Reduced Efficacy of Intermittent Preventive Treatment of Malaria in Malnourished Children

Intermittent preventive treatment in infants with sulfadoxine-pyrimethamine (IPTi-SP) reduces malaria episodes by 20 to 59% across Africa. This protective efficacy, however, may be affected by the high frequency of malnutrition in African infants. We analyzed the impact of malnutrition as defined by anthropometry on the incidence of malaria and on the protective efficacy of IPTi in a cohort of 1,200 children in northern Ghana, where malaria is hyperendemic. These children received IPTi-SP or placebo at 3, 9, and 15 months of age and were monitored until 24 months of age. Malnutrition was present in 32, 40, and 50% of children at ages 3, 9, and 15 months, respectively. It was associated with increased risks of severe anemia and death but not an increased risk of malaria. Although malaria slightly contributed to chronic malnutrition, IPTi did not substantially improve child growth. Importantly, the protective efficacies of IPTi in malnourished children were roughly half or even less of those observed in nonmalnourished children. In the first year of life, IPTi reduced the incidence of malaria to a significantly lesser extent in infants who received both doses in a malnourished condition (25%; 95% confidence interval [CI], −7 to 48%) compared to that of nonmalnourished children (46%; 95% CI, 30 to 58%; P = 0.049). Moreover, in contrast to nutritionally advantaged children, the rate of severe malaria appeared to be increased in malnourished children who took IPTi. IPTi might exhibit reduced efficacy in regions of abundant malnutrition. Concomitant nutrition programs may be needed in these places to achieve the desired impact.Intermittent preventive treatment in infants (IPTi) with sulfadoxine-pyrimethamine (SP) appears to be a promising tool of malaria control in young children. The initial IPTi trial in Tanzania reported a protective efficacy (PE) against uncomplicated malaria in infancy of 59% and some degree of protection persisting into the second year of life (28, 29). In subsequent studies at sites of differing endemicity in sub-Saharan Africa, protection in infancy was confirmed; however, the PEs were lower, at 20 to 33% (5, 12, 15, 17, 23). We have reported previously that in Tamale, northern Ghana, IPTi reduced the incidence of asymptomatic parasitemia, uncomplicated malaria, and severe anemia from 3 to 24 months of age by 29, 17, and 15%, respectively. These effects were greatest in the first year of life and less pronounced in the second (23).As in many regions of Africa, malnutrition is abundant in northern Ghana, reaching prevalences as high as 50% in preschool children, depending on seasonality and food availability (32 and http://www.who.int/nutgrowthdb/database/countries/nchs_reference/gha.pdf). Malnutrition causes relative immunosuppression, and repeated or chronic infections may contribute to poor nutritional status (27). However, the effect of malnutrition on malaria is less clear cut than would be expected: protein-energy malnutrition has been associated with greater malaria morbidity and mortality in some areas but not in others (4, 6, 8, 21, 24, 30). Moreover, the risk of antimalarial treatment failure appears to be increased in malnourished children (13, 14, 22, 39). Taken together, these findings suggest that malnutrition is one factor contributing to malaria-associated morbidity and that malaria control strategies without concomitant nutrition programs may not have the desired impact on childhood morbidity on a large scale (8). We hypothesized that malnutrition affects both malaria morbidity and IPTi efficacy. Alternatively, IPTi might improve children''s growth and nutritional status. We reanalyzed data from a cohort from northern Ghana (23) regarding the effect of malnutrition on the PE of IPTi, and here we report the results of this secondary analysis.     

Amodiaquine Dosage and Tolerability for Intermittent Preventive Treatment To Prevent Malaria in Children

