Optimizing Moxifloxacin Dose in MDR-TB Participants with or without Efavirenz Coadministration Using Population Pharmacokinetic Modeling.

Moxifloxacin is included in some treatment regimens for drug-sensitive tuberculosis (TB) and multidrug-resistant TB (MDR-TB). Aiming to optimize dosing, we described moxifloxacin pharmacokinetic and MIC distribution in participants with MDR-TB. Participants enrolled at two TB hospitals in South Africa underwent intensive pharmacokinetic sampling approximately 1 to 6 weeks after treatment initiation. Plasma drug concentrations and clinical data were analyzed using nonlinear mixed-effects modeling with simulations to evaluate doses for different scenarios. We enrolled 131 participants (54 females), with median age of 35.7 (interquartile range, 28.5 to 43.5) years, median weight of 47 (42.0 to 54.0) kg, and median fat-free mass of 40.1 (32.3 to 44.7) kg; 79 were HIV positive, 29 of whom were on efavirenz-based antiretroviral therapy. Moxifloxacin pharmacokinetics were described with a 2-compartment model, transit absorption, and elimination via a liver compartment. We included allometry based on fat-free mass to estimate disposition parameters. We estimated an oral clearance for a typical patient to be 17.6 L/h. Participants treated with efavirenz had increased clearance, resulting in a 44% reduction in moxifloxacin exposure. Simulations predicted that, even at a median MIC of 0.25 (0.06 to 16) mg/L, the standard daily dose of 400 mg has a low probability of attaining the ratio of the area under the unbound concentration-time curve from 0 to 24 h to the MIC (fAUC0-24)/MIC target of >53, particularly in heavier participants. The high-dose WHO regimen (600 to 800 mg) yielded higher, more balanced exposures across the weight ranges, with better target attainment. When coadministered with efavirenz, moxifloxacin doses of up to 1,000 mg are needed to match these exposures. The safety of higher moxifloxacin doses in clinical settings should be confirmed.

Controlling cleaning agent residues in pharmaceutical manufacturing: A harmonized scientific strategy.

This paper proposes a scientifically justified and harmonized strategy to control cleaning agent ingredients' (CAIs) residues in pharmaceutical manufacturing. Firstly, we demonstrate that worst-case cleaning validation calculations on CAI residues with representative GMP standard cleaning limits (SCLs) are enough to control CAI residues of low concern to safe levels. Secondly, a new harmonized strategy for the toxicological assessment of CAI residues is presented and validated. The results establish a framework applicable to cleaning agent mixtures based on hazard and exposure considerations. This framework is primarily based on the hierarchy of a single CAI's critical effect, where the lowest resulting limit may become the driver of the cleaning validation process. The six critical effect groups are: (1) CAIs of low concern based on safe exposure reasoning; (2) CAIs of low concern based on the mode of action reasoning; (3) CAIs with local concentration-dependent critical effects; (4) CAIs with dose-dependent systemic critical effects for which a route-specific PDE should be calculated; (5) poorly characterized CAIs with unknown critical effect for which a default value of 100 µg/day is proposed; (6) poorly characterized CAIs which should be avoided because of potential mutagenicity and/or potency.

PDE concept for controlling cleaning agent residues in pharmaceuticals- A critical analysis.

Cleaning agents (CAs) are used in multipurpose facilities to control carryover contamination of active pharmaceutical ingredients (APIs) to scientifically justified limits. While this is often done with the PDE methodology used for API impurities, it is unclear if it is justifiable and necessary for cleaning agents, which generally represent a comparatively lower health risk. Comparing calculated oral PDE values for CA ingredients (CAIs) from four companies with PDEs of a selected number of small-molecule APIs showed that the toxicity of CAIs is several orders of magnitude lower. Furthermore, a critical review of the toxicity and everyday exposure to the general population of the main CAIs functional groups showed that the expected health risks are generally negligible. This is particularly true if the associated mode of actions cause local toxicity that is usually irrelevant at the concentration of potential residue carryover. This work points towards alternative approaches to the PDE concept to control CAIs' contamination and provides some guidance on grouping and identifying compounds with lower health risks based on exposure and mode of action reasoning. In addition, this work supports the concept that limit values should only be set for CAIs of toxicological concern.

