Informe diário de evidências: COVID-19 busca realizada em 22 de abril de 2020 / Daily evidence report: COVID-19 search conducted on April 22, 2020

O objetivo da revisão sistemática foi investigar a eficácia e a segurança de tratamentos com antivirais para COVID-19, SARS e MERS. Ao todo, 22 estudos foram incluídos: 1 ensaio clínico, 16 séries de casos e 5 relatos de caso. Os antivirais mais utilizados foram lopinavir / ritonavir, oseltamivir, ribavirina e arbidol. Todos os estudos usaram outras terapias, como antibióticos, imunoglobulina, interferon, glicocorticoides, metilprednisolona e medicamentos antiparasitários e antifúngicos, além da terapia antiviral para pacientes com COVID-19. No único ECR incluído, os pacientes que receberam lopinavir / ritonavir tiveram um processo de recuperação semelhante aos pacientes que receberam tratamento padrão. Os desfechos de mortalidade em 28 dias e carga viral de RNA não foram significativamente diferentes entre os dois grupos. Dentre os achados dos demais estudos, vale destacar que estudos de séries e relatos de casos não avaliam a eficácia de medicamentos, e que em geral as amostras foram pequenas. O estudo de Guan, com 1099 pacientes, chegou a conclusão que oseltamivir foi ineficaz na diminuição da taxa de admissão na UTI, na necessidade de ventilação e na taxa de mortalidade entre os pacientes. O estudo de Shang, com 416 pacientes, indicou que medicamentos antivirais não têm efeito na taxa de mortalidade de pacientes com COVID-19. O estudo de Li, com cinco crianças com COVID-19, indicou que os agentes antivirais não alteraram o resultado ou a duração da internação. A revisão cita outros estudos que foram publicados com os pacientes ainda sob tratamento, sem o desfecho final dessas populações. Quanto a busca por ensaios clínicos para SARS e MERS, foram encontrados protocolos, mas nenhum resultado publicado.

A multivariable assessment of the spatio-temporal distribution of pyrethroids performance on the sea lice Caligus rogercresseyi in Chile.

Synthetic pyrethroids have been widely used in Chile to control the sea lice Caligus rogercresseyi, a major ectoparasite of farmed salmon. Although resistance of C. rogercresseyi to pyrethroids has been reported in Chile, there is no information regarding the geographic extent of this problem. In this study we explored the spatial and temporal variation of C. rogercresseyi's response to pyrethroids in Chile from 2012 to 2013. We modeled lice abundance one week after treatment with a linear mixed-effects regression, and then we performed spatial and spatio-temporal cluster analyses on farm-level effects and on treatment-level residuals, respectively. Results indicate there were two areas where the post-treatment lice counts were significantly higher than in the rest of the study area. These spatial clusters remained even once we adjusted for environmental and management predictors, suggesting unmeasured factors (e.g. resistance) were causing the clustering. Further investigation should be carried out to confirm this hypothesis.

[Deer farming in Switzerland - Current epidemiological situation with focus on husbandry, management and nutrition]. / Gehegewild in der Schweiz ­ Aktuelle epidemiologische Situation mit Schwerpunkt Haltung, Management und Fütterung.

INTRODUCTION: Between September 2016 and February 2017 a survey in Swiss deer farms were conducted to gain information about their husbandry. Questions about the business, feeding, management, health and deworming strategies were asked. 98 (19%) out of 527 registered farms (2016) participated in the survey. The farms were often run on a sideline business, had an average used agricultural area of 7.3 ha with an average of 38 deer. Pasture access was the preferred feeding strategy followed by offering first and second cut hay. Between 2013-2015 the most common causes of death were sudden death and injuries. Parasites were classified as no or rather small problem by 91 out of 102 deer owner. Fecal parasitological examinations of fecal samples were conducted in 36 (35%) of the responding farms. Gastrointestinal roundworms (Trichostrongylidae) were identified as the most common pathogens (in 42-59% of sampled farms), in addition large lungworms (Dictyocaulus sp.) and coccidia were detected. 45% of the participating farmers conducted at least one treatment against parasites between 2013 and 2015.

