The pharmaceutical death-ride of dihydroartemisinin

In the 2010 second edition of WHO's guidelines for the treatment of malaria, the relatively new fixed dose combination dihydroartemisinin-piperaquine is included as one of the recommended artemisinin combination therapies. However, experimental testing demonstrates that, due to its intrinsic chemical instability, dihydroartemisinin is not suitable to be used in pharmaceutical formulations. In addition, data show that the currently available dihydroartemisinin preparations fail to meet the internationally accepted stability requirements. At a time when many efforts aim to ban counterfeit and substandard drugs from the malaria market, the obvious question rises how WHO and public-private partnerships, such as Medicine for Malaria venture (MMV), can support the production and marketing of anti-malarial drugs that do not even meet the International Pharmacopoeia requirements

An overview of early investigational drugs for the treatment of human papilloma virus infection and associated dysplasia

Introduction: High-risk HPV (HR-HPV) related invasive cervical cancer (ICC) causes >270,000 deaths per annum world-wide with over 85% of these occurring in low-resource countries. Ablative and excisional treatment modalities are restricted for use with high-grade pre-cancerous cervical disease with HPV infection and low-grade dysplasia mostly managed by a watch-and-wait policy.Areas Covered: Various pharmacological approaches have been investigated as non-destructive alternatives for the treatment of HR-HPV infection and associated dysplasia. These are discussed dealing with efficacy, ease-of-use (physician or self-applied), systemic or locally applied, side-effects, cost and risks. The main focus is the perceived impact on current clinical practice of a self-applied, effective and safe pharmacological anti-HPV treatment.Expert opinion: Current prophylactic HPV vaccines are expensive, HPV type restricted and have little effect in already infected women. Therapeutic vaccines are under development but are also HPV type-restricted. At present, the developed nations use national cytology screening and surgical procedures to treat only women identified with HPV-related high-grade dysplastic disease. However, since HPV testing is rapidly replacing cytology as the test-of-choice, a suitable topically-applied and low-cost antiviral treatment could be an ideal solution for treatment of HPV infection per se with test-of-cure carried out by repeat HPV testing. Cytology would only then be necessary for women who remained HPV positive. Although of significant benefit in the developed countries, combining such a treatment with self-sampled HPV testing could revolutionise the management of this disease in the developing world which lack both the infrastructure and resources to establish national cytology screening programs

VERTOS II: Percutaneous vertebroplasty versus conservative therapy in patients with painful osteoporotic vertebral compression fractures; rationale, objectives and design of a multicenter randomized controlled trial

ABSTRACT: BACKGROUND: The standard care in patients with a painful osteoporotic vertebral compression fracture (VCF) is conservative therapy. Percutaneous vertebroplasty (PV), a minimally invasive technique, is gaining popularity as a new treatment option. Many prospective and retrospective studies have reported on the effectiveness and safety of PV, but no large randomized controlled trial (RCT) has been published. OBJECTIVE: To estimate cost-effectiveness of PV compared to conservative therapy in terms of: pain reduction, quality of life, complications, secondary fractures and mortality. MATERIALS AND METHODS: The VERTOS II study is designed as a prospective, multicenter RCT. Patients with a painful VCF with bone edema on MR imaging, local back pain for 6 weeks or less, osteopenia and aged 50 years or older, after obtaining informed consent are included and randomized for PV or conservative therapy. In total 200 patients will be enrolled. Follow-up is at regular intervals during a 1-year period with standard questionnaires, addressing: clinical symptoms, pain medication, Visual Analogue Scale (VAS) score, quality of life and cost-effectiveness. Secondary fractures, necessary additional therapies and complications are recorded. CONCLUSION: The VERTOS II study is the first methodologically sound RCT designed to assess the cost-effectiveness of PV compared to conservative therapy in patients with an acute osteoporotic VCF. TRIAL REGISTRATION: http://www.clinicaltrials.gov, NCT00232466

Efficacy and safety of a fixed dose artesunate-sulphamethoxypyrazine-pyrimethamine compared to artemether-lumefantrine for the treatment of uncomplicated falciparum malaria across Africa: a randomized multi-centre trial

