Safety profile of Coartem®: the evidence base

Background

Dihydroartemisinin (DHA), a powerful anti-malarial drug, has been used as monotherapy and artemisinin-based combination therapy (ACT) for more than decades. So far, however, the tissue distribution and metabolic profile of DHA data are not available from animal and humans.

Methods

Pharmacokinetics, tissue distribution, mass balance, and elimination of [¹⁴C] DHA have been studieded in rats following a single intravenous administration. Protein binding was performed with rat and human plasma. Drug concentrations were obtained up to 192 hr from measurements of total radioactivity and drug concentration to determine the contribution by the parent and metabolites to the total dose of drug injected from whole blood, plasma, urine and faecal samples.

Results

Drug was widely distributed after 1 hr and rapidly declined at 24 hr in all tissues except spleen until 96 hrs. Only 0.81% of the total radioactivity was detected in rat brain tissue. DHA revealed a high binding capacity with both rat and human plasma proteins (76–82%). The concentration of total radioactivity in the plasma fraction was less than 25% of that in blood total. Metabolism of DHA was observed with high excretion via bile into intestines and approximately 89–95% dose of all conjugations were accounted for in blood, urine and faeces. However, the majority of elimination of [¹⁴C] DHA was through urinary excretion (52% dose). The mean terminal half-lives of plasma and blood radioactivity (75.57–122.13 h) were significantly prolonged compared with that of unchanged DHA (1.03 h).

Conclusion

In rat brain, the total concentration of [¹⁴C] was 2-fold higher than that in plasma, indicating the radioactivity could easily penetrate the brain-blood barrier. Total radioactivity distributed in RBC was about three- to four-fold higher than that in plasma, suggesting that the powerful anti-malarial potency of DHA in the treatment of blood stage malaria may relate to the high RBC binding. Biliary excretion and multiple concentration peaks of DHA have been demonstrated with high urinary excretion due to a most likely drug re-absorption in the intestines (enterohepatic circulation). The long lasting metabolites of DHA (> 192 hr) in the rats may be also related to the enterohepatic circulation.     

Safety in numbers? Shoaling behaviour of the Amazonian red-bellied piranha

Red-bellied piranha (Pygocentrus nattereri) shoals have a fearsome reputation. However, the variety and abundance of piranha predators in the flooded forests of the Amazon in which they live indicate that an important reason for shoal formation may be predator defence. Experiments using wild-caught piranhas supported the hypothesis that individual perception of risk, as revealed by elevated ventilatory frequency (opercular rate), is greater in small shoals. Moreover, exposure to a simulated predator attack by a model cormorant demonstrated that resting opercular rates are regained more quickly by piranhas in shoals of eight than they are in shoals of two. Together, these results show that shoaling has a cover-seeking function in this species.     

Ethanol Causes Protein Precipitation—New Safety Issues for Catheter Locking Techniques

Objective

The ethanol lock technique has shown great potential to eradicate organisms in biofilms and to treat or prevent central venous catheter related infections. Following instillation of ethanol lock solution, however, the inherent density gradient between blood and ethanol causes gravity induced seepage of ethanol out of the catheter and blood influx into the catheter. Plasma proteins so are exposed to highly concentrated ethanol, which is a classic agent for protein precipitation. We aimed to investigate the precipitating effect of ethanol locks on plasma proteins as a possible cause for reported catheter occlusions.

Methods

Plasma samples were exposed in-vitro to ethanol (concentrations ranging from 7 to 70 v/v%) and heparin lock solutions. In catheter studies designed to mimic different in-vivo situations, the catheter tip was placed in a plasma reservoir and the material contained within the catheter was analyzed after ethanol lock instillation. The samples underwent standardized investigation for protein precipitation.

Results

Protein precipitation was observed in plasma samples containing ethanol solutions above a concentration of 28%, as well as in material retrieved from vertically positioned femoral catheters and jugular (subclavian) catheters simulating recumbent or head down tilt body positions. Precipitates could not be re-dissolved by dilution with plasma, urokinase or alteplase. Plasma samples containing heparin lock solutions showed no signs of precipitation.

