Effects of antiepileptic comedication on levetiracetam pharmacokinetics: a pooled analysis of data from randomized adjunctive therapy trials

PURPOSE: To assess the influence of commonly used antiepileptic drugs (AEDs) on levetiracetam pharmacokinetics at steady state. METHODS: Plasma levetiracetam concentrations at steady state were determined by capillary gas chromatography in 590 epilepsy patients included in phase III trials and treated with doses of 1000-4000 mg per day in two divided daily doses. The data were pooled and kinetic parameters estimated by repeated measurement covariance analysis on log-transformed dose-adjusted concentrations (regression line as function of time elapsed since last dose). RESULTS: Estimated pharmacokinetic values, normalized to a dose of 1 mgkg(-1) b.i.d., were: concentration at 1h (C(1h)) 2.1 microgram ml(-1), concentration at 12h (C(12h)) 0.8 microgram ml(-1), area under the curve from 0 to 12h (AUC(0-12h)) 17.1 microgram ml(-1)h, half-life (t(1/2)) 8.1h, and apparent oral clearance (CL/F) 0.97 mlmin(-1)kg(-1). Parameters were similar between genders and among dosage subgroups. Compared with patients receiving comedication not considered to affect drug metabolizing enzymes (gabapentin, lamotrigine, vigabatrin), levetiracetam concentrations and t(1/2) tended to be lower in patients receiving enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbital, primidone) and higher in patients receiving valproic acid, but the differences were modest. CONCLUSIONS: Estimated parameters were dose independent, comparable to those from smaller scale studies and not affected to any major extent by gender or comedication with other AEDs. Based on this, no need is anticipated for adjusting levetiracetam dosage according to type of concomitantly prescribed AEDs.     

Cadazolid for the treatment of Clostridium difficile

Introduction: Antibiotic development goals for CDI include potent antimicrobial effect against C. difficile, limited killing of host microbiota, potential effect on spores, and ability to interfere with toxin production. Cadazolid, a novel, non-absorbable hybrid antibiotic has many of these criteria. In phase I and II clinical trials, cadazolid was shown to be safe, well tolerated, and efficacious positioning itself as a potential future viable therapeutic option for CDI.

Areas covered: This review provides an in-depth evaluation of the chemistry, microbiology, pharmacodynamics, pharmacokinetics, and clinical trial results for cadazolid. Clinical therapeutic outcomes are compared between cadazolid, fidaxomicin, and surotomycin.

Expert opinion: Preclinical and early clinical studies demonstrated that cadazolid has unique properties that will likely be valuable to treat CDI and reduce recurrent infection. With compelling phase II clinical results, results from the ongoing phase III trial will better define the role of cadazolid for treating CDI in the future.     

Investigating the potential of erythromycin and derivatives as chiral selector in capillary electrophoresis

Macrocyclic antibiotics are present in an increasing number of chiral separation applications. In this study, erythromycin and some derivatives, belonging to the group of macrolide antibiotics, were investigated for their potential as chiral selector. Erythromycin A itself and five related substances namely erythromycin A N-oxide, anhydroerythromycin A, anhydroerythromycin A N-oxide, erythralosamine and erythralosamine N-oxide were included. Twenty-one chiral compounds with a wide difference in physico-chemical properties were used to test the chiral activity of the erythromycins. The chiral compounds were analysed using capillary zone electrophoresis with the erythromycins dissolved in the running buffer at different concentrations ranging from 0.1 to 10 mM, with three different BGEs: sodium phosphate pHs 3.0 and 7.0 and sodium borate pH 9.2. The erythromycins showed more interactions with the acidic compounds (as observed with leucovorin, dopa, carbidopa, ketoprofen, indoprofen and warfarin) than with the neutral or weakly basic ones, especially in acidic medium. Unfortunately, no chiral separations were obtained for any of the 21 racemic mixtures. The complexation constants were calculated for the compounds showing interaction, based on the variation of electrophoretic mobility of the compounds in the presence of different concentrations of erythromycins. Finally, the size of erythromycin A was calculated using computational modelling. It was shown that the aglycone ring is only half as big as the β-cyclodextrin cavity, giving a possible explanation for the negative response of erythromycin in this study.     

