Search

The present work describes the construction and application of a simple, low cost and sensitive microfluidic paper-based device with electrochemical detection for the detection of paracetamol and 4-aminophenol. The separation channels of a width of 2.0 mm were created on paper using a wax printing process to define the regions of the device. A baseline separation level of the analytes can be obtained in 0.1 mol L(-1) acetate buffer solution at pH 4.5 and by injecting 500 nL of the standard solutions at 12 mm from the working electrode. The electrochemical detection system was created at the end of the channels through a process known as sputtering. The previously separated analytes were detected at the end of the hydrophilic separation channel by applying a potential of 400 mV vs. pseudo Au on the working electrode. Experimental variables such as type of paper (cation exchanger and n1), pH, sample volume, applied potential and distance of sample injection were evaluated and, under the conditions of higher response, it was possible to obtain detection limits of 25.0 and 10.0 μmol L(-1) for paracetamol and 4-aminophenol, respectively.

Background Fever is one of the most common symptoms in children and is the physiological response of the human immune system to external pathogens. However, effectiveness studies of single and combined antipyretic therapy are relatively few due to lack of data. In this study, we used large-scale patient-generated health data from mobile apps to compare antipyretic affects between single and combination antipyretics. Objective We aimed to establish combination patterns of antipyretics and compare antipyretic affects between single and combination antipyretics using large-scale patient-generated health data from mobile apps. Methods This study was conducted using medical records of feverish children from July 2015 to June 2017 using the Fever Coach mobile app. In total, 3,584,748 temperature records and 1,076,002 antipyretic records of 104,337 children were analyzed. Antipyretic efficacy was measured by the mean difference in the area under the temperature change curve from baseline for 6 hours, 8 hours, 10 hours, and 12 hours after antipyretic administration in children with a body temperature of ≥38.0 ℃ between single and combination groups. Results The single antipyretic and combination groups comprised 152,017 and 54,842 cases, respectively. Acetaminophen was the most commonly used single agent (60,929/152,017, 40.08%), and acetaminophen plus dexibuprofen was the most common combination (28,065/54,842, 51.17%). We observed inappropriate use, including triple combination (1205/206,859, 0.58%) and use under 38 ℃ (11,361/206,859, 5.50%). Combination antipyretic use increased with temperature; 23.82% (33,379/140,160) of cases were given a combination treatment when 38 ℃ ≤ temperature < 39 ℃, while 41.40% (1517/3664) were given a combination treatment when 40 ℃ ≤ temperature. The absolute value of the area under the curve at each hour was significantly higher in the single group than in the combination group; this trend was consistently observed, regardless of the type of antipyretics. In particular, the delta fever during the first 6 hours between the two groups showed the highest difference. The combination showed the lowest delta fever among all cases. Conclusions Antipyretics combination patterns were analyzed using large-scale data. Approximately 75% of febrile cases used single antipyretics, mostly acetaminophen, but combination usage became more frequent as temperature increased. However, combination antipyretics did not show definite advantages over single antipyretics in defervescence, regardless of the combination. Single antipyretics are effective in reducing fever and relieving discomfort in febrile children.

Prophylactic paracetamol administration impacts vaccine immune response; this study (www.clinicaltrials.gov: NCT01235949) is the first to assess PHiD-CV immunogenicity following prophylactic ibuprofen administration. In this phase IV, multicenter, open-label, randomized, controlled, non-inferiority study in Romania (November 2010–December 2012), healthy infants were randomized 3:3:3:1:1:1 to prophylactically receive immediate, delayed or no ibuprofen (IIBU, DIBU, NIBU) or paracetamol (IPARA, DPARA, NPARA) after each of 3 primary doses (PHiD-CV at age 3/4/5 months co-administered with DTPa-HBV-IPV/Hib at 3/5 and DTPa-IPV/Hib at 4 months) or booster dose (PHiD-CV and DTPa-HBV-IPV/Hib; 12–15 months). Non-inferiority of immune response one month post-primary vaccination in terms of percentage of infants with anti-pneumococcal antibody concentrations ≥0.2 µg/mL (primary objective) was demonstrated if the upper limit (UL) of the 98.25% confidence interval of difference between groups (NIBU vs IIBU, NIBU vs DIBU) was

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel gated by noxious heat, playing major roles in thermoregulation. Forsythoside A (FT-A) is the most abundant phenylethanoid glycosides in Fructus Forsythiae, which has been prescribed as a medicinal herb for treating fever in China for a long history. However, how FT-A affects pyrexia and what is the underlying molecular mechanism remain largely unknown. Here we found that FT-A exerted apparent antipyretic effect through decreasing the levels of prostaglandin E2 (PGE2) and interleukin 8 (IL-8) in a dose-dependent fashion on the yeast induced pyrexia mice. Interestingly, FT-A significantly downregulated TRPV1 expression in the hypothalamus and dorsal root ganglion (DRG) of the yeast induced pyrexia mice. Moreover, FT-A inhibited IL-8 and PGE2 secretions, and calcium influx in the HEK 293T-TRPV1 cells after stimulated with capsaicin, the specific TRPV1 agonist. Further investigation of the molecular mechanisms revealed that FT-A treatment rapidly inhibited phosphorylation of extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38 in both yeast induced pyrexia mice and HEK 293T-TRPV1 cells. These results suggest that FT-A may serve as a potential antipyretic agent and the therapeutic action of Fructus Forsythiae on pyretic related disease is, in part, due to the FT-A activities.