INTRODUCTION: Dans le but d'avoir une vue d'ensemble sur la détention du gibier d'élevage en Suisse, une enquête a été menée entre septembre 2016 et février 2017, comprenant des questions relatives à l'exploitation, à l'alimentation, à la situation sanitaire et aux stratégies en matière de vermifugation. 98 des 527 exploitations annoncées en 2016 (19%) ont participé à cette étude. Ces exploitations, qui constituent fréquemment un gain accessoire, avaient une surface agricole d'en moyenne 7,3 ha avec 38 cervidés. En matière d'alimentation, c'est le foin et le regain qui étaient le plus souvent utilisés en complément du pâturage. Les causes de pertes dans les troupeaux entre 2013 et 2015 étaient principalement les cas de mort subite ainsi que les blessures. 91 de 102 détenteurs de cervidés considéraient les parasites comme n'étant pas un problème ou n'étant qu'un faible problème. Des échantillons de selles, prélevés dans 36 (35%) des exploitations ayant répondu au questionnaire, montraient que les nématodes gastro-intestinaux (Trichostrongylidae) étaient les plus fréquents (présents dans 42-59% des exploitations testées); des vers pulmonaires (Dictyocaulus sp.) et des coccidies ont également été trouvés. Environ 45 % des détenteurs de cervidés ayant participé à l'enquête avaient effectué, dans la période comprise entre 2013 et 2015 au moins un traitement antiparasitaire.

In-home assessment of either topical fluralaner or topical selamectin for flea control in naturally infested cats in West Central Florida, USA.

BACKGROUND: An investigation was conducted in West Central Florida, USA to evaluate the efficacy of either topically applied fluralaner or topically applied selamectin to control flea infestations, minimize dermatologic lesions and reduce pruritus in naturally flea infested cats over a 12-week period. When dogs were present in the households, they were treated with either oral fluralaner (if household cats were treated with topical fluralaner) or oral sarolaner (if household cats were treated with topical selamectin). METHODS: Thirty-one cats in 20 homes were treated once with fluralaner topical solution on day 0 and 18 dogs in these homes were administered a single fluralaner chewable. Twenty-nine cats in 18 homes were treated once monthly with a selamectin topical solution for 3 treatments and 13 dogs in these same homes were treated once monthly for 3 treatments with a sarolaner chewable. Fleas on cats were counted by flea combing, fleas on dogs were estimated using visual area counts and fleas in the indoor premises were assessed using intermittent-light flea traps. Blinded-assessments of feline dermatologic lesions were conducted monthly and pruritus severity was evaluated by pet owners. RESULTS: A single topical application of fluralaner reduced flea populations on cats by 96.6% within 7 days and by 100% at 12 weeks post-treatment. This efficacy was significantly greater than selamectin treatment where single topical application reduced flea populations on cats by 79.4% within 7 days of initial treatment and 3 consecutive monthly treatments reduced flea populations by 91.3% at the end of 12 weeks. At the end of the 12-week study, all fluralaner-treated cats were flea-free and this was significantly greater than the 38.5% of selamectin treated cats that were flea-free. At the end of the study, fleas were completely eradicated (from cats, dogs and homes) in 95.0% of fluralaner treatment group homes, significantly greater than the 31.3% of selamectin/sarolaner treatment group homes with complete flea eradication. Owner reported cat pruritus was reduced similarly in both treatment groups. Significant improvements in dermatologic lesion scores were achieved by day 30 in fluralaner treated cats and by day 60 in selamectin treated cats. CONCLUSIONS: An in-home investigation in subtropical Florida found that 1 application of topical fluralaner eliminated flea infestations on cats and in homes significantly more effectively than 3 consecutive monthly doses of selamectin.

Field trial assessment of ivermectin pharmacokinetics and efficacy against susceptible and resistant nematode populations in cattle.

