Activity of oxantel pamoate monotherapy and combination chemotherapy against Trichuris muris and hookworms : revival of an old drug

BACKGROUND: It is widely recognized that only a handful of drugs are available against soil-transmitted helminthiasis, all of which are characterized by a low efficacy against Trichuris trichiura, when administered as single doses. The re-evaluation of old, forgotten drugs is a promising strategy to identify alternative anthelminthic drug candidates or drug combinations. METHODOLOGY: We studied the activity of the veterinary drug oxantel pamoate against Trichuris muris, Ancylostoma ceylanicum and Necator americanus in vitro and in vivo. In addition, the dose-effect of oxantel pamoate combined with albendazole, mebendazole, levamisole, pyrantel pamoate and ivermectin was studied against T. muris in vitro and additive or synergistic combinations were followed up in vivo. PRINCIPAL FINDINGS: We calculated an ED50 of 4.7 mg/kg for oxantel pamoate against T. muris in mice. Combinations of oxantel pamoate with pyrantel pamoate behaved antagonistically in vitro (combination index (CI) = 2.53). Oxantel pamoate combined with levamisole, albendazole or ivermectin using ratios based on their ED50s revealed antagonistic effects in vivo (CI = 1.27, 1.90 and 1.27, respectively). A highly synergistic effect (CI = 0.15) was observed when oxantel pamoate-mebendazole was administered to T. muris-infected mice. Oxantel pamoate (10 mg/kg) lacked activity against Ancylostoma ceylanicum and Necator americanus in vivo. CONCLUSIONSIGNIFICANCE: Our study confirms the excellent trichuricidal properties of oxantel pamoate. Since the drug lacks activity against hookworms it is necessary to combine oxantel pamoate with a partner drug with anti-hookworm properties. Synergistic effects were observed for oxantel pamoate-mebendazole, hence this combination should be studied in more detail. Since, of the standard drugs, albendazole has the highest efficacy against hookworms, additional investigations on the combination effect of oxantel pamoate-albendazole should be launche

Not all intravenous immunoglobulin preparations are equally well tolerated

Intravenous immunoglobulin (IVIG) is used for many indications beyond the original substitution in primary antibody deficiency. Whereas many reports mention adverse reactions, no comparative data exist concerning the incidence of side-effects among the different brands of IVIG. We describe here our experience with the use of different IVIG formulations and their tolerability in a select cohort of 40 patients. The IVIG dose ranged from 0.4 to 3 g/kg/day and was given for 1–2742 days. Fourteen patients (35%) experienced mild to severe adverse reactions during or within 48 h of administration of standard IVIG preparation, which did not recur after switching to an alternative preparation. Adverse reactions included headache, fever, chills, nausea, emesis, hypotension and muscle cramps. One patient experienced a severe adverse reaction; he had a 3-day headache following IVIG infusion. Among the 16 patients who received alternative preparation initially, none experienced adverse reactions. In conclusion, this study shows that IVIG preparations are not all equally well tolerated in patients. The data suggest that, perhaps to a comparable extent to the preparation itself, the infusion rate has a major effect. If a reduction in the infusion rate does not minimize side-effects, one should consider switching the IVIG formulation

Egg excretion indicators for the measurement of soil-transmitted helminth response to treatment