Ophthalmic Thelazia callipaeda infections: first feline and new canine imported cases in Germany.

The first case of feline ocular Thelazia callipaeda infection and two new canine imported infections in West Germany are here described. The three animals had a history of recent travel to/from other countries. The young adult cat imported from Spain presented an intermittent unilateral ocular discharge. During in-depth ophthalmic examination, a single alive nematode was removed from the conjunctival compartment of the affected eye. Referring to the canine cases, an adult female dog originated from Kenya presented epiphora and mucous whitish-grey discharge of the right eye. During flushing of the nasolacrimal duct two small, thin and long nematodes were removed. Furthermore, a male Borzoi racing dog with regular visit to racing tracks in different countries presented ocular mucous discharge. At ophthalmologic examination, two transparent-whitish vital nematodes were removed. All nematode specimens of the three cases were morphologically identified as adult T. callipaeda parasites. The animals were treated orally with milbemycin oxime (2.0 mg/kg; cat) or milbemycin oxime/praziquantel (0.5 mg/kg and 5.0 mg/kg; dogs) twice with 1-week interval resulting in complete resolution of symptoms. The repeated introduction of patent T. callipaeda-infected animals, especially from southern and eastern endemic countries, will ease the establishment of ophthalmic thelaziosis in Northern Europe. The male fruit fly, Phortica variegata, an intermediate host of T. callipaeda, is endemic within European countries. Considering the clinical and zoonotic relevance of ophthalmic thelaziosis, enhanced disease awareness of European medical and veterinarian doctors and in-depth eye examination for proper detection of T. callipaeda are crucial for appropriate anthelmintic treatments and to limit spreading of the infection.

Pharmacokinetics of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol in Infants Dosed According to Revised WHO-Recommended Treatment Guidelines.

There are limited pharmacokinetic data for use of the first-line antituberculosis drugs during infancy (<12 months of age), when drug disposition may differ. Intensive pharmacokinetic sampling was performed in infants routinely receiving antituberculosis treatment, including rifampin, isoniazid, pyrazinamide, and ethambutol, using World Health Organization-recommended doses. Regulatory-approved single-drug formulations, including two rifampin suspensions, were used on the sampling day. Assays were conducted using liquid chromatography-mass spectrometry; pharmacokinetic parameters were generated using noncompartmental analysis. Thirty-nine infants were studied; 14 (36%) had culture-confirmed tuberculosis. Fifteen (38%) were premature (<37 weeks gestation); 5 (13%) were HIV infected. The mean corrected age and weight were 6.6 months and 6.45 kg, respectively. The mean maximum plasma concentrations (Cmax) for rifampin, isoniazid, pyrazinamide, and ethambutol were 2.9, 7.9, 41.9, and 1.3 µg/ml, respectively (current recommended adult target concentrations: 8 to 24, 3 to 6, 20 to 50, and 2 to 6 µg/ml, respectively), and the mean areas under the concentration-time curves from 0 to 8 h (AUC0-8) were 12.1, 24.7, 239.4, and 5.1 µg · h/ml, respectively. After adjusting for age and weight, rifampin exposures for the two formulations used differed inCmax(geometric mean ratio [GMR],2.55; 95% confidence interval [CI], 1.47 to 4.41;P= 0.001) and AUC0-8(GMR, 2.52; 95% CI, 1.34 to 4.73;P= 0.005). HIV status was associated with lower pyrazinamideCmax(GMR, 0.85; 95% CI, 0.75 to 0.96;P= 0.013) and AUC0-8(GMR, 0.79; 95% CI, 0.69 to 0.90;P< 0.001) values. No other important differences were observed due to age, weight, prematurity, ethnicity, or gender. In summary, isoniazid and pyrazinamide concentrations in infants compared well with proposed adult target concentrations; ethambutol concentrations were lower but similar to previously reported pediatric studies. The low rifampin exposures require further investigation. (This study has been registered at ClinicalTrials.gov under registration no. NCT01637558.).

