which enantiomer is responsible. The results suggest that drug induced torsade de pointes is a type A (concentration dependent) adverse drug reaction.

Concomitant single-dose and multiple-dose pharmacokinetics of terodiline in man, with a note on its enantiomers and major metabolites.

Single-dose and multiple-dose pharmacokinetics of terodiline were studied in 20 healthy volunteers by giving an initial oral dose of deuterium-labelled terodiline (12.5 mg or 25 mg) followed by multiple doses of Mictrol tablets (12.5 mg b.i.d. for 14 days and 25 mg b.i.d. for 14 days or vice versa). The enantiomer serum concentration ratio of S(-)/R(+) terodiline was close to unity at steady-state as well as during the disposition phase. The average single-dose kinetic parameters for the racemate after the 12.5 mg dose were: maximum serum concentration 41 micrograms/l, the corresponding time 3.4 hr, terminal half-life 61 hr, oral clearance 77 ml/min., renal clearance 12 ml/min. and apparent volume of distribution 382 1. The single-dose kinetics for the 25 mg dose and the multiple-dose kinetic parameters showed that linear kinetics prevailed. The average steady-state serum concentration was 275 micrograms/l at the lower dose and 509 micrograms/l at the higher dose. The degree of fluctuation during a dosage interval was 19% and the time to steady-state was about 9 days. The fraction unbound was about 8%. Unconjugated p-hydroxylated terodiline, p-hydroxy-m-methoxyterodiline and hydroxy-tert-butyl-terodiline constituted 15%, < 1% and 5%, respectively, of the terodiline steady-state levels.

Randomized double-blind trial of terodiline in the treatment of urge incontinence in women.

OBJECTIVE: To evaluate the effects of terodiline in women with urge incontinence. METHODS: After a 2-week run-in period, 93 women with urinary frequency and urge incontinence were randomized to either placebo or terodiline, 25 mg twice daily, in a double-blind study for 4 weeks. Symptoms were evaluated using daily frequency-volume charts to record voiding frequency, number of incontinent episodes, absorbent pad use, and quality of life. RESULTS: The terodiline group showed a 70% decrease in the mean (+/- standard deviation) number of incontinent episodes per week (15.8 +/- 24, decreasing to 4.9 +/- 11.9; P < .01), which persisted throughout the study period. The placebo group achieved a 9% reduction in the mean number of incontinent episodes (13.0 +/- 11.3, decreasing to 11.9 +/- 16; P < .05) only in the final week of treatment. Side effects, especially anticholinergic side effects, were more common in the terodiline group, but resulted in only one dropout. Both the treated and placebo groups improved in daytime frequency and quality-of-life indices. CONCLUSION: Terodiline is well tolerated and effective in reducing urge incontinent episodes in women.

Is QT interval prolongation harmful? A regulatory perspective.

Drugs that prolong the QT interval may increase the risk of torsades de pointes, a potentially lethal ventricular arrhythmia. In recent years, spontaneous reports have highlighted these complications in patients receiving certain antihistamines (e.g., terfenadine or astemizole) or an agent for the treatment of incontinence (terodiline). Examination of these reports has revealed that hepatic disease or concomitant therapy with ketoconazole or macrolide antibiotics may increase the risk of QT prolongation or torsades in patients receiving terfenadine. In patients receiving astemizole, doses exceeding that recommended or concomitant therapy with ketoconazole or macrolide antibiotics have been implicated in the increased risk of these complications. With terodiline (which remains investigational in the United States), the risk of QT prolongation and torsades are of particular concern in the frail elderly, who are most likely to be treated with this agent. A possible explanation for the elevated risk may be marked increases in the elimination half-life and serum level of the drug in this group. The lessons learned from the experiences with these drugs hold implications for the future development of agents that prolong the QT interval and suggest the need for dose-response relation data and metabolic evaluations to define the subpopulations at particular risk.

[Torsades de pointes ventricular tachycardia caused by terodiline (Mictrol)?]. / Torsades de pointes ventrikulaer takykardi udløst af terodilin (Mictrol)?

We report a 84 year old man taking terodiline who had torsades de pointes ventricular tachycardia with prolongation of the QT-interval. The QT-interval became normal after withdrawal of terodiline. Worldwide, the manufacturers have received a total of 37 reports of ventricular tachyarrhythmia during the past months, 28 of which were torsades de pointes ventricular tachycardia and have decided to recall the product temporarily.

[Clinical study of terodiline hydrochloride for the treatment of urinary frequency and urinary incontinence, and its cardiovascular adverse effects].

We evaluated the effectiveness and side effects of terodiline hydrochloride in 109 patients with urinary frequency and urinary incontinence. The drug was administered at a dose of 24 mg once a day or 12 mg twice a day for 4 weeks. Symptoms such as urinary frequency and urinary incontinence were alleviated in 101 out of 109 patients (92.7%). Mild side effects such as thirst, dysuria, sense of residual urine, orthostatic hypotension and arrhythmia were observed in 9 out of 109 patients (8.2%). Side effects such as orthostatic hypotension and arrhythmia were observed on the 28th day or the 20th day of the administration, but these symptoms disappeared with discontinued use of this medicine. The results obtained from this study suggest that terodiline hydrochloride may be greatly useful for the patients with urinary frequency and urinary incontinence. But we must take account of the side effects such as orthostatic hypotension and arrhythmia.