BACKGROUND: Periodic administration of anthelmintic drugs is a cost-effective intervention for morbidity control of soil-transmitted helminth (STH) infections. However, with programs expanding, drug pressure potentially selecting for drug-resistant parasites increases. While monitoring anthelmintic drug efficacy is crucial to inform country control program strategies, different factors must be taken into consideration that influence drug efficacy and make it difficult to standardize treatment outcome measures. We aimed to identify suitable approaches to assess and compare the efficacy of different anthelmintic treatments. METHODOLOGY: We built an individual participant-level database from 11 randomized controlled trials and two observational studies in which subjects received single-agent or combination therapy, or placebo. Eggs per gram of stool were calculated from egg counts at baseline and post-treatment. Egg reduction rates (ERR; based on mean group egg counts) and individual-patient ERR (iERR) were utilized to express drug efficacy and analyzed after log-transformation with a linear mixed effect model. The analyses were separated by follow-up duration (14-21 and 22-45 days) after drug administration. PRINCIPAL FINDINGS: The 13 studies enrolled 5,759 STH stool-positive individuals; 5,688 received active medication or placebo contributing a total of 11,103 STH infections (65% had two or three concurrent infections), of whom 3,904 (8,503 infections) and 1,784 (2,550 infections) had efficacy assessed at 14-21 days and 22-45 days post-treatment, respectively. Neither the number of helminth co-infections nor duration of follow-up affected ERR for any helminth species. The number of participants treated with single-dose albendazole was 689 (18%), with single-dose mebendazole 658 (17%), and with albendazole-based co-administrations 775 (23%). The overall mean ERR assessed by day 14-21 for albendazole and mebendazole was 94.5% and 87.4%, respectively on Ascaris lumbricoides, 86.8% and 40.8% on hookworm, and 44.9% and 23.8% on Trichuris trichiura. The World Health Organization (WHO) recommended criteria for efficacy were met in 50%, 62%, and 33% studies of albendazole for A. lumbricoides, T. trichiura, and hookworm, respectively and 25% of mebendazole studies. iERR analyses showed similar results, with cure achieved in 92% of A. lumbricoides-infected subjects treated with albendazole and 93% with mebendazole; corresponding figures for hookworm were 70% and 17%, and for T. trichiura 22% and 20%. CONCLUSIONS/SIGNIFICANCE: Combining the traditional efficacy assessment using group averages with individual responses provides a more complete picture of how anthelmintic treatments perform. Most treatments analyzed fail to meet the WHO minimal criteria for efficacy based on group means. Drug combinations (i.e., albendazole-ivermectin and albendazole-oxantel pamoate) are promising treatments for STH infections

Bosentan therapy for chronic thromboembolic pulmonary hypertension. A national open label study assessing the effect of Bosentan on haemodynamics, exercise capacity, quality of life, safety and tolerability in patients with chronic thromboembolic pulmonary hypertension (BOCTEPH-Study).

we performed an open-label national study to evaluate the effects of Bosentan on haemodynamics, exercise capacity, quality of life, safety and tolerability in patients with chronic thromboembolic pulmonary hypertension (CTEPH). fifteen patients with CTEPH not eligible or waiting for surgery were enrolled. The primary endpoint was the change in pulmonary vascular resistance (PVR). Secondary endpoints included quality of life (measured by the Minnesota living with heart failure questionnaire, MLHF), 6 minute walk distance (6MWD), World Health Organization (WHO) functional class, Borg dyspnoea scale, plasma endothelin, serum values of disease severity such as uric acid, N-terminal-pro brain natriuretic peptide (NTproBNP), C-reactive protein measured by a highly sensitive method (CRPs) and other serum and haemodynamic parameters. after six months of treatment with bosentan, the PVR decreased from 852 (319) to 657(249) dyn*s*m-5 (p = 0.02). Quality of life considerably improved from a mean total score of 48(14) to 35(17) (p = 0.003) with improvements in the physical (from 25(5) to 17(7)) and emotional (from 11(6) to 6(5)) subscores (p = 0.005 and 0.011), respectively. The 6MWD improved from 389(78) to 443(79) meters (p = 0.005). 4 patients (27%) improved and 11 patients (73%) maintained their WHO class with no deterioration during the six months of bosentan treatment (p = 0.02). Uric acid serum levels declined from 525(145) to 453(151) micromol/l (p = 0.006), NTproBNP and CRPs declined insignificantly. Endothelin serum levels increased from 4.3(1.5) to 5.9(2.2) pg/ml (p = 0.025). Patients tolerated the treatment well, and there were no severe adverse events or deaths. this open-label study suggests a beneficial effect of bosentan therapy not only on pulmonary haemodynamics, but also on quality of life and exercise capacity for patients with severe CTEPH