The novel meningococcal serogroup B vaccine (4CMenB, Bexsero(®)), recently approved in Europe and Australia, may soon be included in routine infant immunization schedules, subject to guidance from national or regional recommending bodies. In the development of 4CMenB and consistent with other newly introduced vaccines, clinical studies have shown concomitant administration with routine infant vaccines induces an incremental increase in some reactions, including fever. As this may hinder acceptability, we examined the impact of prophylactic paracetamol on the occurrence of fever and other solicited reactions, as well as the immune responses to study vaccines, in a prospectively designed study. 4CMenB was administered as a 4-dose series at 2, 3, 4, and 12 months of age concomitantly with routine infant vaccines: DTaP-HBV-IPV/Hib and PCV7, with or without prophylactic paracetamol; a third group received MenC vaccine. Immune responses to 4CMenB were not decreased by the use of paracetamol prophylaxis and there were no clinically relevant effects on immune responses to routine vaccines. Occurrence of fever was higher in infants co-administered with 4CMenB compared with those given MenC vaccine, but was significantly decreased by prophylactic paracetamol, as were other solicited reactions to vaccination, both local and systemic. Co-administration of 4CMenB had an acceptable tolerability profile, with no withdrawals due to vaccination-related adverse events. Inclusion of 4CMenB in routine infant immunization schedules will be a major advance in the control of meningococcal disease, and our study indicates that by using paracetamol prophylaxis, post-vaccination reactions are reduced without clinically relevant negative consequences on vaccine immunogenicity.

Ruta graveolens has been used to treat toothache, earache, rheumatism and fever with little scientific evidence corroborating these uses.The leaf methanol extract of Ruta graveolens was evaluated for antinociceptive activity using the acetic acid writhing and hot-plate tests in mice, also anti-inflammatory and antipyretic activities using the carrageenan-induced oedema and E. coli-induced pyrexia tests in rats, respectively.R. graveolens (100 mg/kg, i.p.), significantly reduced the number of acetic acid-induced writhes by 54 %. R. graveolens (400 mg/kg, i.p.), significantly delayed the reaction time in mice to thermal stimulation 15, 30, 45, and 60 min after treatment. Combined treatment of the lowest and sub-effective doses of the leaf methanol extract (25 mg/kg, i.p.), and indomethacin (10 mg/kg, i.p.) significantly reduced the number of acetic acid-induced writhes in mice. The leaf methanol extract of R. graveolens (50 - 400 mg/kg, i.p.), significantly reduced carrageenan-induced oedema over the 4 h period of testing. Combined treatment of the lowest doses of R. graveolens (25 mg/kg, i.p.) and indomethacin (2 mg/kg, i.p.) produced a significant reduction in carrageenan-induced oedema over the 4 h period of testing. R. graveolens (100 -400 mg/kg, i.p.) significantly reduced E. coli-induced pyrexia over the 5 h period of testing. Given together, the lowest dose of R. graveolens (25 mg/kg, i.p.) and pentoxifylline (10 mg/kg, i.p.) produced a significant reduction in pyrexia induced by E. coli (50 µg/kg, i.m.) over the 5 h period of measurement. The LD50 value obtained for R. graveolens was greater than 4000mg/kg (p.o), suggesting that the plant species may be safe in or nontoxic to mice.The data obtained indicate that R. graveolens has antinociceptive, anti-inflammatory and antipyretic activities, justifying the use of the plant species by traditional medicine practitioners in the management and treatment of pain, inflammation and fever.

This study investigated the possible anti-inflammatory, analgesic, and antipyretic effects of ethanolic extract of Pedalium murex Linn. fruits in selected experimental animal models. Anti-inflammatory activity of Pedalium murex Linn., with doses of 200 mg/kg and 400 mg/kg, p.o., was evaluated by Lambda-carrageenan induced paw oedema in Wistar albino rats; analgesic activity with doses of 280 mg/kg and 560 mg/kg, p.o., was evaluated by hot plate method and acetic acid induced writhing method in Swiss albino mice; and antipyretic activity with doses of 110 mg/kg and 220 mg/kg, p.o., was evaluated in New Zealand white rabbits by injecting gram -ve lipopolysaccharide obtained from E. coli. Results were analysed by one way ANOVA followed by Dunnet's multiple comparison test. Pedalium murex Linn. showed significant anti-inflammatory activity from 15 min to 180 min as compared to vehicle treated animals. It was comparable to diclofenac sodium at 180 min. The extract did not prolong the reaction time on hot plate method but significantly reduced the number of writhing after acetic acid administration. Also the extract did not show any antipyretic activity on lipopolysaccharide induced pyrexia. It is therefore concluded that the ethanolic extract of Pedalium murex Linn. fruits has an anti-inflammatory and peripheral analgesic effects.