The study compared the pharmacokinetic (PK) behaviour and anthelmintic efficacy against susceptible and resistant nematodes following subcutaneous (SC) and oral administration of ivermectin (IVM) to cattle. Six commercial farms were involved: Farms 1 and 2 (IVM-susceptible nematode population) and Farms 3, 4, 5 and 6 (IVM-resistant nematode population). On each farm, forty-five calves naturally infected with gastrointestinal (GI) nematodes were randomly allocated into three groups (n = 15): untreated control, IVM SC administration, and IVM oral administration (both at 0.2 mg/kg). PK assessment (plasma and faeces) was performed on Farm 1. Efficacy was determined by Faecal Egg Count Reduction Test. IVM systemic availability upon SC administration (421 ±â€¯70.3 ng·d/mL) was higher (P < 0.05) compared to the oral treatment (132 ±â€¯31.3 ng·d/mL). However, higher (P < 0.05) faecal IVM concentrations were observed following oral treatment (9896 ±â€¯1931 ng·d/mL) compared to SC administration (4760 ±â€¯924 ng·d/mL). Similar (91-93%) IVM efficacy was observed on Farms 1 and 2 by both routes. Efficacy against resistant nematodes was slightly higher on Farms 3 and 4 after the oral (63 and 82%, respectively) compared to the SC (36 and 68%, respectively) treatment. However, there was complete therapeutic failure (0% efficacy) on Farm 5 and a very low response on Farm 6 (40 and 41% for SC and oral administration, respectively). Although larger faecal concentrations following IVM oral administration may increase drug exposure of GI adult worms, this does not always improve efficacy against resistant nematodes. The potential therapeutic advantages of oral treatments should be cautiously assessed, especially in presence of anthelmintic resistance.

The Repurposing of Ivermectin for Malaria: A Prospective Pharmacokinetics-Based Virtual Clinical Trials Assessment of Dosing Regimen Options.

Ivermectin has demonstrated many successes in the treatment of a range of nematode infections. Considering the increase in malaria resistance, attention has turned toward ivermectin as a candidate for repurposing for malaria. This study developed and validated an ivermectin physiology-based pharmacokinetic model in healthy adults (20-50 years), pediatric (3-5 years/15-25 kg) subjects, and a representative adult malaria population group (Thailand). Dosing optimization demonstrating a twice-daily dose for 3- or 5-day regimens would provide a time above the LC50 of more than 7 days for adult and pediatric subjects. Furthermore, to address the occurrence of CYP450 induction that is often encountered with antiretroviral agents, simulated drug-drug interaction studies with efavirenz highlighted that a 1-mg/kg once-daily dose for 5 days would counteract the increased ivermectin hepatic clearance and enable a time above LC50 of 138.8 h in adults and 141.2 h in pediatric subjects. It was also demonstrated that dosage regimen design would require consideration of the age-weight geographical relationship of the subjects, with a dosage regimen for a representative Thailand population group requiring at least a single daily dose for 5 days to maintain ivermectin plasma concentrations and a time above LC50 similar to that in healthy adults.

Assessment of ß-lapachone loaded in lecithin-chitosan nanoparticles for the topical treatment of cutaneous leishmaniasis in L. major infected BALB/c mice.

Patients affected by cutaneous leishmaniasis need a topical treatment which cures lesions without leaving scars. Lesions are produced not only by the parasite but also by an uncontrolled and persistent inflammatory immune response. In this study, we proposed the loading of ß-lapachone (ß-LP) in lecithin-chitosan nanoparticles (NP) for targeting the drug to the dermis, where infected macrophages reside, and promote wound healing. Although the loading of ß-LP in NP did not influence the drug antileishmanial activity it was critical to achieve important drug accumulation in the dermis and permeation through the skin. When topically applied in Leishmania major infected BALB/c mice, ß-LP NP achieved no parasite reduction but they stopped the lesion progression. Immuno-histopathological assays in CL lesions and quantitative mRNA studies in draining lymph nodes confirmed that ß-LP exhibited anti-inflammatory activity leading to the down-regulation of IL-1ß and COX-2 expression and a decrease of neutrophils infiltrate. FROM THE CLINICAL EDITOR: Cutaneous leishmaniasis often leaves patients with unsightly scars due to the body's inflammatory response to the infection. The authors in this paper described topical treatment using ß-lapachone (ß- LP) loaded in lecithin-chitosan nanoparticles (NP) in an animal model. Results confirmed the reduction of inflammatory response without affecting the parasite killing efficacy. These findings would pave way for further clinical testing in the near future.