<p>Abstract</p> <p>Background</p> <p>The efficacy of artemisinin-based combination therapy has already been demonstrated in a number of studies all over the world, and some of them can be regarded as comparably effective. Ease of administration of anti-malarial treatments with shorter courses and fewer tablets may be key determinant of compliance.</p> <p>Methods</p> <p>Patients with uncomplicated falciparum malaria and over six months of age were recruited in Cameroon, Mali, Rwanda and Sudan. 1,384 patients were randomly assigned to receive artesunate-sulphamethoxypyrazine-pyrimethamine (AS-SMP) three-day (once daily for 3 days) regimen (N = 476) or AS-SMP 24-hour (0 h, 12 h, 24 h) regimen (N = 458) or artemether-lumefantrine (AL), the regular 6 doses regimen (N = 450). The primary objective was to demonstrate non-inferiority (using a margin of -6%) of AS-SMP 24 hours or AS-SMP three days versus AL on the PCR-corrected 28-day cure rate.</p> <p>Results</p> <p>The PCR corrected 28-day cure rate on the intention to treat (ITT) analysis population were: 96.0%(457/476) in the AS-SMP three-day group, 93.7%(429/458) in the AS-SMP 24-hour group and 92.0%(414/450) in the AL group. Likewise, the cure rates on the PP analysis population were high: 99.3%(432/437) in the AS-SMP three-day group, 99.5%(416/419) in the AS-SMP 24-hour group and 99.7(391/394)% in the AL group. Most common drug-related adverse events were gastrointestinal symptoms (such as vomiting and diarrhea) which were slightly higher in the AS-SMP 24-hour group.</p> <p>Conclusion</p> <p>AS-SMP three days or AS-SMP 24 hours are safe, are as efficacious as AL, and are well tolerated.</p> <p>Trial registration</p> <p>NCT00484900 <url>http://www.clinicaltrials.gov</url>.</p

Skills training in minimally invasive surgery in Dutch obstetrics and gynecology residency curriculum

The complexity of acquiring minimally invasive surgical (MIS) skills, combined with smaller case volumes for residents have pushed the development of skills training facilities on simulators outside the operating room (OR). Medico-legal and financial constraints have stimulated this development even more. However, the implementation of simulator training into a residency curriculum is shown to be troublesome. MIS skills training is organized in a uniform and easily applicable way in the Dutch obstetrics and gynecology residency curriculum. Every resident is obliged to attend the same basic surgical skills course, named Cobra-alpha course, intentionally during postgraduate year (PGY) 1 or 2. Furthermore, surgical skills are trained, evaluated and expanded on simulators in teaching hospitals. Additional to the Cobra-alpha course, residents may attend advanced training courses and congresses focusing on laparoscopy and hysteroscopy. This organization guarantees a uniform introduction to MIS skills training for every resident. However, preconditions for continuous training and evaluation after this introduction have to be optimized

Different tissue reaction of oesophagus and diaphragm after mesh hiatoplasty. Results of an animal study

<p>Abstract</p> <p>Background</p> <p>Laparoscopic mesh-reinforcement of the hiatal region in the treatment of gastroesophageal reflux disease (GERD) and paraesophageal hernia (PEH) reduces the risk of recurrence. However, there are still controversies about the technique of mesh placement, shape, structure and material. We therefore compared tissue integration and scar formation after implantation of two different polypropylene-meshes in a rabbit model.</p> <p>Methods</p> <p>A total of 20 female chinchilla rabbits were included in this study. Two different meshes (Polypropylene PP, Polyglecaprone 25 Composite PP-PG) were implanted on the abdominal diaphragm around the oesophagus. After 3 months the implanted meshes were excised en-bloc. Histological and morphological analyses were carried out accordingly proliferation rate, apoptosis and collagen type I/III ratio.</p> <p>Results</p> <p>Regarding proliferation rate of oesophagus PP (9.31 ± 3.4%) and PP-PG (13.26 ± 2.54%) differ in a significant (p = 0.0097) way. In the diaphragm we found a significant (p = 0.00066) difference between PP (9.43 ± 1.45%) and PP-PG (18.73 ± 5.92%) respectively. Comparing oesophagus and diaphragm we could prove a significant difference within PP-PG-group (p = 0.0195). Within PP-group the difference reached no statistical significance (p = 0.88). We found analogous results regarding apoptosis.</p> <p>Furthermore, there is a significant (p = 0.00013) difference of collagen type I/III ratio in PP-PG (12.28 ± 0.8) compared to PP (8.44 ± 1,63) in case of oesophageal tissue. Concerning diaphragm we found a significant difference (p = 0.000099) between PP-PG (8.85 ± 0.81) and PP (6.32 ± 1.07) as well.</p> <p>Conclusion</p> <p>The histologic and morphologic characteristics after prosthetic enforcement of the hiatus in this animal model show a more distinct tissue integration using PP-PG compared to PP. Additionally, different wound healing and remodelling capability influence tissue integration of the mesh in diaphragm and oesophagus.</p

Retracting and seeking movements during laparoscopic goal-oriented movements. Is the shortest path length optimal?