The antipyretic and hypothermic prodrug dipyrone prevents PGE2 -dependent and -independent fever induced by LPS from Escherichia coli and Tityus serrulatus venom (Tsv) respectively. We aimed to identify the dipyrone metabolites responsible for the antipyretic and hypothermic effects.Male Wistar rats were treated i.p. with indomethacin (2 mg·kg(-1) ), dipyrone, 4-methylaminoantipyrine (4-MAA), 4-aminoantipyrine (4-AA) (60-360 mg·kg(-1) ), 4-formylaminoantipyrine, 4-acethylaminoantipyrine (120-360 mg·kg(-1) ) or vehicle 30 min before i.p. injection of LPS (50 μg·kg(-1) ), Tsv (150 μg·kg(-1) ) or saline. Rectal temperatures were measured by tele-thermometry and dipyrone metabolite concentrations determined in the plasma, CSF and hypothalamus by LC-MS/MS. PGE2 concentrations were determined in the CSF and hypothalamus by elisa.In contrast to LPS, Tsv-induced fever was not followed by increased PGE2 in the CSF or hypothalamus. The antipyretic time-course of 4-MAA and 4-AA on LPS-induced fever overlapped with the period of the highest concentrations of 4-MAA and 4-AA in the hypothalamus, CSF and plasma. These metabolites reduced LPS-induced fever and the PGE2 increase in the plasma, CSF and hypothalamus. Only 4-MAA inhibited Tsv-induced fever. The higher doses of dipyrone and 4-MAA also induced hypothermia.The presence of 4-MAA and 4-AA in the CSF and hypothalamus was associated with PGE2 synthesis inhibition and a decrease in LPS-induced fever. 4-MAA was also shown to be an antipyretic metabolite for PGE2 -independent fever induced by Tsv suggesting that it is responsible for the additional antipyretic mechanism of dipyrone. Moreover, 4-MAA is the hypothermic metabolite of dipyrone.

Drymaria cordata (Linn.) Willd (Caryophyllaceae) is an herbaceous plant widely used in traditional African medicine (TAM) for the treatment of diverse ailments including painful and febrile conditions. This study was conducted to investigate the analgesic and antipyretic properties of the whole plant extract of D. cordata. The acetic acid-induced writhing, formalin, and tail clip tests were used to evaluate analgesic activity while the 2,4-dinitrophenol (DNP)-, d-amphetamine-, and yeast-induced hyperthermia tests were used to investigate antipyretic activity in rodents. D. cordata (100, 200, and 400 mg kg(-1), p.o) produced significant (p0.05) analgesic activity in the mouse writhing, formalin (second phase), and tail clip tests. The effects of D. cordata were generally comparable to those of acetylsalicylic acid (ASA, 100 mg kg(-1), p.o) and morphine (2 mg kg(-1), s.c). Also, D. cordata produced significant (p0.05) dose-dependent inhibition of temperature elevation in the 2,4-DNP and yeast-induced hyperthermia models with peak effects produced at the dose of 400 mg kg(-1). The effect at this dose was comparable to that of ASA in the two models. In the d-amphetamine method, D. cordata produced significant (p0.05) dose- and time-dependent reduction of temperature elevation with peak effect produced at the dose of 200 mg kg(-1). The effect of the extract at this dose was greater than that of ASA. The results obtained in this study demonstrate that the aqueous whole plant extract of Drymaria cordata possesses analgesic and antipyretic properties mediated through peripheral and central mechanisms.