Conclusions

Our in-vitro results demonstrate that ethanol locks may be associated with plasma protein precipitation in central venous catheters. This phenomenon could be related to occlusion of vascular access devices locked with ethanol, as has been reported. Concerns should be raised regarding possible complications upon injection or spontaneous gravity induced leakage of such irreversibly precipitated protein particles into the systemic circulation. We suggest limiting the maximum advisable concentration of ethanol to 28 v/v% in catheter lock solutions.     

The Efficacy and Safety of Systemic Antifungals in Children’s Onychomycosis

Purpose of Review

There are few reports about onychomycosis in children with inconclusive results about the better and safer option. We have observed and reported on the literature a significant increase in the prevalence of onychomycosis in this age group.

Recent Findings

Fungal infections, especially on the nails, are common health diseases with increasing prevalence according to age; however, it is rare in the pediatric population, except in patients with Down syndrome and primary and secondary immunodeficiency.

Summary

In this review, we focused on characteristics of children’s onychomycosis as well as the efficacy and safety of systemic antifungals, mainly terbinafine and itraconazole. Clinicians must consider onychomycosis as the differential diagnosis of nail disease in children and be aware of the adverse events of systemic treatments in onychomycosis.

     

Solute Carriers in the Blood–Brain Barier: Safety in Abundance

Blood–brain barrier formed by brain capillary endothelial cells, being in contact with astrocytes endfeet and pericytes, separates extracellular fluid from plasma. Supply of necessary nutrients and removal of certain metabolites takes place due to the activity of transporting proteins from ABC (ATP binding cassette) and SLC (solute carrier) superfamilies. This review is focused on the SLC families involved in transport though the blood–brain barrier of energetic substrates (glucose, monocarboxylates, creatine), amino acids, neurotransmitters and their precursors, as well as organic ions. Members of SLC1, SLC2, SLC3/SLC7, SLC5, SLC6, SLC16, SLC22, SLC38, SLC44, SLC47 and SLCO (SLC21), whose presence in the blood–brain barriers has been demonstrated are characterized with a special emphasis put on polarity of transporters localization in a luminal (blood side) versus an abluminal (brain side) membrane.     

Working on Sundays–Effects on Safety,Health, and Work-life Balance

Several attributes of the work schedule can increase the risk of occupational injuries and accidents, health impairments, and reduced social participation. Although previous studies mainly focused on the effects of shiftwork and long working hours on employee health and safety, there is little evidence of a potential negative impact of working Sundays on the incidence of occupational accidents, health impairments, and work-life balance. A representative sample of employed workers in 31 member and associated states of the European Union (n?=?23,934) served as the database for a cross-sectional analysis. The sample was collected via face-to-face interviews in the year 2005. The association of the risks of occupational accidents, health impairments, and decreases in work-life balance with working Sundays was calculated using logistic regression models, controlling for potential confounders, such as shiftwork, workload, and demographic characteristics. The results indicated that working one or more Sundays/month was associated with increase both in the risk of reporting one or more health impairments (odds ratio [OR]: 1.17, 95% confidence interval [CI]: 1.06–1.29) and poorer work-life balance (OR: 1.15, 95% CI: 1.02–1.28). These effects remained after controlling for potentially confounding factors, such as other work schedule attributes, intensity of physical and mental workload, and individual characteristics. Furthermore, working Sundays was also related to increased risk of occupational accidents within the last year (OR: 1.34, 95% CI: 1.03–1.73). Controlling again for individual, workload, and working-time characteristics, a significant association with accident risk, however, remained only in work sectors with low a priori risk of occupational accidents (OR: 1.40, 95% CI: 1.02–1.91), although the increased risk could be observed for both medium and high a priori risk sectors working Sundays (without controlling for additional confounders). The results thus indicate that the detrimental effects of working Sundays on safety, health, and social well-being should be taken into account when designing work schedules. The potential hazards to employees' safety, health, and work-life balance, in particular, should be considered in discussions concerning extending work on Sundays in certain sectors, e.g., retail. (Author correspondence: awirtz@hsph.harvard.edu)     

Safe To Walk? Neighborhood Safety and Physical Activity Among Public Housing Residents

Background

Despite its health benefits, physical inactivity is pervasive, particularly among those living in lower-income urban communities. In such settings, neighborhood safety may impact willingness to be regularly physically active. We examined the association of perceived neighborhood safety with pedometer-determined physical activity and physical activity self-efficacy.