Sulfadoxine-pyrimethamine with amodiaquine (SP-AQ) is a highly efficacious regimen for intermittent preventive treatment to prevent malaria in children (IPTc), but the amodiaquine component is not always well tolerated. We determined the association between amodiaquine dosage by body weight and mild adverse events (AEs) and investigated whether alternative age-based regimens could improve dosing accuracy and tolerability, using data from two trials of IPTc in Senegal, one in which AQ dose was determined by age and the other in which it was determined by weight category. Both dosage strategies resulted in some children receiving AQ doses above the recommended therapeutic range. The odds of vomiting increased with increasing amodiaquine dosage. In one study, incidence of fever also increased with increasing dosage. Anthropometric data from 1,956 children were used to predict the dosing accuracy of existing and optimal alternative regimens. Logistic regression models describing the probability of AEs by dosage were used to predict the potential reductions in mild AEs for each regimen. Simple amendments to current AQ dosing schedules based on the child''s age could substantially increase dosing accuracy and thus improve the tolerability of IPTc using SP-amodiaquine in situations where weighing the child is impractical.Relatively minor adverse reactions to antimalarials that may be acceptable when malaria illness is being treated may not be acceptable when drugs are used on a large scale for intermittent preventive treatment in children (IPTc), when the majority of recipients will be healthy. The response of children and their parents to adverse reactions, even those relatively minor in nature, could limit the uptake of IPTc as a strategy. It is, therefore, important to minimize the side effects associated with this intervention.Sulfadoxine-pyrimethamine combined with amodiaquine (SP-AQ) has been identified as a highly efficacious regimen for treatment of malaria (4, 8, 11, 23-26) and for IPT (5, 14). However, when used for IPT in children, SP-AQ has been associated with an increased incidence of mild adverse events, particularly vomiting and fever, in the days following the IPT course (5, 14). One answer to this problem would be to use other antimalarials as the partner drug to SP, which has been shown extensively to be safe and well tolerated when used for intermittent preventive treatment (1, 6). Long-acting antimalarials are preferable to artemisinins for IPT because they provide a longer period of posttreatment prophylaxis, which is central to the protection given by IPT (4a, 19). Piperaquine has been identified as a promising partner drug (5) (K. Bojang et al., unpublished data). However, SP-piperaquine is currently not licensed as a combination for use in IPT and there may be some delay in obtaining sufficient safety and pharmacokinetic data to allow deployment of this combination. Any measures that can improve the tolerability of SP-AQ for use in the meantime could therefore be beneficial.One way in which the tolerability of SP-AQ might be improved is by ensuring that children receive as accurate a dose as possible. The recommended dose for a course of amodiaquine is 30 mg amodiaquine base/kg body weight over 3 days, i.e., 10 mg/kg/day (22). Dosing by weight is therefore the ideal approach, but limitations in resources and training may make this impractical in resource-poor areas (2, 9). Weighing children may be particularly problematic with a large-scale preventive intervention such as IPTc, in which many children will be treated in a short space of time and mobility of health workers may be important for successful delivery (Bojang et al., unpublished data). Development of an accurate dose-for-age schedule would thus be advantageous. Dose-for-age has already been developed for amodiaquine as part of a fixed dose combination with artesunate used for treatment of malaria cases (13, 16), but the priorities may be different for IPT because most children will not be unwell when they are treated. Regimens could be developed specifically for use in IPT.The regimen used in previous and ongoing trials of IPTc in Senegal consists of one 200-mg AQ tablet for children aged 2 years or over and half a 200-mg tablet for younger children (5; www.clinicaltrials.gov, identifier {"type":"clinical-trial","attrs":{"text":"NCT00712374","term_id":"NCT00712374"}}NCT00712374). Since health workers are used to dichotomizing the dose given to children at 2 years of age, replacing the 200-mg tablet with one with lower AQ content might be a simple way to improve dosing accuracy. One option would be to use a 153-mg AQ tablet that is currently available for treatment. An alternative age-based regimen for amodiaquine was developed using a large anthropometric data set by Taylor et al. (16) and was recently shown to be well tolerated (13). The AQ doses for this regimen are 67.5 mg for infants as a single tablet and 135 mg for children over 12 months (as two 67.5-mg tablets). The chief problem with this regimen is that children aged between 12 and 23 months are more likely to be overdosed (16). Amending this AQ regimen to include a separate dose for 12- to 23-month-old children might be feasible within an IPT program. Because SP and AQ can both be manufactured to contain any specified amount of the active component, a more flexible option would be to manufacture tablets specifically for seasonal IPT with the optimal concentration of AQ for dosing by age.This study investigated the accuracy of the amodiaquine dosing strategy used in two recent trials of IPTc using SP-AQ, the relationship between dosage and adverse events, and the potential for alternative amodiaquine regimens to reduce overdosing and adverse events.     