Chantaleela recipe is indicated for relieving fever in Thai traditional folk medicine. In the present study, Chantaleela recipe was investigated for anti-inflammatory, analgesic, antipyretic and anti-ulcerogenic activities. In preliminary investigation Chantaleela recipe was found to exert an inhibitory activity on the acute phase of inflammation as seen in ethyl phenylpropiolate-induced ear edema as well as in carrageenan-induced hind paw edema in rats. The results suggest that the anti-inflammatory activity of Chantaleela recipe may be due to an inhibition via cyclooxygenase pathway. In the analgesic test, Chantaleela recipe showed a significant analgesic activity in both the early and late phases of formalin test, but exerted the most pronounced effect in the late phase. The analgesic activity of Chantaleela recipe may act via mechanism at peripheral and partly central nervous system. In antipyretic test, Chantaleela recipe significantly decreased rectal temperature of brewer’s yeast-induced hyperthermia rats, probably by inhibiting synthesis and/or release of prostaglandin E2 in the hypothalamus. Therefore, the key mechanism of anti-inflammatory, analgesic, and antipyretic activity of the Chantaleela recipe likely involves the inhibition of the synthesis and/or release of inflammatory or pain mediators, especially prostaglandins. The oral administration of the Chantaleela recipe reduced ulcer formation in acute gastric ulcer models (EtOH/HCl-, indomethacin-, and stress-induced gastric lesions). In contrast, this recipe did not reduce the secretory rate, total acidity, and increase pH in rat stomach. These results indicated that Chantaleela seem to possess anti-ulcerogenic effect. This activity may be due to the increase of gastric mucosal resistance or potentiation of defensive factors and/or the decrease of aggressive factors but did not associate the anti-secretory activity. Moreover, the high oral doses treated did not cause acute toxicity in rats and the long term oral administration did not produce gastric and ileum lesions.

Geographical variance in the incidence of type 1 diabetes mellitus (T1DM) and its etiological link to viruses and gut microbiome imply causative environmental agents. Antipyretics and especially acetaminophen received some attention recently due to the associations with some autoimmune conditions and lack of studies on the mechanisms influencing the immune system. A couple of recent studies involving large cohorts have found no association between the use of acetaminophen in early childhood and seroconversion leading to T1DM (TEDDY, involving international cohort) or diagnosis of overt T1DM (Norwegian MoBa) in the follow up years. The paper gives the supplemental argumentation for the antipyretic hypothesis presented in Medical Hypotheses in 2016 that is still valid in face of the mentioned conclusions. The hypothesis assumes that critical effect of acetaminophen and possibly other antipyretics expresses itself as the immediate influence on the immune system in the unfortunate coincidence with the other environmental factors, supposedly involving feverish, new to immunity, viral infection, all creating triggering circumstances regardless of age. Young age, in this respect should be regarded as a risk factor due to immatureness of immunity. The paper discusses that antipyretics and particularly acetaminophen need more attention evaluating their possible immunity modulations during infection or through negative effects on intestinal microbiota or both.

© 2017 Paediatrics and Child Health Division (The Royal Australasian College of Physicians) Aim: The use of antipyretics to manage the febrile child is becoming increasingly popular. Paracetamol and ibuprofen are the most commonly used interventions to manage fever in children; however, there have been no comparative analyses. The aim of the study is to evaluate the evidence comparing paracetamol to ibuprofen in the treatment of fever in children. Methods: A systematic review of randomised controlled trials investigating the administration of oral paracetamol and ibuprofen to reduce fever in children. Children aged 1 month to 12 years with a temperature between 37.5 and 41°C were included. A total of 3023 papers were identified. After removal of duplications, application of inclusion criteria and screening, eight papers were subjected to critical appraisal and included in this study. Results: Six of the studies identified that ibuprofen was slightly, but not significantly, better at reducing fever in children than paracetamol. Dosage variances and route of temperature measurement ranged between studies, limiting the comparability of studies. While ibuprofen was reported to be marginally more effective at reducing fever and fever associated discomfort in children, there is insufficient data to conclude that ibuprofen is superior to paracetamol. Conclusion: There is little evidence supporting the superior efficacy of paracetamol or ibuprofen in the treatment of fever in children with indications that both drugs are equally effective.

The use of antipyretics to manage the febrile child is becoming increasingly popular. Paracetamol and ibuprofen are the most commonly used interventions to manage fever in children; however, there have been no comparative analyses. The aim of the study is to evaluate the evidence comparing paracetamol to ibuprofen in the treatment of fever in children.A systematic review of randomised controlled trials investigating the administration of oral paracetamol and ibuprofen to reduce fever in children. Children aged 1 month to 12 years with a temperature between 37.5 and 41°C were included. A total of 3023 papers were identified. After removal of duplications, application of inclusion criteria and screening, eight papers were subjected to critical appraisal and included in this study.Six of the studies identified that ibuprofen was slightly, but not significantly, better at reducing fever in children than paracetamol. Dosage variances and route of temperature measurement ranged between studies, limiting the comparability of studies. While ibuprofen was reported to be marginally more effective at reducing fever and fever associated discomfort in children, there is insufficient data to conclude that ibuprofen is superior to paracetamol.There is little evidence supporting the superior efficacy of paracetamol or ibuprofen in the treatment of fever in children with indications that both drugs are equally effective.