The interaction between artemether-lumefantrine and lopinavir/ritonavir-based antiretroviral therapy in HIV-1 infected patients.

BACKGROUND: Artemether-lumefantrine is currently the most widely recommended treatment of uncomplicated malaria. Lopinavir-based antiretroviral therapy is the commonly recommended second-line HIV treatment. Artemether and lumefantrine are metabolised by cytochrome P450 isoenzyme CYP3A4, which lopinavir/ritonavir inhibits, potentially causing clinically important drug-drug interactions. METHODS: An adaptive, parallel-design safety and pharmacokinetic study was conducted in HIV-infected (malaria-negative) patients: antiretroviral-naïve and those stable on lopinavir/ritonavir-based antiretrovirals. Both groups received the recommended six-dose artemether-lumefantrine treatment. The primary outcome was day-7 lumefantrine concentrations, as these correlate with antimalarial efficacy. Adverse events were solicited throughout the study, recording the onset, duration, severity, and relationship to artemether-lumefantrine. RESULTS: We enrolled 34 patients. Median day-7 lumefantrine concentrations were almost 10-fold higher in the lopinavir than the antiretroviral-naïve group [3170 versus 336 ng/mL; p = 0.0001], with AUC(0-inf) and Cmax increased five-fold [2478 versus 445 µg.h/mL; p = 0.0001], and three-fold [28.2 versus 8.8 µg/mL; p < 0.0001], respectively. Lumefantrine Cmax, and AUC(0-inf) increased significantly with mg/kg dose in the lopinavir, but not the antiretroviral-naïve group. While artemether exposure was similar between groups, Cmax and AUC(0-8h) of its active metabolite dihydroartemisinin were initially two-fold higher in the lopinavir group [p = 0.004 and p = 0.0013, respectively]. However, this difference was no longer apparent after the last artemether-lumefantrine dose. Within 21 days of starting artemether-lumefantrine there were similar numbers of treatment emergent adverse events (42 vs. 35) and adverse reactions (12 vs. 15, p = 0.21) in the lopinavir and antiretroviral-naïve groups, respectively. There were no serious adverse events and no difference in electrocardiographic QTcF- and PR-intervals, at the predicted lumefantrine Tmax. CONCLUSION: Despite substantially higher lumefantrine exposure, intensive monitoring in our relatively small study raised no safety concerns in HIV-infected patients stable on lopinavir-based antiretroviral therapy given the recommended artemether-lumefantrine dosage. Increased day-7 lumefantrine concentrations have been shown previously to reduce the risk of malaria treatment failure, but further evidence in adult patients co-infected with malaria and HIV is needed to assess the artemether-lumefantrine risk : benefit profile in this vulnerable population fully. Our antiretroviral-naïve patients confirmed previous findings that lumefantrine absorption is almost saturated at currently recommended doses, but this dose-limited absorption was overcome in the lopinavir group. TRIAL REGISTRATION: Clinical Trial Registration number NCT00869700. Registered on clinicaltrials.gov 25 March 2009.

Combinations of potent topical steroids, mercury and hydroquinone are common in internationally manufactured skin-lightening products: a spectroscopic study.