Intranasal Lidocaine for the Treatment of Migraine Headache: A Randomized, Controlled Trial

OBJECTIVE: To evaluate the effect of intranasal lidocaine for immediate relief (5 minutes) of migraine headache pain. METHODS: A randomized, double-blind, placebo-controlled clinical trial at two university-affiliated community teaching hospitals enrolled patients 18-50 years old with migraine headache as defined by the International Headache Society. Patients who were pregnant, lactating, known to abuse alcohol or drugs, or allergic to one of the study drugs, those who used analgesics within two hours, or those with a first headache were excluded. Statistical significance was assessed by using chi-square or Fisher's exact test for categorical variables and Student's t-test for continuous variables. Patients rated their pain on a 10-centimeter visual analog scale (VAS) prior to drug administration and at 5, 10, 15, 20, and 30 minutes after the initial dose. Medication was either 1 mL of 4% lidocaine or normal saline (placebo) intranasally in split doses 2 minutes apart and intravenous prochlorperazine. Medications were packaged so physicians and patients were unaware of the contents. Successful pain relief was achieved if there was a 50% reduction in pain score or a score below 2.5 cm on the VAS. RESULTS: Twenty-seven patients received lidocaine and 22 placebo. No significant difference was observed between groups in initial pain scores, 8.4 (95% CI = 7.8 to 9.0) lidocaine and 8.6 (95% CI = 8.0 to 9.2) placebo (p = 0.75). Two of 27 patients (7.4%, 95% CI = 0.8, 24.3) in the lidocaine group and three of 22 patients (13.6%, 95% CI = 2.8 to 34.9) in the placebo group had immediate successful pain relief (p = 0.47), with average pain scores of 6.9 (95% CI = 5.9 to 7.8) and 7.0 (95% CI = 5.8 to 8.2), respectively. No difference in pain relief was detected at subsequent measurements. CONCLUSION: There was no evidence that intranasal lidocaine provided rapid relief for migraine headache pain in the emergency department setting.     

普卢利沙星治疗急性尿路感染的随机双盲对照试验

目的评价普卢利沙星治疗急性尿路感染的有效性和安全性。方法根据本研究的纳入和排除标准,选取急性尿路感染患者144例,按计算机随机表产生的随机号将患者分为两组,进行随机双盲、双模拟对照试验。试验组服用普卢利沙星200mgbid;对照组服用左氧氟沙星200mgbid。疗程均为5～10天。结果两组各有67和61例可进入全分析集(FAS),各有63和59例可进行符合方案集(PP)分析。FAS分析结果显示,试验组和对照组的临床有效率分别为85.07%和88.52%;细菌阴转率试验组为93.75%,对照组为93.88%。PP分析结果显示,试验组和对照组的有效率分别为90.48%和91.53%;细菌阴转率分别为97.83%和97.87%。两组临床疗效和细菌学疗效阴转率差异均无统计学意义(P>0.05)。普卢利沙星和左氧氟沙星的不良反应发生率分别为2.8%和5.6%。结论普卢利沙星对敏感菌引起的尿路感染疗效确切,安全性好。     

Prior Pain Exposure and Mere Possession of a Placebo Analgesic Predict Placebo Analgesia: Findings From a Randomized,Double-Blinded,Controlled Trial

A recent study found that merely possessing a placebo analgesic reduces pain. The current study tested for a possible moderator of this effect. Specifically, does the mere possession of a placebo analgesic affect pain for individuals with and without immediate prior experience with the pain task? Healthy participants (N = 127) were randomized to prior pain (PP) condition or without prior pain (No-PP) condition. In the PP condition, participants first did a preliminary trial of a cold pressor test (CPT) to induce direct experience with this pain stimulus. Then they were randomized to possess an inert cream described as either an analgesic cream or an anti-itch cream (pain-irrelevant control object). Participants then completed the main CPT. In the No-PP condition, participants underwent identical procedures and randomization except that they did not do a preliminary CPT, thus having no immediate prior CPT pain experience. We found a significant prior pain experience and possession status interaction effect on placebo analgesia. Participants in the No-PP condition showed evidence of lower pain when they merely possessed an analgesic cream than an anti-itch cream. Such mere possession effect was not found in the PP condition. The impact of expectancy and emotion on the underlying process are discussed.PerspectiveThis article presents a novel finding that prior pain exposure and mere possession of a placebo analgesic predicted placebo analgesia. It offers a novel perspective on the time course of placebo effect. It provides practical implications on potential pain intervention for clinicians and paradigm design for researchers of placebo study.     