Methods and Findings

Participants were 1,180 predominantly racial/ethnic minority adults recruited from 12 urban low-income housing complexes in metropolitan Boston. Participants completed a 5-d pedometer data-collection protocol and self-reported their perceptions of neighborhood safety and self-efficacy (i.e., confidence in the ability to be physically active). Gender-stratified bivariate and multivariable random effects models were estimated to account for within-site clustering. Most participants reported feeling safe during the day, while just over one-third (36%) felt safe at night. We found no association between daytime safety reports and physical activity among both men and women. There was also no association between night-time safety reports and physical activity among men (p = 0.23) but women who reported feeling unsafe (versus safe) at night showed significantly fewer steps per day (4,302 versus 5,178, p = 0.01). Perceiving one''s neighborhood as unsafe during the day was associated with significantly lower odds of having high physical activity self-efficacy among both men (OR 0.40, p = 0.01) and women (OR 0.68, p = 0.02).

Conclusions

Residing in a neighborhood that is perceived to be unsafe at night is a barrier to regular physical activity among individuals, especially women, living in urban low-income housing. Feeling unsafe may also diminish confidence in the ability to be more physically active. Both of these factors may limit the effectiveness of physical activity promotion strategies delivered in similar settings.     

Safety of the production process of SURFACEN® to inactivate and remove virus

SURFACEN^® is a biological product produced from pig lungs. Since these animals can be potential sources of microbial pathogens such as viruses, the manufacturing process of this product should guarantee safety from health hazards. The SURFACEN^® production procedure is capable of effective viral clearance (inactivation/removal) by involving two stages of organic solvent extraction followed by acetone precipitation and heat treatment. In this study, we evaluated the clearance capacity of these four stages for a wide range of viruses by performing spiking experiments. Residual contamination was assessed using a Tissue Culture Infectious Dose assay (log₁₀ TCID₅₀). The validation study demonstrated that, for all viruses tested, the TCID₅₀ titers were reduced by more than 2 log₁₀ in each stage. Total log reduction values achieved were between ≥17.82 log₁₀ and ≥27.93 log₁₀, depending on the virus physical properties, titer, and the number of processing stages applied. Results indicated that the production procedure of SURFACEN^® can inactivate or remove contaminant viruses from the raw material.     

Patient Safety in Medical Education: Students’ Perceptions,Knowledge and Attitudes

Patient safety is a new and challenging discipline in the Iranian health care industry. Among the challenges for patient safety improvement, education of medical and paramedical students is intimidating. The present study was designed to assess students’ perceptions of patient safety, and their knowledge and attitudes to patient safety education. This cross-sectional analytical study was conducted in 2012 at Urmia University of Medical Sciences, West Azerbaijan province, Iran. 134 students studying medicine, nursing, and midwifery were recruited through census for the study. A questionnaire was used for collecting data, which were then analyzed through SPSS statistical software (version 16.0), using Chi-square test, Spearman correlation coefficient, F and LSD tests. A total of 121 questionnaires were completed, and 50% of the students demonstrated good knowledge about patient safety. The relationships between students’ attitudes to patient safety and years of study, sex and course were significant (0.003, 0.001 and 0.017, respectively). F and LSD tests indicated that regarding the difference between the mean scores of perceptions of patient safety and attitudes to patient safety education, there was a significant difference among medical and nursing/midwifery students. Little knowledge of students regarding patient safety indicates the inefficiency of informal education to fill the gap; therefore, it is recommended to consider patient safety in the curriculums of all medical and paramedical sciences and formulate better policies for patient safety.     