Pneumonia is a major research core topic in the medical field, and clinical trials of pneumonia and respiratory tract infection have been ongoing. The purpose of this study was to investigate the clinical efficacy and safety of Shuanghuanghua granules in the treatment of pneumonia and respiratory tract infection based on NMR molecular imaging, and to lay a foundation for the development of new drugs. In this paper, 126 patients were randomly divided into the control group, the treatment group 1, the and treatment group 2, and were given Fengreganmao granules, Shuanghuanghua granules (ultrafine preparation), and Shuanghuanghua granules (extract preparation), respectively. The main symptom scores, sign scores, antipyretic time, and virus content before and after treatment were recorded. Statistical analysis was carried out on this basis. The experiment showed that the body temperature of the subjects in the three groups before treatment was: control group (37.59 ± 0.78), treatment group 1 (37.8 ± 0.81), and treatment group 2 (37.6 ± 0.76). After treatment, the body temperature of subjects in the three groups was: control group (36.67 ± 0.71), treatment group 1 (36.49 ± 0.43), and treatment group 2 (36.19 ± 0.25). Experiments show that Shuanghuanghua granules can significantly reduce the nasal virus, adenovirus, parainfluenza virus, etc. in the patient’s body. And it can shorten the antipyretic time of patients and has good clinical application. In addition, this study gave full play to the role of MRI molecular imaging and provided ideas and references for the clinical treatment of pneumonia and respiratory tract infection.

The present paper presents results of analgesic, antipyretic activity and anti-inflammatory potential of extract obtained from Acacia cyanophylla when tested at different doses. Analgesic potential of the crude methanolic extract tested by acetic acid assay was dose dependent and maximum activity of 61.60% was measured at 400 mg/kg. Analgesic activity by hot plate method revealed that maximum activity of 36.98% was noted when the mice were exposed to 90 minutes at higher dose of 400 mg/kg. Similar pattern for antipyretic activity was observed as noted for analgesic activity. Anti-inflammatory activity was dose and time dependent when evaluated by Carrageenan-induced paw edema and Xylene-induced ear edema model. Maximum anti-inflammatory activity (43.32%) was shown by crude methanolic extract of Acacia cyanophylla at 400mg/kg

Tremendous efforts in research without a conclusion on the cause of type 1 diabetes allow the presumption that there is still a blind spot in the development of T1D that is not covered by current hypotheses. The review of geographical knowledge suggests that there is a well-expressed anthropogenic element within the complex environmental trigger of T1D. On the other hand, the initiation of T1D’s directed autoimmunity is temporally related to the organism’s immune response, induced by entero-viruses, most expectedly. Consequently, the searched for anthropogenic environmental factor is a player temporally linked to enteroviral infections. This paper discusses the participation of antipyretic medicines, and especially paracetamol, with a whole century’s history of growing sales and popularity, including indirect influence through phenacetin during the first half of the 20th century. As proposed by several independent studies, the use of pharmaceuticals to reduce fever may counteract with the protective features of the immune system and create favourable conditions for a virus to spread within the organism and damage specific tissue. A preliminary comparison of paracetamol sales with the incidence of T1D data in Lithuania and the other countries in the North-eastern Baltic region supports this hypothesis.

Qingkailing injection (QKLI) has a notable antipyretic effect and is widely used in China as a clinical emergency medicine. To elucidate the pharmacological action thoroughly, following the investigation of the urine metabolome and hypothalamus metabolome, plasma metabolomics combined with lipidomics profiling of the QKLI antipyretic effect in a rat model is described in this paper. Compared with pure metabolomics profiling, this non-targeted plasma metabolomics combined with lipidomics profiling based on ultra-performance liquid chromatography-coupled with quadrupole time-of-flight mass spectrometry (UPLC Q-TOF/MS) could be used for a large-scale detection of features in plasma samples. The results showed that 15 metabolites at the 1 h time point and 19 metabolites at the 2 h time point after QKLI administration were associated with the antipyretic effect of QKLI, including amino acid, phosphatidylcholine and lysophosphatidylcholine. The metabolism pathway analysis revealed that the potential biomarkers, which were important for the antipyretic mechanism of QKLI, were closely responsible for correcting the perturbed pathways of amino acid metabolism and lipid metabolism. In conclusion, the use of complementary UPLC Q-TOF/MS based metabolomics and lipidomics allows for the discovery of new potential plasma biomarkers in the QKLI antipyretic process and the associated pathways, and aided in advancing the understanding of the holism and synergism of the Chinese drug.