BACKGROUND: The topical steroids betamethasone (BM) and clobetasol propionate (CP) are illegal in cosmetics. Hydroquinone (HQ) and mercury (Hg) are either illegal or allowed only in limited concentrations (2% and 1 ppm, respectively). AIM: To investigate active ingredients and countries of origin of popular skin-lightening products available in Cape Town, South Africa. METHODS: In total, 29 products were examined; of these, 22 products were purchased from informal vendors, and 2 products (out of a total of 29) were purchased over the counter. HQ, Hg(2+) and steroids were quantified by high-performance liquid chromatography-ultraviolet spectrophotometry, inductively coupled plasma-mass spectrometry and liquid chromatography-mass spectrometry, respectively. RESULTS: Of the 29 products, 22 (75.9%), all imported and bought from informal vendors, contained illegal or banned ingredients: 13 (44.8%) contained steroids (9 CP, 4 BM), 12 (41.4%) contained Hg (30-2300 ppm), and 11 (37.9%) contained HQ. Sequentially, the products originated from Italy (27.3%, n = 6), India (22.7%, n = 5), the Democratic Republic of Congo (DRC) (22.7%, n = 5), Cote d'Ivoire (9.1%, n = 2), USA (9.1%, n = 2), UK (4.5%, n = 1) and France (4.5%, n = 1). Two products, one from India and one from the DRC, contained all four ingredients (HQ, Hg, BM, CP). Of the 12 products containing Hg, 10 also contained HQ and/or a steroid, yet none listed Hg as an ingredient. A significant proportion of the steroid-containing products (76.9%) also contained at least one other skin-lightening agent. Not all internationally available products were tested, which is a limitation of the study. CONCLUSION: In spite of a European Union ban on skin lighteners, a third of the products tested were from Europe. Combinations of Hg and ultrapotent steroids were prominent. International law enforcement and random testing is needed to encourage industry compliance and help protect consumers.

Lipid-based nutrient supplements do not affect efavirenz but lower plasma nevirapine concentrations in Ethiopian adult HIV patients.

OBJECTIVES: Lipid-based nutrient supplements (LNSs) are increasingly used in HIV programmes in resource-limited settings. However, the possible effects of LNSs on the plasma concentrations of antiretroviral drugs have not been assessed. Here, we aimed to assess the effects of LNSs on plasma efavirenz and nevirapine trough concentrations in Ethiopian adult HIV-infected patients. METHODS: The effects of LNSs were studied in adults initiating antiretroviral therapy (ART) in a randomized trial. Patients with body mass index (BMI) > 17 kg/m(2) (n = 282) received daily supplementation of an LNS containing whey (LNS/w), an LNS containing soy (LNS/s) or no LNS. Trough plasma concentrations of efavirenz and nevirapine were measured at 1 and 2 months. Genotyping for 516 G>T and 983 T>C polymorphisms of the cytochrome P450 (CYP) 2B6 locus was performed. Multilevel linear mixed-effects models were used to assess the associations between LNS and plasma efavirenz and nevirapine concentrations. RESULTS: In patients with BMI > 17 kg/m(2), nevirapine concentrations were lower in the LNS/w and LNS/s groups by a median of -2.3 µg/mL [interquartile range (IQR) -3.9; -0.9 µg/mL; P = 0.002] and -2.1 µg/mL (IQR -3.9; -0.9 µg/mL; P = 0.01), respectively, compared with the group not receiving supplements. There were no differences between groups with respect to efavirenz plasma concentrations. The CYP2B6 516 G>T polymorphism was associated with a 5 µg/mL higher plasma efavirenz concentration compared with the wild type (P < 0.0001), while it was not associated with plasma nevirapine concentrations. CONCLUSIONS: Intake of an LNS was associated with lower plasma nevirapine trough concentrations, indicating possible drug-LNS interactions. The clinical relevance of such reductions in nevirapine exposure is not clear. Plasma efavirenz concentration was not affected by the LNS.

Pharmacokinetics of ofloxacin and levofloxacin for prevention and treatment of multidrug-resistant tuberculosis in children.

Limited data on fluoroquinolone pharmacokinetics and cardiac effects in children exist. Among 22 children receiving drug-resistant tuberculosis prophylaxis or treatment, serum concentrations following oral doses of levofloxacin (15 mg/kg of body weight) and ofloxacin (20 mg/kg) were lower than those expected from existing pediatric data, possibly due to differences in the formulations (crushed tablets). Drug exposures were lower than those in adults following standard doses and below the proposed pharmacodynamic targets, likely due to more rapid elimination in children. No QT prolongation was observed.

Mapping and engineering RNA-controlled architecture of the multiphase nucleolus.