Do pharmacists' reports of adverse drug reactions reflect patients' concerns?

Aim: The aim of the present study was to investigate whether the concerns patients express to a Drug Information Line about possible adverse drug reactions (ADRs) they have experienced, are sufficiently reflected by the ADR reports submitted by pharmacists to the Netherlands Pharmacovigilance Centre Lareb with regard to the type of ADRs and the drug groups involved. Methods: ADR-related questions patients addressed to the Dutch Drugs Information Line were compared with the ADR reports pharmacists sent in to Lareb in the same period. The similarities and differences between the characteristics of the suspected ADRs and the kinds of drugs mentioned were investigated, as well as the severity of the reported ADRs. To compare the two data sets and to establish whether significant differences were present, a logistic regression analysis was conducted on the reported drugs and ADRs. Results: Analysis of the content of the phone calls yielded 1168 (14.6%) calls concerning possible experienced ADRs. The suspected ADRs pharmacists reported to the Netherlands Pharmacovigilance Centre Lareb in the same period included 1734 reports. There were only slight differences between the queries patients put to the Drug Information Line regarding possible adverse drug reactions and the reports on suspected ADRs pharmacists submitted to the pharmacovigilance centre. With respect to possible ADRs in the psychiatric spectrum and ADRs associated with the use of antidepressants, there seems to be a deficiency in the reporting by pharmacists. Conclusion: The ADRs pharmacists report to the national pharmacovigilance centre reflect patients' concerns about ADRs they experience in relation to the medication they are taking.     

Expectations of general practitioners and specialist doctors regarding the feedback received after reporting an adverse drug reaction

OBJECTIVE: Aim of this study is to gain insight in experiences and expectations of general practitioners and specialist doctors regarding the feedback information of the Netherlands Pharmacovigilance Centre Lareb. METHOD: A questionnaire survey was conducted among a random sample of 400 doctors, divided in general practitioners and specialist doctors. Within these groups, a difference was made between those who reported only once and those who are frequent reporters. A structured questionnaire consisted of 23 questions about expectations, experiences, the influence of feedback information and what the doctors would like to change in the feedback from Lareb. A comparison between the groups will give insight in what they think separately and how Lareb can seize on their wishes. KEY FINDINGS: The response rate was 54.4% (n = 217) after one reminder. The respondents are satisfied with the feedback information and regarded the information of good quality. The expectations were higher on information about sources (significance 0.00, caused by specialist doctors who reported once) and co-medication (0.025 caused by all groups). The experiences of the four groups were also very positive. They all find the feedback information of Lareb reliable, scientifically well considered and to the point. CONCLUSIONS: General practitioners and specialist doctors are satisfied about the follow-up information and they like to see the same format of information and communication in the future.     

Quantification of carbamazepine, carbamazepine-10,11-epoxide, phenytoin and phenobarbital in plasma samples by stir bar-sorptive extraction and liquid chromatography

A sensitive and reproducible stir bar-sorptive extraction and high-performance liquid chromatography-UV detection (SBSE/HPLC-UV) method for therapeutic drug monitoring of carbamazepine, carbamazepine-10,11-epoxide, phenytoin and phenobarbital in plasma samples is described and compared with a liquid:liquid extraction (LLE/HPLC-UV) method. Important factors in the optimization of SBSE efficiency such as pH, extraction time and desorption conditions (solvents, mode magnetic stir, mode ultrasonic stir, time and number of steps) assured recoveries ranging from 72 to 86%, except for phenytoin (62%). Separation was obtained using a reverse phase C(18) column with UV detection (210nm). The mobile phase consisted of water:acetonitrile (78:22, v/v). The SBSE/HPLC-UV method was linear over a working range of 0.08-40.0mugmL(-1) for carbamazepine, carbamazepine-10,11-epoxide and phenobarbital and 0.125-40.0mugmL(-1) for phenytoin, The intra-assay and inter-assay precision and accuracy were studied at three concentrations (1.0, 4.0 and 20.0mugmL(-1)). The intra-assay coefficients of variation (CVs) for all compounds were less than 8.8% and all inter-CVs were less than 10%. Limits of quantification were 0.08mugmL(-1) for carbamazepine, carbamazepine-10,11-epoxide and phenobarbital and 0.125mugmL(-1) for phenytoin. No interference of the drugs normally associated with antiepileptic drugs was observed. Based on figures of merit results, the SBSE/HPLC-UV proved adequate for antiepileptic drugs analyses from therapeutic levels. This method was successfully applied to the analysis of real samples and was as effective as the LLE/HPLC-UV method.     