Objectives To determine the effectiveness of antipyretics use in prevention of subsequent febrile seizures in children. Data sources A search for all available electronic databases (MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, ACP Journal Club, Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register of Controlled Trials, Cochrane Methodology Register) from 1950 to July 2011 was done. No language restrictions were applied, but English abstract required. Study selection We included randomized controlled trials comparing the efficacy of antipyretic drugs to placebo in reducing the recurrence rate of febrile seizures in children (6–72 months) with previous febrile seizures. We excluded reviews, letters, and uncontrolled or non-randomized studies. Data extraction and synthesis The literature search was performed by a professional medical librarian. Based of the preliminary search, two reviewers independently pooled studies for detailed manual review per the inclusion criteria. We used the Cochrane Review Manager software (Revman 5) to calculate the odds ratio and 95% confidence intervals (CI) for seizure recurrence, assuming a random-effects model. Results Initial search identified 479 citations, five articles underwent further rigorous evaluation by two reviewers and three papers met the inclusion criteria. In these three studies, 540 children were included, of whom 348 received antipyretics (acetaminophen (15 mg/kg), ibuprofen (5–10 mg/kg) or diclofenac (1.5 mg/kg)) and 192 received placebo for prevention of subsequent febrile seizures during a 1–2 year follow-up period. Seventy-nine patients (22.7%) in the antipyretics group and forty-seven patients (24.4%) in the placebo group had febrile seizure recurrence during follow up. No statistically significant difference was found between the antipyretics and the placebo groups in the recurrence rate of febrile seizures (OR 0.9, 95% CI: 0.57–1.43). Conclusion Antipyretics were ineffective in reducing the recurrence of febrile seizures.

Chagas disease is a significant health problem in Latin America and the available treatments have significant issues in terms of toxicity and efficacy. There is thus an urgent need to develop new treatments either via a repurposing strategy or through the development of new chemical entities. A key first step is the identification of compounds with anti-Trypanosoma cruzi activity from compound libraries. Here we describe a hit discovery screening cascade designed to specifically identify hits that have the appropriate anti-parasitic properties to warrant further development. The cascade consists of a primary imaging-based assay followed by newly developed and appropriately scaled secondary assays to predict the cidality and rate-of-kill of the compounds. Finally, we incorporated a cytochrome P450 CYP51 biochemical assay to remove compounds that owe their phenotypic response to inhibition of this enzyme. We report the use of the cascade in profiling two small libraries containing clinically tested compounds and identify Clemastine, Azelastine, Ifenprodil, Ziprasidone and Clofibrate as molecules having appropriate profiles. Analysis of clinical derived pharmacokinetic and toxicity data indicates that none of these are appropriate for repurposing but they may represent suitable start points for further optimisation for the treatment of Chagas disease., Author Summary Chagas disease is an important health problem in Latin America. The disease is caused by the parasite Trypanosoma cruzi, which is transmitted to people via insects of the Triatomine family. There are currently only two treatments available, Nifurtimox and Benznidazole. These have serious problems including poor efficacy, strain-dependent drug sensitivity, resistance and toxicity to the patients. There is thus a great need to find new drugs for this disease. The first step in a typical drug discovery project is to find compounds that kill the parasite by screening large amounts of compounds in the laboratory. To do this one requires assays in which the effect of the compounds on the parasites can be seen. In this paper we describe two assays that together try to identify compounds that kill T.cruzi parasites. Such compounds are good candidates for further development and may eventually become new drugs. We tested our assays against a library of compounds with known clinical activity and identified several interesting hits. As a great deal of data already exists for these compounds they could potentially be developed into new treatments much faster than completely new compounds.

Background Randomized clinical trials [RCT] are the Gold Standard of medical evidence. However, observational comparative effectiveness research [CER] based on real-world data is receiving national attention. This paper demonstrates how observational CER can fill important gaps in clinical knowledge left behind by RCT approaches. An example of CER in bipolar disorders is presented. Methods Paid claims data from a large commercial insurer were used to identify episodes of drug therapy. Episodes were defined each time a patient initiated or restarted therapy using an antipsychotic, antidepressant or mood stabilizing medication. Episode definitions were based on calculations of continuous days of drug therapy using a 15 day gap definition. 105,440 episodes of drug therapy were included in the analysis. Results Most episodes were initiated using a mood stabilizing drug (40%) or an antidepressant (40%). Over 59% of all episodes were for augmentation therapy, followed by switching episodes (25%) and restart episodes (16%). Patient outcomes measured by either duration of uninterrupted therapy or one-year post-treatment cost varied significantly with patient treatment history, especially episode type. The comparative effectiveness of alternative therapies was sensitive to the extent to which treatment history is taken into account. Conclusions Observational research can evaluate patient outcomes across a wide range of clinical presentations with regard to the patient's treatment history. Treatment history is a major determinant of patient compliance and future treatment costs. Failure to account for treatment history can introduce bias into comparative effectiveness results. Observational CER research can also uncover important questions that require future research.