The present and future system for measuring the Atlantic meridional overturning circulation and heat transport

of the global combined atmosphere-ocean heat flux and so is important for the mean climate of the Atlantic sector of the Northern Hemisphere. This meridional heat flux is accomplished by both the Atlantic Meridional Overturning Circulation (AMOC) and by basin-wide horizontal gyre circulations. In the North Atlantic subtropical latitudes the AMOC dominates the meridional heat flux, while in subpolar latitudes and in the subtropical South Atlantic the gyre circulations are also important. Climate models suggest the AMOC will slow over the coming decades as the earth warms, causing widespread cooling in the Northern hemisphere and additional sea-level rise. Monitoring systems for selected components of the AMOC have been in place in some areas for decades, nevertheless the present observational network provides only a partial view of the AMOC, and does not unambiguously resolve the full variability of the circulation. Additional observations, building on existing measurements, are required to more completely quantify the Atlantic meridional heat transport. A basin-wide monitoring array along 26.5°N has been continuously measuring the strength and vertical structure of the AMOC and meridional heat transport since March 31, 2004. The array has demonstrated its ability to observe the AMOC variability at that latitude and also a variety of surprising variability that will require substantially longer time series to understand fully. Here we propose monitoring the Atlantic meridional heat transport throughout the Atlantic at selected critical latitudes that have already been identified as regions of interest for the study of deep water formation and the strength of the subpolar gyre, transport variability of the Deep Western Boundary Current (DWBC) as well as the upper limb of the AMOC, and inter-ocean and intrabasin exchanges with the ultimate goal of determining regional and global controls for the AMOC in the North and South Atlantic Oceans. These new arrays will continuously measure the full depth, basin-wide or choke-point circulation and heat transport at a number of latitudes, to establish the dynamics and variability at each latitude and then their meridional connectivity. Modeling studies indicate that adaptations of the 26.5°N type of array may provide successful AMOC monitoring at other latitudes. However, further analysis and the development of new technologies will be needed to optimize cost effective systems for providing long term monitoring and data recovery at climate time scales. These arrays will provide benchmark observations of the AMOC that are fundamental for assimilation, initialization, and the verification of coupled hindcast/forecast climate models

Monitoring the oceanic flow between Africa and Antarctica: Report of the first GoodHope cruise

The southern ocean plays a major role in the global oceanic circulation role in the global oceanic circulation, as a component of the Meridional Overturning Circulation, and it is postulated that it has a great influence on present-day climate. However, our understanding of its complex three-dimensional dynamics and of the impact of its variability on the climate system is rudimentary. The newly constituted, international GoodHope research venture aims to address this knowledge gap by establishing a programme of regular observations across the Southern Ocean between the African and Antarctic continents. The objectives of this programme are fivefold: (1) to improve understanding of Indo-Atlantic inter-ocean exchanges and their impact on the global thermohaline circulation and thus on global climate change; (2) to understand in more detail the influence these exchanges have on the climate variability of the southern African subcontinent; (3) to monitor the variability of the main Southern Ocean frontal systems associated with the Antarctic Circumpolar Current; (4) to study air–sea exchanges and their role on the global heat budget, with particular emphasis on the intense exchanges occurring within the Agulhas Retroflection region south of South Africa, and (5) to examine the role of major frontal systems as areas of elevated biological activity and as biogeographical barriers to the distribution of plankton. We present here preliminary results on the physical and biological structure of the frontal systems using the first GoodHope transect that was completed during February–March 2004

Potentiation of thrombus instability: a contributory mechanism to the effectiveness of antithrombotic medications

© The Author(s) 2018The stability of an arterial thrombus, determined by its structure and ability to resist endogenous fibrinolysis, is a major determinant of the extent of infarction that results from coronary or cerebrovascular thrombosis. There is ample evidence from both laboratory and clinical studies to suggest that in addition to inhibiting platelet aggregation, antithrombotic medications have shear-dependent effects, potentiating thrombus fragility and/or enhancing endogenous fibrinolysis. Such shear-dependent effects, potentiating the fragility of the growing thrombus and/or enhancing endogenous thrombolytic activity, likely contribute to the clinical effectiveness of such medications. It is not clear how much these effects relate to the measured inhibition of platelet aggregation in response to specific agonists. These effects are observable only with techniques that subject the growing thrombus to arterial flow and shear conditions. The effects of antithrombotic medications on thrombus stability and ways of assessing this are reviewed herein, and it is proposed that thrombus stability could become a new target for pharmacological intervention.Peer reviewedFinal Published versio