POLIOMYELITIS VACCINE—Epidemiologic Observations on the Safety and Effectiveness in California in 1955

During the past year California has participated with other states in a nationwide field evaluation of the safety and effectiveness of poliomyelitis vaccine. Among 227,000 children who received Cutter vaccine, and the household contracts of these children, the incidence of poliomyelitis was higher during the early postvaccinal period than in comparable age groups of the population at large. Among 238,000 children who received poliomyelitis vaccine made by other manufacturers early in 1955 no increase in poliomyelitis was observed in the inoculated children or their household contacts.Subsequent observation on over 500,000 additional children vaccinated in California alone since September 1955 with vaccine that was made under revised safety standards has uncovered no evidence of unsafe vaccine. In children who received a single inoculation of vaccine prior to the onset of the poliomyelitis season in 1955 the incidence of paralytic poliomyelitis was about 60 per cent less than in unvaccinated children. Among those who received two inoculations an 85 per cent reduction was observed. The average reduction in paralytic poliomyelitis for the entire vaccinated group was approximately 75 per cent. Data thus far on children vaccinated since September 1955 with poliomyelitis vaccine made by methods now approved indicate that a similar overall effectiveness is still being maintained.     

Wild Foods: Safety Net or Poverty Trap? A South African Case Study

Wild foods contribute towards the food security of an estimated one billion people. In light of expectations of the contribution of wild foods to sustainable and climate-resilient livelihoods and widespread evidence of their consumption, their contribution to households’ diets requires a more nuanced understanding, specifically with respect to their safety net function during food shortages. Data were collected from two villages in Venda, South Africa, selected due to differences in mean annual precipitation. Semi-structured interviews were administered to 170 households and a Participatory Rural Appraisal was conducted to assess the influence of multiple variables, including household characteristics and site, on wild food use. Household archetypes were defined based on the frequency of consumption in response to increasing food scarcity. Our findings suggest limitations to the safety net function of wild foods including seasonal fluctuations in availability and decreased availability during extreme events, with dependent households decreasing their consumption frequency in response to food scarcity. Given this potential poverty trap, further research is required, particularly in terms of when the safety net function of wild foods may be weak or detrimental to the livelihoods of the vulnerable.     

Pharmacokinetics, Efficacy, and Safety Evaluation of Docetaxel/Hydroxypropyl-Sulfobutyl-β-Cyclodextrin Inclusion Complex

Hydroxypropyl-sulfobutyl-β-cyclodextrin (HP-SBE-β-CD) inclusion complex was developed and used as a drug delivery system for DTX (DTX/HP-SBE-β-CD). The objective of the present study was to evaluate and compare the biological properties of DTX/HP-SBE-Β-CD with Taxotere®. The pharmacokinetics, biodistribution, antitumor efficacy in vivo and in vitro, and safety evaluation of DTX/HP-SBE-β-CD were studied. The most significant finding was that it was possible to prepare a Polysorbate-80-free inclusion complex for DTX. Studies based on pharmacokinetics, biodistribution, and antitumor efficacy indicated that DTX/HP-SBE-β-CD had similar pharmacokinetic properties and antitumor efficacy both in vitro and in vivo as Taxotere®. Fortunately, this new drug delivery system attenuated the side effects when used in vivo. As a consequence, DTX/HP-SBE-β-CD may be a promising alternative to Taxotere® for cancer chemotherapy treatment with reduced side effects. The therapeutic potential against a variety of human tumors and low toxicity demonstrated in a stringent study clearly warrant clinical investigation of DTX/HP-SBE-β-CD for possible use against human tumors.Key words: antitumor efficacy, biodistribution, DTX/HP-SBE-β-CD, pharmacokinetics, safety evaluation     

Safety in numbers? Supplanting data quality with fanciful models in wildlife monitoring and conservation

Ecologists and conservation biologists seem increasingly attracted to sophisticated modelling approaches, sometimes at the expense of attention to data quality and appropriateness of fieldwork design. This dissociation may lead to a loss of perspective promoting biological unrealities as conclusions, which may be used in conservation applications. We illustrate this concern by focusing on recent attempts to estimate population size of breeding birds at large scales without any explicit testing of the reliability of the predictions through comparison with direct counts. Disconnection of analysts from “nature” can lead to cases of biological unrealities such as that used here to illustrate such trends. To counter this risk, we encourage investment in well-rounded scientists or more collaborative, multi-disciplinary teams capable of integrating sophisticated analyses with in-depth knowledge of the natural history of their study subjects.     