Effects of Oxytocin on Placebo and Nocebo Effects in a Pain Conditioning Paradigm: A Randomized Controlled Trial

Oxytocin has been shown to increase trust, decrease anxiety, and affect learning as has been observed in conditioning paradigms. Trust, anxiety, and learning are important factors that influence placebo effects. In this study, we investigated whether oxytocin can increase placebo analgesia, decrease nocebo hyperalgesia, and influence extinction processes of both. Eighty male volunteers were assigned to a 40 IU of oxytocin nasal spray group, or to a placebo control group. Placebo analgesia and nocebo hyperalgesia were induced by a conditioning procedure in combination with verbal suggestions. The results demonstrate that the conditioning procedure successfully elicited significant placebo analgesia and nocebo hyperalgesia responses (P < .001). Furthermore, extinction was observed (P < .001), although placebo and nocebo responses did not return to baseline and remained significant. Oxytocin did not influence placebo analgesia or nocebo hyperalgesia and had no effect on extinction. This study provides support against the placebo-boosting effects of oxytocin and was the first one to demonstrate that it also did not influence nocebo effects or extinction processes, however, these results pertain to only a male sample. As managing placebo and nocebo effects has widespread clinical implications, further research should investigate other neurobiological or behavioral pathways to boost placebo and decrease nocebo effects.PerspectiveThe present study demonstrated that placebo analgesia and nocebo hyperalgesia can be successfully induced by conditioning and verbal suggestions. We could not confirm the hypothesis that oxytocin affects either of these phenomena. Other pharmacological agents and behavioral manipulations for increasing placebo and decreasing nocebo effects should be investigated.     

A Comparative Study of Treatment Interventions for Patellar Tendinopathy: A Randomized Controlled Trial

ObjectivesTo determine the additional effect of dry needling (DN) or percutaneous needle electrolysis (PNE) combined with eccentric exercise (EE) and determine which is the most effective for patients with patellar tendinopathy (PT).DesignBlinded, randomized controlled trial, with follow-up at 10 and 22 weeks.SettingsRecruitment was performed in sport clubs. Diagnosis and intervention were conducted at San Jorge University.ParticipantsPatients (N=48) with PT with pain for at least 3 months between the ages of 18 and 45 years.InterventionsThree interventions were carried out: DN and EE, PNE and EE, and EE with sham needle as the control group.Main Outcome MeasuresDisability was measured using the Victorian Institute of Sports Assessment Questionnaire, patellar tendon. Visual analog scale was used to measure pain over time, the Short Form-36 was used to measure quality of life, and ultrasound was used to measure structural abnormalities.ResultsA total of 48 participants (42 men, 6 women; average age, 32.46y; SD, 7.14y) were enrolled. The improvement in disability and pain in each group between baseline and post-treatment and baseline and follow-up was significant (P≤.05), without differences among groups.ConclusionDN or PNE combined with an EE program has not shown to be more effective than a program of only EE to improve disability and pain in patients with PT in the short (10wk) and medium (22wk) terms. Clinical improvements were not associated with structural changes in the tendon.     

Efficacy of Cartoon Viewing Devices During Phlebotomy in Children: A Randomized Controlled Trial

PurposeThe purpose of this study was to examine the efficacy of different cartoon viewing devices during phlebotomy in children.DesignThis study was a prospective, randomized controlled trial.MethodsThe study included inpatients from the Biochemical Laboratory of a private university hospital in Turkey and was conducted between September 2017 and April 2018. A computer-based random number generator was used to randomly assign the patients into three groups (virtual reality [VR], tablet, and control) with 40 children each. Data were collected using the Wong-Baker FACES Pain Rating Scale and the Children's Fear Scale. Pain and anxiety scores were reported by children, parents, and observers in tablet and control groups. In the VR group, pain and anxiety were determined only by children's reports.FindingsAccording to the children reports, the VR group reported significantly less pain and anxiety than those in the tablet and control groups (P < .05).ConclusionsThe cartoon distraction performed using a VR device reduced the perception of pain and anxiety during phlebotomy in school-age children.     