Integrated assessment of ivermectin pharmacokinetics, efficacy against resistant Haemonchus contortus and P-glycoprotein expression in lambs treated at three different dosage levels.

The main goals of the current work were: (a) to assess the ivermectin (IVM) systemic exposure and plasma disposition kinetics after its administration at the recommended dose, x5 and x10 doses to lambs, (b) to compare the clinical efficacy of the same IVM dosages in lambs infected with an IVM-resistant isolate of Haemonchus contortus, and (c) to assess the expression of the transporter protein P-glycoprotein (P-gp) in H. contortus recovered at 14 days after administration of the IVM dose regimens. There were two separated trials where IVM was administered either subcutaneously (SC, Experiment I) or intraruminally (IR, Experiment II). Each experiment involved twenty-four (24) lambs artificially infected with a highly resistant H. contortus isolate. Animals were allocated into 4 groups (n=6) and treated with IVM at either 0.2 (IVM x1), 1 (IVM x5) or 2mg/kg (IVM x10). Plasma samples were collected up to 12 days post-treatment and analysed by HPLC. An untreated-control Group was included to assess the comparative anthelmintic efficacy of the different treatments. The level of expression of Pgp in H. contortus specimens obtained from lambs both untreated and IR treated with the different IVM doses was quantified by real time PCR. Parametric and non-parametric tests were used to compare the statistical significance of the results (P<0.05). After the SC treatment, the IVM plasma area under the concentration-time curve (AUC0-LOQ) increased from 41.9 (IVM SCx1) up to 221 (IVM SCx5) and 287 (IVM SCx10)ng.day/mL and after the IR treatment from 20.8 (IVM IRx1) up to 121 (IVM IRx5) and 323 (IVM IRx10)ng.day/mL. Dose-adjusted AUC0-LOQ and Cmax were similar among doses, demonstrating dose proportionality for IVM after both SC and IR administration at the three different doses. The efficacies against resistant H. contortus after the SC treatment were 42% (IVM SC1), 75% (IVM SCx5) and 75% (IVM SCx10). However, the IR IVM treatment reached clinical efficacies ranging from 48% (IVM IRx1) up to 96% (IVM IRx5) and 98% (IVM IRx10). None of the IR IVM treatments increased the expression of P-gp in adult H. contortus at 14 days post-treatment compared to samples collected from the untreated control group. An enhanced parasite exposure of the drug at the abomasum may explain the improved efficacy against this recalcitrant H. contortus isolate observed only after the IR administration at 5- and 10-fold the IVM therapeutic dosage.

Clinical assessment of post-adulticide complications in Dirofilaria immitis-naturally infected dogs treated with doxycycline and ivermectin.

This study shows that a combination of doxycycline (10mg/kg/sid for 30 days) and ivermectin (6 µg/kg/every 15 days for 6 months) is well tolerated for the treatment of canine heartworm disease (HWD). Monthly echocardiography showed that 84% of treated dogs either progressively improved parameters indicative of pulmonary hypertension or, following slight worsening, resolved all signs. Thoracic radiography showed the persistence of interstitial inflammation, even though also in this case, approximately 70% of the dogs steadily improved or worsened but then improved by the end of the study.

Assessment of the onset of action of afoxolaner against existing adult flea (Ctenocephalides felis) infestations on dogs.