Biomolecular condensates are key features of intracellular compartmentalization. As the most prominent nuclear condensate in eukaryotes, the nucleolus is a layered multiphase liquid-like structure and the site of ribosome biogenesis. In the nucleolus, ribosomal RNAs (rRNAs) are transcribed and processed, undergoing multiple maturation steps that ultimately result in formation of the ribosomal small subunit (SSU) and large subunit (LSU). However, how rRNA processing is coupled to the layered nucleolar organization is poorly understood due to a lack of tools to precisely monitor and perturb nucleolar rRNA processing dynamics. Here, we developed two complementary approaches to spatiotemporally map rRNA processing and engineer de novo nucleoli. Using sequencing in parallel with imaging, we found that rRNA processing steps are spatially segregated, with sequential maturation of rRNA required for its outward movement through nucleolar phases. Furthermore, by generating synthetic de novo nucleoli through an engineered rDNA plasmid system in cells, we show that defects in SSU processing can alter the ordering of nucleolar phases, resulting in inside-out nucleoli and preventing rRNA outflux, while LSU precursors are necessary to build the outermost layer of the nucleolus. These findings demonstrate how rRNA is both a scaffold and substrate for the nucleolus, with rRNA acting as a programmable blueprint for the multiphase architecture that facilitates assembly of an essential molecular machine.

Detection of karakin poisoning using a targeted mass spectrometric workflow.

Treatment and management of plant toxicosis is made more difficult when an alien plant species is ingested, as identification of the toxin may pose a challenge. High-resolution mass spectrometers are required for the toxicological analysis of samples in these cases owing to their ability to scan large mass ranges and accurately identify mass features. We present this case to highlight the value of this technology in clinical toxicology. A middle-aged woman reported visual impairment, dizziness and numbness of her mouth and tongue following the ingestion of a berry. Over time her condition deteriorated, warranting toxicological analysis. The tree the berry came from was identified as Cornynocarpus laevigatus, which is known to produce the karakin neurotoxin. The patient's samples and the husk and pulp of the berries were analysed using a high-resolution mass spectrometer. This resulted in the identification of the toxin in the berry kernel and husk and patient's hair, suggesting that karakin could have contributed to the patient's condition.

Recency of HIV infection, antiretroviral therapy use and viral loads among symptomatic sexually transmitted infection service attendees in South Africa.

BACKGROUND: Better integration of HIV and sexually transmitted infection (STI) prevention and treatment services is needed to accelerate progress towards the goal of zero new HIV infections. OBJECTIVES: To describe HIV positivity, antiretroviral therapy (ART) use, viral suppression and recency of HIV infection among symptomatic STI service attendees at two primary care clinics in South Africa. METHODS: In a cross-sectional study, male and female STI service attendees presenting with symptoms consistent with STI syndromes were enrolled following informed consent. An interviewer-administered questionnaire was completed and appropriate genital and blood specimens were collected for STI testing and HIV biomarker measurements including recency of infection and antiretroviral (ARV) drug levels. Descriptive statistics were used to describe enrolled attendees, and to determine the proportion of attendees who were HIV-positive, recently infected, taking ART and virally suppressed. HIV-positive attendees with detectable ARVs were considered to be on ART, while those with viral loads (VLs) ≤200 copies/mL were considered virally suppressed. RESULTS: Of 451 symptomatic attendees whose data were analysed, 93 (20.6%) were HIV-positive, with 15/93 (16.1%) being recently infected. Recent infection was independently associated with genital ulcer disease at presentation, especially ulcers with no detectable STI pathogens. Among the 78 (83.9%) with long-term infection, only 30 (38.5%) were on ART, with 23/30 (76.7%) virally suppressed. CONCLUSIONS: In a population at risk of HIV transmission, there was a high burden of recent infection and unsuppressed VLs. Incorporating pre-exposure prophylaxis, ART initiation and adherence support into STI services will be necessary for progress towards eliminating HIV transmission.

Interaction between artemether-lumefantrine and nevirapine-based antiretroviral therapy in HIV-1-infected patients.