Health Care Costs and the Socioeconomic Consequences of Work Injuries in Brazil: A Longitudinal Study

Work injuries are a worldwide public health problem but little is known about their socioeconomic impact. This prospective longitudinal study estimates the direct health care costs and socioeconomic consequences of work injuries for 406 workers identified in the emergency departments of the two largest public hospitals in Salvador, Brazil, from June through September 2005. After hospital discharge workers were followed up monthly until their return to work. Most insured workers were unaware of their rights or of how to obtain insurance benefits (81.6%). Approximately half the cases suffered loss of earnings, and women were more frequently dismissed than men. The most frequently reported family consequences were: need for a family member to act as a caregiver and difficulties with daily expenses. Total costs were US$40,077.00 but individual costs varied widely, according to injury severity. Out-of-pocket costs accounted for the highest proportion of total costs (50.5%) and increased with severity (57.6%). Most out-of-pocket costs were related to transport and purchasing medicines and other wound care products. The second largest contribution (40.6%) came from the public National Health System − SUS. Employer participation was negligible. Health care funding must be discussed to alleviate the economic burden of work injuries on workers.     

Potential therapeutic effect of Allium cepa L. and quercetin in a murine model of Blomia tropicalis induced asthma

Background

Asthma is an inflammatory condition characterized by airway hyperresponsiveness and chronic inflammation. The resolution of inflammation is an essential process to treat this condition. In this study we investigated the effect of Allium cepa L. extract (AcE) and quercetin (Qt) on cytokine and on smooth muscle contraction in vitro and its therapeutic potential in a murine model of asthma.

Methods

AcE was obtained by maceration of Allium cepa L. and it was standardized in terms of quercetin concentration using high performance liquid chromatography (HPLC). In vitro, using AcE 10, 100 or 1000 μg/ml or Qt 3.5, 7.5, 15 μg/ml, we measured the concentration of cytokines in spleen cell culture supernatants, and the ability to relax tracheal smooth muscle from A/J mice. In vivo, Blomia tropicalis (BT)-sensitized A/J mice were treated with AcE 100, 1000 mg/kg or 30 mg/kg Qt. We measured cell influx in bronchoalveolar lavage (BAL), eosinophil peroxidase (EPO) in lungs, serum levels of Bt-specific IgE, cytokines levels in BAL, and lung histology.

Results

We observed a reduction in the production of inflammatory cytokines, a relaxation of tracheal rings, and a reduction in total number of cells in BAL and EPO in lungs by treatment with AcE or Qt.

Conclusion

AcE and Qt have potential as antiasthmatic drugs, as they possess both immunomodulatory and bronchodilatory properties.     

Ridinilazole for the treatment of Clostridioides difficile infection

Introduction: Ridinilazole is a novel antibiotic being developed for the treatment of Clostridioides difficile infection (CDI). Ridinilazole has completed two phase II trials and phase III trials which are denoted Ri-CoDIFy 1 and 2, are planned (ClinicalTrials.gov identifiers: NCT03595553 and NCT03595566).

Areas covered: This article covers the chemistry, mechanism of action, in vitro microbiology versus C. difficile and host microbiota, pre-clinical and clinical efficacy, pharmacokinetics, pharmacodynamics and safety and tolerability of ridinilazole.

Expert opinion: Ridinilazole is a novel antibiotic with ideal properties for the treatment of CDI. Given the promising results from the phase II clinical trial, ridinilazole may have the capability to lower the risk for CDI recurrence thus improving sustained clinical response rates – a current unmet medical need. Assuming a positive phase III trial, ridinilazole will enter a market with heightened awareness on the importance of prevention of CDI. This along with further research into the economic consequences and decreased patient quality of life associated with recurrent CDI, should provide clinicians with further evidence for the need for therapy that limits CDI recurrence and improves sustained clinical cure.