The speed of kill of afoxolaner against experimental infestations by Ctenocephalides felis was evaluated after oral administration of afoxolaner in a soft chew (NEXGARD(®)) at a dose to achieve 2.5mg/kg bodyweight. Forty beagles were allocated to two treatment groups. Dogs in Treatment Group 1 were untreated controls. Dogs in Treatment Group 2 were treated on Day-0 with afoxolaner, according to their pre-treatment bodyweight. All dogs were infested with approximately 100 C. felis on Day-1. Live fleas were counted upon removal at 5 time points after treatment (i.e., 2, 4, 8, 12 and 24h after treatment). For each time point, counts were performed on 4 dogs from each of the treated and the untreated groups. Early curative flea killing efficacy was evaluated with respect to the untreated control group. The afoxolaner treated group had significantly fewer fleas than the untreated control group at 8, 12, and 24h (p<0.001). The percent efficacies of orally administered afoxolaner were 15.0%, 87.8%, 99.5%, 100.0%, and 100.0% at 2, 4, 8, 12, and 24h, respectively. In this study, afoxolaner began killing fleas by 2h after treatment with increasing efficacy at subsequent time points and had >99.5% efficacy at 8, 12, and 24h after treatment demonstrating an early onset of action.

The cost of annual versus biannual community-directed treatment of onchocerciasis with ivermectin: Ghana as a case study.

BACKGROUND: It has been proposed that switching from annual to biannual (twice yearly) mass community-directed treatment with ivermectin (CDTI) might improve the chances of onchocerciasis elimination in some African foci. However, historically, relatively few communities have received biannual treatments in Africa, and there are no cost data associated with increasing ivermectin treatment frequency at a large scale. Collecting cost data is essential for conducting economic evaluations of control programmes. Some countries, such as Ghana, have adopted a biannual treatment strategy in selected districts. We undertook a study to estimate the costs associated with annual and biannual CDTI in Ghana. METHODOLOGY: The study was conducted in the Brong-Ahafo and Northern regions of Ghana. Data collection was organized at the national, regional, district, sub-district and community levels, and involved interviewing key personnel and scrutinizing national records. Data were collected in four districts; one in which treatment is delivered annually, two in which it is delivered biannually, and one where treatment takes place biannually in some communities and annually in others. Both financial and economic costs were collected from the health care provider's perspective. PRINCIPAL FINDINGS: The estimated cost of treating annually was US Dollars (USD) 0.45 per person including the value of time donated by the community drug distributors (which was estimated at USD 0.05 per person per treatment round). The cost of CDTI was approximately 50-60% higher in those districts where treatment was biannual than in those where it was annual. Large-scale mass biannual treatment was reported as being well received and considered sustainable. CONCLUSIONS/SIGNIFICANCE: This study provides rigorous evidence of the different costs associated with annual and biannual CDTI in Ghana which can be used to inform an economic evaluation of the debate on the optimal treatment frequency required to control (or eliminate) onchocerciasis in Africa.

Assessment of Cryptosporidium parvum infection in immunocompetent and immunocompromised mice and its role in triggering intestinal dysplasia.

OBJECTIVES: There is an association between chronic inflammation and cancer, including colon cancer. Cryptosporidium parvum is a protozoan parasite that infects the gastrointestinal epithelial cells causing several parasitological and pathological changes. It is incriminated in the development of colorectal cancer in immunosuppressed individuals. Cyclin D1 expression is essential for cell cycle progression and its overexpression has been reported in colorectal cancer. This work aimed to study the gastrointestinal changes, including parasitological and pathological changes, induced by C. parvum infection in both immunocompetent and in chemically immunosuppressed mice, together with immunohistochemical assessment of cyclin D1 expression in infected tissues. In addition, the effectiveness of nitazoxanide (NTZ) in the treatment of cryptosporidiosis was evaluated. METHODS: This study included six groups of mice: group I, infected; group II, infected and immunosuppressed; group III, infected and treated with NTZ; group IV, infected, immunosuppressed, and treated with NTZ; and groups V and VI representing non-infected controls. Mice were subjected to stool examination for oocyst counts and were later sacrificed for intestinal dissection and routine histopathological examination of pathological changes; the endogenous developmental stages of the parasite were counted and immunohistochemical staining was carried out for the determination of cyclin D1. RESULTS: Group II showed the highest numbers of oocysts shed and endogenous developmental stages compared to the other groups. Intestinal dysplastic changes were seen only in groups I and II, where these changes were in favor of group II compared to group I. High-grade dysplasia was seen in four out of 20 mice in group II and was significantly associated with the number of endogenous developmental stages of C. parvum. NTZ was effective in the treatment of Cryptosporidium infection, with a greater effect in group III than in group IV. CONCLUSIONS: C. parvum is one of the infectious agents that may induce intestinal dysplasia, including the high-grade category, which occurs particularly in the presence of immune suppression states and elevated endogenous parasite loads. Cyclin D1 is a good and useful marker for the detection of intestinal dysplasia. The effectiveness of NTZ is dependent on the immune status of the infected host.