Artemether-lumefantrine and nevirapine-based antiretroviral therapy (ART) are the most commonly recommended first-line treatments for malaria and HIV, respectively, in Africa. Artemether, lumefantrine, and nevirapine are metabolized by the cytochrome P450 3A4 enzyme system, which nevirapine induces, creating potential for important drug interactions. In a parallel-design pharmacokinetic study, concentration-time profiles were obtained in two groups of HIV-infected patients: ART-naïve patients and those stable on nevirapine-based therapy. Both groups received the recommended artemether-lumefantrine dose. Patients were admitted for intense pharmacokinetic sampling (0 to 72 h) with outpatient sampling until 21 days. Concentrations of lumefantrine, artemether, dihydroartemisinin, and nevirapine were determined by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. The primary outcome was observed day 7 lumefantrine concentrations, as these are associated with therapeutic response in malaria. We enrolled 36 patients (32 females). Median (range) day 7 lumefantrine concentrations were 622 ng/ml (185 to 2,040 ng/ml) and 336 ng/ml (29 to 934 ng/ml) in the nevirapine and ART-naïve groups, respectively (P = 0.0002). The median artemether area under the plasma concentration-time curve from 0 to 8 h [AUC((0-8 h))] (P < 0.0001) and dihydroartemisinin AUC((60-68 h)) (P = 0.01) were lower in the nevirapine group. Combined artemether and dihydroartemisinin exposure decreased over time only in the nevirapine group (geometric mean ratio [GMR], 0.76 [95% confidence interval {CI}, 0.65 to 0.90]; P < 0.0001) and increased with the weight-adjusted artemether dose (GMR, 2.12 [95% CI, 1.31 to 3.45]; P = 0.002). Adverse events were similar between groups, with no difference in electrocardiographic Fridericia corrected QT and P-R intervals at the expected time of maximum lumefantrine concentration (T(max)). Nevirapine-based ART decreased artemether and dihydroartemisinin AUCs but unexpectedly increased lumefantrine exposure. The mechanism of the lumefantrine interaction remains to be elucidated. Studies investigating the interaction of nevirapine and artemether-lumefantrine in HIV-infected patients with malaria are urgently needed.

Pharmacokinetics of high-dose isoniazid in children affected by multidrug-resistant TB.

BACKGROUND: High-dose isoniazid (INHH) (15-20 mg/kg/day) could be administered to overcome low-level INH resistance, but pharmacokinetic data are sparse.METHODS: This observational study included South African children (<15 years) receiving INHH as preventive therapy, or treatment for multidrug-resistant TB (MDR-TB) exposure or disease. Pharmacokinetic sampling was performed after an INH dose of 20 mg/kg. Non-compartmental analysis and multivariable regression models were used to evaluate associations of key covariates with area under the curve (AUC0-24) and maximum concentration (Cmax). AUC and Cmax values were compared against proposed adult targets.RESULTS: Seventy-seven children were included, with median age of 3.7 years; 51 (66%) had MDR-TB disease and 26 (34%) had MDR-TB exposure. Five were HIV-positive, of whom four were ≥5 years old. The median AUC0-24 was 19.46 µgh/mL (IQR 10.76-50.06) and Cmax was 5.14 µg/mL (IQR 2.69-13.2). In multivariable analysis of children aged <5 years, MDR-TB disease (vs. exposure) was associated with considerably lower AUC0-24 (geometric mean ratio GMR 0.19, 95% CI 0.15-0.26; P < 0.001) and Cmax (GMR 0.20, 95% CI 0.15-0.26; P < 0.001).CONCLUSIONS: INH concentrations in children with MDR-TB disease were much lower than expected, but comparable to previous reports in children with MDR-TB exposure. Further studies should confirm these findings and explore possible causes.

Effect of malnutrition on the pharmacokinetics of anti-TB drugs in Ghanaian children.