The Tiotropium Safety and Performance in Respimat? (TIOSPIR?) Trial: Spirometry Outcomes

Background

Tiotropium Safety and Performance in Respimat® (TIOSPIR®) compared the safety and efficacy of tiotropium Respimat® and tiotropium HandiHaler® in patients with chronic obstructive pulmonary disease (COPD). A prespecified spirometry substudy compared the lung function efficacy between treatment groups.

Methods

TIOSPIR® was a large-scale, long-term (2.3-year), event-driven, randomized, double-blind, parallel-group trial of 17,135 patients with COPD. In the spirometry substudy, trough forced expiratory volume in 1 second (FEV₁) and forced vital capacity (FVC) were measured at baseline and every 24 weeks for the duration of the trial.

Results

The substudy included 1370 patients who received once-daily tiotropium Respimat® 5 μg (n = 461), 2.5 μg (n = 464), or tiotropium HandiHaler® 18 μg (n = 445). Adjusted mean trough FEV₁ (average 24–120 weeks) was 1.285, 1.258, and 1.295 L in the Respimat® 5 μg, 2.5 μg, and HandiHaler® 18 μg groups (difference versus HandiHaler® [95 % CI]: −10 [−38, 18] mL for Respimat® 5 μg and, −37 [−65, −9] mL for Respimat® 2.5 μg); achieving noninferiority to tiotropium HandiHaler® 18 μg for tiotropium Respimat® 5 but not for 2.5 μg (prespecified analysis). Adjusted mean trough FVC was 2.590, 2.544, and 2.593 L in the Respimat® 5 μg, 2.5 μg, and HandiHaler® 18 μg groups. The rates of FEV₁ decline over 24 to 120 weeks were similar for the three treatment arms (26, 40, and 34 mL/year for the tiotropium Respimat® 5-μg, 2.5-μg, and HandiHaler® 18-μg groups). The rate of FEV₁ decline in GOLD I + II patients was greater than in GOLD III + IV patients (46 vs. 23 mL/year); as well as in current versus ex-smokers, in patients receiving combination therapies at baseline versus not, and in those experiencing an exacerbation during the study versus not.

Conclusions

The TIOSPIR® spirometry substudy showed that tiotropium Respimat® 5 μg was noninferior to tiotropium HandiHaler® 18 μg for trough FEV₁, but Respimat® 2.5 μg was not. Tiotropium Respimat® 5 μg provides similar bronchodilator efficacy to tiotropium HandiHaler® 18 μg with comparable rates of FEV₁ decline. The rate of FEV₁ decline varied based on disease severity, with a steeper rate of decline observed in patients with moderate airway obstruction.

Trial registration

{"type":"clinical-trial","attrs":{"text":"NCT01126437","term_id":"NCT01126437"}}NCT01126437.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-015-0269-4) contains supplementary material, which is available to authorized users.     

Should the Same Safety Scrutiny of Antiobesity Medications be Applied to Other Chronic Usage Drugs?

Obesity treatment is highly stigmatized, mainly because of the stigma of obesity itself. The frequent withdrawal of medications, lorcaserin being the last example, contributes to this stigma, but it is also probably a reflection of it, as data suggest that the threshold for a withdrawal is lower than with other classes of drugs. Safety should always be an absolute priority for every new medication, especially when used on a chronic basis; however, the safety scrutiny given to antiobesity medications is not given for other medications, such as postmenopausal hormone therapy and central nervous system drugs for psychiatric use. The withdrawal of medications for obesity can also impact future research in the area, so we need transparency and equality. Transparency in knowing exactly what reason led to a drug being discontinued and equality in long‐term safety should be a concern with any medication prescribed for chronic diseases.     