Initial assessment of the ability of ivermectin to kill Ixodes scapularis and Dermacentor variabilis ticks feeding on humans.

OBJECTIVE: The purpose of this study was to determine Ixodes scapularis and Dermacentor variabilis tick mortality when fed on humans who have consumed 400 µg/kg oral ivermectin. METHODS: Six study subjects, 3 in each group, were randomly assigned to receive either 400 µg/kg ivermectin or placebo in a blinded manner. After consuming either ivermectin or placebo, each study subject had 2 colostomy bags attached to his or her abdomen. One of the colostomy bags contained 7 I scapularis nymphs and 7 adults. The other colostomy bag contained 7 D variabilis nymphs and 7 adults. Tick mortality was recorded over the next 24 hours. RESULTS: Fifty-five percent (6 of 11) of the attached I scapularis nymphs exposed to ivermectin had morbidity (3 of 11) or died (3 of 11), compared with 0% morbidity and mortality in the 2 I scapularis nymphs that attached in the placebo group. No I scapularis adults or D variabilis nymphs attached to feed. Among D variabilis adults that attached to feed, there was a 0% mortality rate for both the placebo group (0 of 6) and the ivermectin group (0 of 8). CONCLUSIONS: We demonstrate a novel method to confine ticks to human subjects to study tick-borne diseases. While there was a trend toward I scapularis morbidity and mortality in the ivermectin arm, the low number of ticks that attached in the placebo group limited our analysis. Most ticks began feeding in the last 12 hours of the experiment, significantly limiting their exposure to ivermectin. Ivermectin does not cause early death in D variabilis adults.

Soil transmitted helminths and scabies in Zanzibar, Tanzania following mass drug administration for lymphatic filariasis--a rapid assessment methodology to assess impact.

BACKGROUND: Ivermectin and albendazole are used in annual mass drug administration (MDA) for the lymphatic filariasis elimination programmes in African countries co-endemic for onchocerciasis, but have additional impact on soil transmitted helminths and the ectoparasitic mite which causes scabies. Assessing these collateral impacts at scale is difficult due to the insensitivity of available parasite detection techniques. METHODS: The numbers of cases diagnosed with intestinal helminths and scabies and who received prescriptions for treatment were evaluated in 50 health centres in Zanzibar. Records were examined from 2000, prior to the initiation of MDA to 2005, after six rounds of MDA for lymphatic filariasis had taken place. RESULTS: Health centre records showed a consistent decline in the number of cases of intestinal helminths and scabies diagnosed by community health workers in Zanzibar and the number of prescriptions issued across five age groups. A 90-98% decline in soil transmitted helminths and 68-98% decline in scabies infections were recorded. Poisson regression models aggregated to both the island-level and district-level indicated that the decline was statistically significant. CONCLUSIONS: The described method of examining health centre records has the potential for use on a large scale, despite limitations, as a rapid method to evaluate the impacts resulting from both lymphatic filariasis and onchocerciasis MDA. This would result in a reduction in the need for parasitological evaluations to determine prevalence and intensity.

Neurocysticercosis among resettled refugees from Burma.

Taenia solium is the most common helminthic infection of the central nervous system and a leading cause of epilepsy in developing nations. Little is known about neurocysticercosis in refugees from Southeast Asia which is endemic for T solium. We present two cases in a single household of refugees from Burma.