Aims- Minimally invasive surgery (MIS) requires a high degree of eye–hand coordination from the surgeon. To facilitate the learning process, objective assessment systems based on analysis of the instruments’ motion are being developed. To investigate the influence of performance on motion characteristics, we examined goaloriented movements in a box trainer. In general, goal-oriented movements consist of a retracting and a seeking phase, and are, however, not performed via the shortest path length. Therefore, we hypothesized that the shortest path is not an optimal concept in MIS. Methods-Participants were divided into three groups (experts, residents, and novices). Each participant performed a number of one-hand positioning tasks in a box trainer. Movements of the instrument were recorded with the TrEndo tracking system. The movement from point A to B was divided into two phases: A-M (retracting) and M-B (seeking). Normalized path lengths (given in %) of the two phases were compared. Results- Thirty eight participants contributed. For the retracting phase, we found no significant difference between experts [median (range) %: 152 (129–178)], residents [164 (126–250)], and novices [168 (136–268)]. In the seeking phase, we find a significant difference (<0.001) between experts [180 (172–247)], residents [201 (163–287)], and novices [290 (244–469)]. Moreover, within each group, a significant difference between retracting and seeking phases was observed. Conclusions- Goal-oriented movements in MIS can be split into two phases: retracting and seeking. Novices are less effective than experts and residents in the seeking phase. Therefore, the seeking phase is characteristic of performance differences. Furthermore, the retracting phase is essential, because it improves safety by avoiding intermediate tissue contact. Therefore, the shortest path length, as presently used during the assessment of basic MIS skills, may be not a proper concept for analyzing optimal movements and, therefore, needs to be revised.Biomechanical EngineeringMechanical, Maritime and Materials Engineerin

Anti-plasmodial polyvalent interactions in Artemisia annua L. aqueous extract – possible synergistic and resistance mechanisms

Artemisia annua hot water infusion (tea) has been used in in vitro experiments against P. falciparum malaria parasites to test potency relative to equivalent pure artemisinin. High performance liquid chromatography (HPLC) and mass spectrometric analyses were employed to determine the metabolite profile of tea including the concentrations of artemisinin (47.5±0.8 mg L-1), dihydroartemisinic acid (70.0±0.3 mg L-1), arteannuin B (1.3±0.0 mg L-1), isovitexin (105.0±7.2 mg L-1) and a range of polyphenolic acids. The tea extract, purified compounds from the extract, and the combination of artemisinin with the purified compounds were tested against chloroquine sensitive and chloroquine resistant strains of P. falciparum using the DNA-intercalative SYBR Green I assay. The results of these in vitro tests and of isobologram analyses of combination effects showed mild to strong antagonistic interactions between artemisinin and the compounds (9-epi-artemisinin and artemisitene) extracted from A. annua with significant (IC50 <1 μM) anti-plasmodial activities for the combination range evaluated. Mono-caffeoylquinic acids, tri-caffeoylquinic acid, artemisinic acid and arteannuin B showed additive interaction while rosmarinic acid showed synergistic interaction with artemisinin in the chloroquine sensitive strain at a combination ratio of 1:3 (artemisinin to purified compound). In the chloroquine resistant parasite, using the same ratio, these compounds strongly antagonised artemisinin anti-plasmodial activity with the exception of arteannuin B, which was synergistic. This result would suggest a mechanism targeting parasite resistance defenses for arteannuin B’s potentiation of artemisinin

RELEASE-HF study: a protocol for an observational, registry-based study on the effectiveness of telemedicine in heart failure in the Netherlands

Introduction Meta-analyses show postive effects of telemedicine in heart failure (HF) management on hospitalisation, mortality and costs. However, these effects are heterogeneous due to variation in the included HF population, the telemedicine components and the quality of the comparator usual care. Still, telemedicine is gaining acceptance in HF management. The current nationwide study aims to identify (1) in which subgroup(s) of patients with HF telemedicine is (cost-)effective and (2) which components of telemedicine are most (cost-) effective. Methods and analysis The RELEASE-HF ('REsponsible roLl-out of E-heAlth through Systematic Evaluation -Heart Failure') study is a multicentre, observational, registry-based cohort study that plans to enrol 6480 patients with HF using data from the HF registry facilitated by the Netherlands Heart Registration. Collected data include patient characteristics, treatment information and clinical outcomes, and are measured at HF diagnosis and at 6 and 12 months afterwards. The components of telemedicine are described at the hospital level based on closed-ended interviews with clinicians and at the patient level based on additional data extracted from electronic health records and telemedicine-generated data. The costs of telemedicine are calculated using registration data and interviews with clinicians and finance department staff. To overcome missing data, additional national databases will be linked to the HF registry if feasible. Heterogeneity of the effects of offering telemedicine compared with not offering on days alive without unplanned hospitalisations in 1 year is assessed across predefined patient characteristics using exploratory stratified analyses. The effects of telemedicine components are assessed by fitting separate models for component contrasts. Ethics and dissemination The study has been approved by the Medical Ethics Committee 2021 of the University Medical Center Utrecht (the Netherlands). Results will be published in peer-reviewed journals and presented at (inter)national conferences. Effective telemedicine scenarios will be proposed among hospitals throughout the country and abroad, if applicable and feasible