The mechanism responsible for the initiation of endotoxic hypotension is not fully understood, although it is often attributed to a direct effect of LPS and other vasoactive mediators on the vasculature. Alternatively, recent evidence raises the possibility that endotoxic hypotension may be initiated through a central mechanism. Previous studies have shown that LPS initiates fever, sickness behavior, and other aspects of the inflammatory response through a neural pathway that sends peripheral inflammatory signals to the preoptic anterior hypothalamic area (POA). It is also well known that the POA plays a role in the regulation of cardiovascular function, but its involvement in LPS-induced hypotension has not been examined previously. Therefore, the aim of the present paper was to investigate whether the initial abrupt fall in arterial pressure evoked by LPS in septic shock is mediated by the POA. LPS (1 mg/kg, im.) administration to halothane-anesthetized or conscious rats lowered arterial blood pressure by 24.8 +/- 2.9 and 25.1 +/- 5.8 mmHg, respectively. Bilateral lidocaine (2%; 1 mu L) injection into the POA, but not the lateral hypothalamus, prevented the hypotension evoked by LPS entirely in both anesthetized and conscious animals. Remarkably, this blockade significantly inhibited the second, delayed fall in arterial pressure induced by LPS, and simultaneously decreased TNF-alpha plasma levels. Together, these data indicate that the initial phase of endotoxic hypotension is mediated by the POA and suggest that the initiation of the hypotensive response induced by LPS can be essential for the development of the late fall in blood pressure.

You are a senior house officer (SHO) working in a busy district general hospital. A 9-month-old boy is brought in by his parents with a fever of 2 days duration. There is no obvious focus but the child appears well. A urine dipstick is negative. When reviewing the child, the registrar is concerned to learn that the fever has not responded to paracetamol (acetaminophen). You wonder if there is any evidence that a febrile child is more likely to have a serious illness if their fever fails to respond to antipyretics. In children with a fever (population) does a failure to respond to antipyretics (indicator) compared with children who do respond to antipyretics (comparison) increase the likelihood of a serious bacterial illness (outcome)? ### Primary search MEDLINE (1946–March 2013) and EMBASE (1947–March, 2013) using the OVID interface were searched. Search terms were: (Fever AND paracetamol AND bacteraemia); limits were: English language, child (0–18). There were 84 hits of which four studies were relevant. The references of these papers were checked, along with the linked articles, and four further studies were found. A further search of the same databases with the …

The aim of this paper was to evaluate the level of knowledge and general attitude to acute respiratory diseases and behavior of antibiotic usage and related factors.The study included 122 mothers of children between 2 and 16 years of age who applied the complaint of respiratory infections and experienced the respiratory infections previous year, to policlinics between January and May 2012. A survey form was used to evaluate the sociodemographic properties of the mothers, and the level of knowledge, attitude and behavior of mothers to childhood acute respiratory infections, fever and antibiotic use.Of the children, 58.1% applied with cough, and 40.9% applied with fever to the doctor. Before attendance 28.6% of mothers had used antibiotics and 27.8% antipyretics. The rate use of not prescribed antibiotics was 12.3%. Before medical evaluation of children, the use of a variety of traditional and alternative medical methods was at the high rate of 57.4%. The average attitude scores of mothers about the antibiotics use for acute respiratory infections fell into the category of being against antibiotic use and income level toward antibiotic use and a correlation between duration of mother's education against antibiotic use.We found that the level of knowledge of parents about medications used by their children was insufficient and there is a high percentage of non-prescription use of antibiotics. In low income and low education level of parents the use of antibiotics increased. Health workers must correctly inform parents about symptoms, course and medication. The effects of health education in the management of common diseases must be evaluated with studies.

The paper presents data on the pharmacokinetics of the nonsteroidal anti-inflammatory drug ibuprofen and a review of the evidence base that suggests its clinical efficacy and safety in different categories of patients and discusses new, potentially possible indications for the use of this drug. Ibuprofen has marked anti-inflammatory, analgesic, and antipyretic effects, which along with its good tolerability, predictability of side effects, and a low risk of complications, allows it to be widely use in clinical practice. There are various ibuprofen formulations on the drug market. There may be not only an oral formulation of ibuprofen, but its topical (gel), rectal (suppositories), and parenteral (solution for intravenous injection) ones. More than 40 years' experience with ibuprofen used as an over-the-counter drug in wide clinical practice in approximately 80 countries worldwide serves as an illustrative example of the efficacy and safety of this agent.

This paper reports the establishment of a method for rapid identification 15 effective components of anti common cold medicine (paracetamol, aminophenazone, pseudoephedrine hydrochloride, methylephedrine hydrochloride, caffeine, amantadine hydrochloride, phenazone, guaifenesin, chlorphenamine maleate, dextromethorphen hydrobromide, diphenhydramine hydrochloride, promethazine hydrochloride, propyphenazone, benorilate and diclofenac sodium) with MRM by LC-MS/MS. The samples were extracted by methanol and were separated from a Altantis T3 column within 15 min with a gradient of acetonitrile-ammonium acetate (containing 0.25% glacial acetic acid), a tandem quadrupole mass spectrometer equipped with electrospray ionization source (ESI) was used in positive ion mode, and multiple reaction monitoring (MRM) was performed for qualitative analysis of these compounds. The minimum detectable quantity were 0.33-2.5 microg x kg(-1) of the 15 compounds. The method is simple, accurate and with good reproducibility for rapid identification many components in the same chromatographic condition, and provides a reference for qualitative analysis illegally added chemicals in anti common cold medicine.