Preventive Chemotherapy and Transmission Control (PCT) databank: a tool for planning, implementation and monitoring of integrated preventive chemotherapy for control of neglected tropical diseases.

The integration of vertical control programmes of neglected tropical diseases (NTDs) aims to contain operational cost, simplify the application of the control measures and further extend the coverage of interventions. The Preventive Chemotherapy and Transmission Control (PCT) databank was established by the WHO to facilitate access and sharing of information from national programmes with stakeholders involved in NTD control. The PCT databank contains compilations of historical and current information on disease-specific epidemiological situations, the geographical overlapping of NTDs and progress of control activities in all the NTD-endemic countries. A summary of country-specific epidemiological maps and the progress of control activities are available from the online PCT databank and the Country Profiles. Annual progress of preventive chemotherapy interventions targeting specific NTDs is reported in the Weekly Epidemiological Record (WER) published annually for each disease targeted. In this paper, the method of data collection and compilation used to establish the PCT databank is explained and the key features of the online PCT databank, the Country Profiles and WER are presented.

From chemical graphs in computer-aided drug design to general Markov-Galvez indices of drug-target, proteome, drug-parasitic disease, technological, and social-legal networks.

Complex Networks are useful in solving problems in drug research and industry, developing mathematical representations of different systems. These systems move in a wide range from relatively simple graph representations of drug molecular structures to large systems. We can cite for instance, drug-target protein interaction networks, drug policy legislation networks, or drug treatment in large geographical disease spreading networks. In any case, all these networks have essentially the same components: nodes (atoms, drugs, proteins, microorganisms and/or parasites, geographical areas, drug policy legislations, etc.) and edges (chemical bonds, drug-target interactions, drug-parasite treatment, drug use, etc.). Consequently, we can use the same type of numeric parameters called Topological Indices (TIs) to describe the connectivity patterns in all these kinds of Complex Networks despite the nature of the object they represent. The main reason for this success of TIs is the high flexibility of this theory to solve in a fast but rigorous way many apparently unrelated problems in all these disciplines. Another important reason for the success of TIs is that using these parameters as inputs we can find Quantitative Structure-Property Relationships (QSPR) models for different kind of problems in Computer-Aided Drug Design (CADD). Taking into account all the above-mentioned aspects, the present work is aimed at offering a common background to all the manuscripts presented in this special issue. In so doing, we make a review of the most common types of complex networks involving drugs or their targets. In addition, we review both classic TIs that have been used to describe the molecular structure of drugs and/or larger complex networks. Next, we use for the first time a Markov chain model to generalize Galvez TIs to higher order analogues coined here as the Markov-Galvez TIs of order k (MGk). Lastly, we illustrate the calculation of MGk values for different classes of networks found in drug research, nature, technology, and social-legal sciences.

A randomised controlled clinical trial on the safety of co-administration of albendazole, ivermectin and praziquantel in infected schoolchildren in Uganda.

Integrated chemotherapy of neglected tropical diseases (NTD) through mass drug administration given as a single dose would increase treatment coverage and cost-effectiveness. This study reports on the safety of a combination of albendazole, ivermectin and praziquantel in the treatment of lymphatic filariasis (LF), schistosomiasis and soil-transmitted helminthiasis (STH) in infected children. In this randomised, controlled, single-blinded clinical trial conducted in 235 primary school children aged 5-18 years in Yumbe District in Northern Uganda, the triple combination therapy was compared with the current NTD programme regimen. Liver function testing was performed for all children who received combined therapy. The study included 48 children with LF alone, 60 children with schistosomiasis (Schistosoma mansoni), 41 children with STH, 49 children with schistosomiasis + LF and 37 children with all three types of infection. Children were closely monitored by a paediatrician for any adverse reactions for 7 days. No serious adverse events were experienced. However, 4 of 18 children in the test group and 2 of 3 children in the control group who did not report any ill conditions before treatment developed adverse drug reactions. The combined and conventional therapies were found to be equally safe. The efficacies of both therapies were comparable and satisfactory. [ClinicalTrials.gov identifier: NCT01050517].