Is Wetter Better? An Evaluation of Over-the-Counter Personal Lubricants for Safety and Anti-HIV-1 Activity

Because lubricants may decrease trauma during coitus, it is hypothesized that they could aid in the prevention of HIV acquisition. Therefore, safety and anti-HIV-1 activity of over-the-counter (OTC) aqueous- (n = 10), lipid- (n = 2), and silicone-based (n = 2) products were tested. The rheological properties of the lipid-based lubricants precluded testing with the exception of explant safety testing. Six aqueous-based gels were hyperosmolar, two were nearly iso-osmolar, and two were hypo-osmolar. Evaluation of the panel of products showed Gynol II (a spermicidal gel containing 2% nonoxynol-9), KY Jelly, and Replens were toxic to Lactobacillus. Two nearly iso-osmolar aqueous- and both silicone-based gels were not toxic toward epithelial cell lines or ectocervical or colorectal explant tissues. Hyperosmolar lubricants demonstrated reduction of tissue viability and epithelial fracture/sloughing while the nearly iso-osmolar and silicon-based lubricants showed no significant changes in tissue viability or epithelial modifications. While most of the lubricants had no measurable anti-HIV-1 activity, three lubricants which retained cell viability did demonstrate modest anti-HIV-1 activity in vitro. To determine if this would result in protection of mucosal tissue or conversely determine if the epithelial damage associated with the hyperosmolar lubricants increased HIV-1 infection ex vivo, ectocervical tissue was exposed to selected lubricants and then challenged with HIV-1. None of the lubricants that had a moderate to high therapeutic index protected the mucosal tissue. These results show hyperosmolar lubricant gels were associated with cellular toxicity and epithelial damage while showing no anti-viral activity. The two iso-osmolar lubricants, Good Clean Love and PRÉ, and both silicone-based lubricants, Female Condom 2 lubricant and Wet Platinum, were the safest in our testing algorithm.     

Exposure-Based, ‘Like-for-Like’ Assessment of Road Safety by Travel Mode Using Routine Health Data

Background

Official reports on modal risk have not chosen appropriate numerators and denominators to enable like-for-like comparisons. We report age- and sex-specific deaths and injury rates from equivalent incidents in England by travel mode, distance travelled and time spent travelling.

Methods

Hospital admissions and deaths in England 2007–2009 were obtained for relevant ICD-10 external codes for pedestrians, cyclists, and car/van drivers, by age-group and sex. Distance travelled by age-group, sex and mode in England (National Travel Survey 2007–2009 data) was converted to time spent travelling using mean trip speeds. Fatality rates were compared with age-specific Netherlands data.

Results

All-age fatalities per million hours’ use (f/mhu) varied over the same factor-of-three range for both sexes (0.15–0.45 f/mhu by mode for men, 0.09–0.31 f/mhu for women). Risks were similar for men aged 21–49 y for all three modes and for female pedestrians and drivers aged 21–69 y. Most at risk were: males 17–20 y (1.3 f/mhu (95% CI 1.2–1.4)) for driving; males 70+ (2.2 f/mhu(1.6–3.0)) for cycling; and females 70+ (0.95 f/mhu (0.86–1.1)) for pedestrians. In general, fatality rates were substantially higher among males than females. Risks per hour for male drivers <30 y were similar or higher than for male cyclists; for males aged 17–20 y, the risk was higher for drivers (33/Bn km (30–36), 1.3 f/mhu (1.2–1.4)) than cyclists (20/Bn km (10–37), 0.24 f/mhu (0.12–0.45)) whether using distance or time. Similar age patterns occurred for cyclists and drivers in the Netherlands. Age-sex patterns for injuries resulting in hospital admission were similar for cyclists and pedestrians but lower for drivers.

Conclusions

When all relevant ICD-10 codes are used, fatalities by time spent travelling vary within similar ranges for walking, cycling and driving. Risks for drivers were highest in youth and fell with age, while for pedestrians and cyclists, risks increased with age. For the young, especially males, cycling is safer than driving.