Asthma prevalence has increased over the last few decades, especially in developed countries, and possibly due to different reasons. An association between paracetamol use or exposure at different periods of life, including gestation and childhood, and asthma prevalence has been observed in the last few years. Causality can not be established from observational reports, due to the arguable presence of many confounding factors and biases. Randomised trials are needed to elucidate the nature of this association. The Spanish Paediatric societies subscribing to this paper consider that current evidence is insufficient to discourage the use of paracetamol during gestation or in children with or at risk of asthma.

CONTEXT AND OBJECTIVE: Several studies in developed countries have documented that a significant percentage of children are given inappropriate doses of acetaminophen and ibuprofen. The objective of this paper was to investigate parents’ accuracy in giving dipyrone and acetaminophen to their children, in a poor region. DESIGN AND SETTING: Cross-sectional study at the pediatric emergency department of Instituto Materno-Infantil Prof. Fernando Figueira, a teaching hospital in Pernambuco. METHODS: The inclusion criteria were age between 3 and 36 months, main complaint of fever and at least one dose of dipyrone or acetaminophen given to the child during the 24 hours preceding their arrival at the emergency department. The mothers were asked for demographic information and about the antipyretic doses given, which were compared with the recommended dosage. RESULTS: Among the 200 patients studied, 117 received dipyrone and 83 received acetaminophen. Overall, 75 % received an incorrect dose of antipyretic. Of the patients who received dipyrone, 105 (89.7%) were given an incorrect dose; 16 (15.2%) received too little dipyrone, and 89 (84.8%) received too much. Of the patients who received acetaminophen, 45 (54.2%) were given an incorrect dose; 38 (84.4%) received too little acetaminophen, and 7 (15.6%) received too much. There were no differences in maternal and child characteristics between the groups receiving correct and incorrect doses of medication, except for the type of medication (dipyrone versus acetaminophen). CONCLUSIONS: Most of the children treated were given inappropriate doses, mainly dipyrone overdosing and acetaminophen underdosing. CONTEXTO E OBJETIVOS: Alguns estudos em países desenvolvidos têm demonstrado um elevado percentual de crianças que recebem doses inapropriadas de acetaminofen e ibuprofeno. O objetivo deste estudo foi verificar, em uma área carente, a acurácia dos pais na administração da dipirona e do acetaminofen a seus filhos. TIPO DE ESTUDO E LOCAL: Foi realizado um estudo transversal no departamento de Emergência do Instituto Materno-Infantil Professor Fernando Figueira, em Pernambuco. MÉTODOS: Foram admitidas à pesquisa crianças com idade entre 3 a 36 meses, com queixa principal de febre e o uso mínimo de uma dose de dipirona ou acetaminofen nas 24 horas que precederam sua chegada na emergência. Foi aplicado um questionário às mães sobre dados demográficos e o uso de antipiréticos. A dose administrada foi comparada com a recomendada. RESULTADOS: Dos 200 pacientes estudados, 117 receberam dipirona e 83 acetaminofen. 75% deles receberam doses incorretas. Dos pacientes que receberam dipirona, 105 (89,7%) usaram uma dose incorreta; 16 (15,2%) subdosagens e (84,8%) superdosagens. Dos pacientes que receberam acetaminofen, 45 (54,2%) utilizaram uma dose incorreta, 38 (84,4%) sub-dosagens e 7 (15,6%), super-dosagens. Não houve diferenças nas características maternas e das crianças que receberam doses corretas ou incorretas dos antipiréticos, exceto para o tipo de medicação, mais freqüentemente a dipirona. CONCLUSÕES: A maioria das crianças recebeu doses inapropriadas de antipiréticos, principalmente superdosagens de dipirona e subdosagens de acetaminofen.

Objective To review the literature and test the hypothesis that the use of antipyretic drugs in children with acute infections slows recovery. Study design A systematic review and meta-analysis of the literature was undertaken to investigate the effect of antipyretic drugs upon recovery from infectious diseases in children. A search of Medline (1946 until November 2012) and EMBASE (1980 until November 1, 2012) was undertaken to identify studies in which the authors compared the use of antipyretic medications with nonpharmacologic treatments for fever. Results Six papers were identified, 5 of which were included in the meta-analysis. Three studies focused on children with malaria and the other 3 considered general viral and respiratory infections and varicella. The pooled mean difference in time to fever clearance was 4.16 hours and was faster in those receiving antipyretics compared with those not (95% CI −6.35 to −1.96 hours; P = .0002). There was little evidence of statistical heterogeneity (χ 2 4.84; 4 df; P = .3; I 2 17%). Conclusion There is no evidence from these studies that the use of antipyretics slows the resolution of fever in children.