BACKGROUND: Anti-TB drugs dosing based on weight alone may contribute to suboptimal drug concentrations and poor treatment outcomes in malnourished children. We examined the effect of malnutrition on the pharmacokinetics (PK) of first-line anti-TB drugs in children.METHODS: Drug concentrations were measured in Ghanaian children during the intensive phase of TB treatment. Weight-for-age (WFA), height-for-age (HFA), weight-for-height (WFH) and body mass index-for-age (BFA) were calculated and children with Z-scores < -2 SD (standard deviations) were considered as having malnutrition. PK differences of anti-TB drugs were compared by nutritional status.RESULTS: Of 100 participants, 24/48 (50.0%) of those younger than 5 years had wasting, 58/86 (67.4%) were underweight, and 56/99 (56.6%) had stunting; 22/51 (43.1%) children aged ≥5 years had low BFA. Children with stunting were more likely than controls to have lower mean peak concentration (Cmax) and area under the curve (AUC0-8h) of rifampin (RIF) and pyrazinamide (PZA), as well as a higher frequency of Cmax below the normal range. Wasting and underweight were associated with lower mean ethambutol (EMB) Cmax and AUC0-8h.CONCLUSIONS: The current WHO-recommended dosages were associated with lower plasma exposure of RIF, PZA and EMB in children with stunting, wasting and underweight. Anti-TB drugs dosing models for children may need to include height.

Effect of tablet crushing on drug exposure in the treatment of multidrug-resistant tuberculosis.

SETTING: Treatment outcomes in multidrug-resistant tuberculosis (MDR-TB) are poor. Due to drug toxicity and a long treatment duration, approximately half of patients are treated successfully. Medication is often crushed for patients who have difficulty swallowing whole tablets. Whether crushing tablets affects drug exposure in MDR-TB treatment is not known.OBJECTIVE AND DESIGN: We performed a sequential pharmacokinetic study in patients aged >18 years on MDR-TB treatment at two hospitals in Cape Town, South Africa. We compared the bioavailability of pyrazinamide, moxifloxacin, isoniazid (INH), ethambutol and terizidone when the tablets were crushed and mixed with water before administration vs. swallowed whole. We sampled blood at six time points over 10 h under each condition separated by 2 weeks. Non-compartmental analysis was used to derive the key pharmacokinetic measurements.RESULTS: Twenty participants completed the study: 15 were men, and the median age was 31.5 years. There was a 42% reduction in the area under the curve AUC0-10 of INH when the tablets were crushed compared with whole tablets (geometric mean ratio 58%; 90%CI 47-73). Crushing tablets of pyrazinamide, moxifloxacin, ethambutol and terizidone did not affect the bioavailability significantly.CONCLUSION: We recommend that crushing of INH tablets in the MDR-TB treatment regimen be avoided. Paediatric INH formulations may be a viable alternative if the crushing of INH tablets is indicated.

"A change would do you good": Training medical students in Motivational Interviewing using a blended-learning approach - A pilot evaluation.

Objectives This study aims to assess medical students' interest in a Motivational Interviewing (MI), the objective need for a special training, and students' satisfaction with and the effectiveness of such a course. Methods A mandatory MI course was implemented for sixth-semester medical students. Their interest in learning MI was evaluated, along with their satisfaction with the course, which was delivered in a blended-learning teaching approach. Participants' baseline MI skills and general communication skills were assessed. MI non-adherent behavior, like persuading and confronting patients, was noted. Successful learning was measured with a multiple-choice test administered before and after the course that assessed subjective knowledge and skills. Results Students were highly interested in learning MI. At baseline, they showed good communication skills but moderate MI skills. Satisfaction with the course was high. The course was effective, as subjective and objective knowledge and skills improved significantly. Conclusions This pilot study suggests that basic MI skills can be successfully taught in a blended-learning teaching approach. Further research should investigate sustainability and transfer to clinical practice. Practice implications Medical schools should consider providing students with special training in MI to help students counsel patients towards behavioral changes.

A one-year survey on the use of a powder from Rosa canina lito in acute exacerbations of chronic pain.