Midazolam vs. Diphenhydramine for the Treatment of Metoclopramide-induced Akathisia: A Randomized Controlled Trial

Objectives To compare the effects of midazolam, which is a fast and short-acting benzodiazepine, and diphenhydramine, which is a widely used anticholinergic agent, in clinical practice for the treatment of metoclopramide-induced akathisia.
Methods All adults older than 17 years given metoclopramide for nausea and vomiting or for headache and who had akathisia were eligible for this clinical, randomized, double-blind trial. Patients were randomized to receive diphenhydramine or midazolam. Subjective, objective, and total akathisia scores and modified Ramsay Sedation Scale scores were recorded. Repeated-measures analysis of variance was used to compare the efficacy and side effects of the medications.
Results Forty-one (73.3%) of the 56 enrolled patients were women. The mean (±SD) age was 39.9 (±15.7) years in the diphenhydramine group and 40.9 (±16.2) years in the midazolam group. Mean subjective, objective, and total akathisia scores in the first 5 minutes declined considerably in the midazolam group compared with the diphenhydramine group (p < 0.001). However, the mean Ramsay Sedation Scale score in the first 15 minutes increased significantly in the midazolam group compared with the diphenhydramine group (p < 0.001).
Conclusions Midazolam can correct the symptoms of metoclopramide-induced akathisia faster than diphenhydramine, but it causes more sedation.     

天麻素注射液治疗眩晕的多中心随机单盲对照试验

目的评价天麻素注射液治疗眩晕的疗效及安全性.方法采用多中心随机单盲对照试验设计,将240例眩晕住院患者随机分为治疗组和对照组(n=120),分别予天麻素注射液600 mg和盐酸倍他司汀注射液30 mg,静滴,每日1次,疗程7 d.统计分析采用SAS统计软件,治疗前两组的基础数据比较采用非参数检验或t检验;治疗后两组临床疗效比较采用考虑中心效应的CMH方法.结果①眩晕:意向治疗(ITT)分析表明,治疗组(n=117)与对照组(n=120)疗程结束时眩晕症状临床控制率分别为71.19%和54.17%,有效率分别为90.60%和77.50%,两组间比较其差异有统计学意义(P= 0.005和P= 0.004),治疗组优于对照组.符合方案数据分析(PP)结果显示:治疗组(n=116)与对照组(n=117)疗程结束时的眩晕症状临床控制率分别为72.41%和54.70%,有效率分别为91.38%和77.78%,两组间也有统计学差异(P= 0.005和P= 0.004),治疗组优于对照组.ITT与PP分析结果一致.②前庭功能:治疗组(n=53)与对照组(n=58)疗程结束时前庭功能临床控制率分别为62.26%和42.37%,有效率分别为81.13%和76.27%,临床控制率两组间有统计学差异(P= 0.029),治疗组优于对照组,有效率两组间无统计学差异(P= 0.504),ITT与PP分析结果相同.③安全性分析结果表明:治疗组(n=120)与对照组(n=120)的不良反应发生率分别为8.33%和10.83%,两组间无统计学差异(P= 0.538).结论天麻素注射液与倍他司汀注射液均为治疗眩晕的有效药物,天麻素注射液治疗眩晕症状有效率和前庭功能下降的临床控制率优于倍他司汀注射液.昆明制药集团股份有限公司生产的天麻素注射液治疗眩晕临床疗效确切,不良反应少,患者耐受性好.     

The Possible Preventive Role of Pregabalin in Postmastectomy Pain Syndrome: A Double-Blinded Randomized Controlled Trial

Context

Chronic postmastectomy pain syndrome (PMPS) has a considerable negative impact on the quality of life of breast cancer patients.

国产来氟米特治疗类风湿关节炎的随机双盲对照试验

目的与进口来氟米特(商品名:爱若华,美国欣凯公司产品)相比较,观察国产来氟米特(leflunomide,LFM)治疗活动期类风湿关节炎(类风关)的疗效和不良反应.方法采用随机、双盲双模拟、阳性药物平行对照研究方法,将56例活动期类风关患者随机分为两组,分别服用受试药和对应模拟片各2片,疗程24周,并比较其疗效.结果与治疗前比较,治疗12周时,除血沉外,两组在各个主要指标方面均较各自治疗前明显改善(P<0.05);治疗24周后,两组在血沉、C-反应蛋白等指标上与治疗前比较,差异无统计学意义,其它各主要指标均较治疗前明显改善(P<0.05).两组间各项主要指标改善值在治疗12周和24周时差异均无统计学意义(P>0.05).按国内综合评价指标分析,治疗12周时,爱若华组改善率为37.0%,国产来氟米特组为64.0%,两组间差异有统计学意义(P<0.05);治疗24周时,爱若华组为81.5%,国产来氟米特组为77.3%,两组在改善率方面的差异无统计学意义(P>0.05).此外,两组不良事件发生率的差异也无统计学意义.结论国产来氟米特与爱若华比较具有相似的疗效和安全性.