This pilot surveillance included 152 patients with acute exacerbations of chronic pain, 124 (Back group) with non-specific low back pain (NSLBP), 20 with NSLBP overridden by osteoarthritic pain (Knee-Hip group), and eight with specific LBP (included in the safety analysis). Patients were recommended the rose hip and seed powder Litozin at a dose providing up to 3 mg of galactolipid/day for up to 54 weeks. Clinical symptoms and well-being were assessed every 6 weeks. The patients also kept a diary of their pain and the requirement for rescue medication. Data were analysed by intention to treat with last observation carried forward. Only 77 patients completed the year of surveillance. Multivariate analysis suggested an appreciable overall improvement during the surveillance, irrespective of group, and this was reflected for most of the individual measures in repeated measures ANOVA. The degree and time-course of improvement echoed that seen in similar surveillances of patients receiving an aqueous extract of Harpagophytum. Multiple regression analyses indicated that percentage changes from baseline tended to be greater in patients with greater degrees of pain and disability, but were otherwise largely unrelated to the patients' characteristics. There were no serious adverse events. The rose hip and seed powder, Litozin, seems to deserve further, more definitive studies as a possible option in long-term management of NSLBP with or without osteoarthritic pain.

Quality assurance of rifampicin-containing fixed-drug combinations in South Africa: dosing implications.

SETTING: Rifampicin (RMP) drives treatment response in drug-susceptible tuberculosis. Low RMP concentrations increase the risk of poor outcomes, and drug quality needs to be excluded as a contributor to low RMP exposure. OBJECTIVES AND DESIGN: We performed an open-label, three-way cross-over study of three licensed RMP-containing formulations widely used in South Africa to evaluate the bioavailability of RMP in a two-drug fixed-dose combination tablet (2FDC) and a four-drug FDC (4FDC) against a single-drug reference. RMP dosed at 600 mg was administered 2 weeks apart in random sequence. Plasma RMP concentrations were measured pre-dose and 1, 2, 3, 4, 6, 8 and 12 h post-dose. The area under the concentration-time curve (AUC0-12) of the FDCs was compared to the single drug reference. Simulations were used to predict the impact of our findings. RESULTS: Twenty healthy volunteers (median age 22.8 years, body mass index 24.2 kg/m2) completed the study. The AUC0-12 of the 4FDC/reference (geometric mean ratio [GMR] 78%, 90%CI 69-89) indicated an average 20% reduction in RMP bioavailability in the 4FDC. The 2FDC/reference (GMR 104%, 90%CI 97-111) was bioequivalent. Simulations suggested dose adjustments to compensate for the poor bioavailability of RMP with the 4FDC, and revised weight-band doses to prevent systematic underdosing of low-weight patients. CONCLUSION: Post-marketing surveillance of in vivo bioavailability of RMP and improved weight band-based dosing are recommended.

Steady state pharmacokinetics of cycloserine in patients on terizidone for multidrug-resistant tuberculosis.

SETTING: Terizidone/cycloserine (TRD/CS) is included in standard treatment regimens for multidrug-resistant tuberculosis (MDR-TB) in many countries. The steady state pharmacokinetics (PKs) of CS after TRD administration are not known. OBJECTIVES AND DESIGN: We recruited in-patients treated with 250-750 mg oral TRD daily as part of standard treatment regimens for pulmonary MDR-TB in Cape Town, South Africa. Plasma CS assays were performed in samples taken pre-dose and at 2, 4, 6, 8 and 10 h post-dose. CS concentrations were measured using a validated liquid chromatography-tandem mass spectrometry method. Non-compartmental PK analyses were performed. RESULTS: Of 35 participants enrolled, 22 were males, and 20 (57%) were infected with the human immunodeficiency virus; the median age was 37 years. The median duration on TRD at the time of sampling was 33 days (interquartile range [IQR] 28-39). The area under the concentration-time curve at 0-10 h (AUC0-10) was 319 µg.h/ml (IQR 267.5-378.7), and peak concentration was 38.1 µg/ml (IQR 32.6-47.2). On multiple regression, dose (mg/kg) was the only factor independently associated with AUC0-10. CONCLUSION: Steady state concentrations of CS in patients treated with TRD for MDR-TB were higher than those reported with CS formulations. Our findings support once-daily dosing.