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Ludwig Hoellein,1 Eliangiringa Kaale,2 Yonah Hebron Mwalwisi,3 Marco H Schulze,4 Carina Vetye-Maler,5 Ulrike Holzgrabe1 1Institute for Pharmacy and Food Chemistry, Julius-Maximilians-Universität Würzburg, Würzburg, Germany; 2Muhimbili University of Health and Allied Sciences, School of Pharmacy, Dar es Salaam, Tanzania; 3Tanzania Medicines & Medical Devices Authority, Dar es Salaam, Tanzania; 4Georg-August-Universität Göttingen, Institut für Krankenhaushygiene und Infektiologie, Göttingen, Germany; 5Apotheker ohne Grenzen Deutschland e.V., München, GermanyCorrespondence: Ulrike Holzgrabe, Institute for Pharmacy and Food Chemistry, Julius-Maximilians-Universität Würzburg, Am Hubland, Würzburg, 97074, Germany, Tel +49 931 31 85460, Email ulrike.holzgrabe@uni-wuerzburg.deAbstract: Medicine quality and methods for its assessment play a major role in the effectiveness of therapies and the treatment of many infectious diseases. However, poor-quality and/or falsified products are circulating in huge amounts in many low- and middle-income countries and are one of the major reasons why more and more resistant bacteria emerge. The development of resistance is additionally triggered by a plethora of antibiotic medicines which is easily available through pharmacies and unofficial sources. The uncontrolled overuse of these products is a huge problem not only in single countries but worldwide. In this review, we aim to demonstrate the factors which are involved in an emerging resistance development and how strong regulatory authorities, routine quality control by means of proficiency testing, and post-marketing surveillance as well as training personnel and patients can be combined to curb the problem.Keywords: medicine quality, falsified, antimicrobial resistance, proficiency testing, post-marketing surveillance, Africa, Latin America

Background Reproducibility of reported antibacterial activities of plant extracts has long remained questionable. Although plant-related factors should be well considered in serious pharmacognostic research, they are often not addressed in many research papers. Here we highlight the challenges in reproducing antibacterial activities of plant extracts. Methods Plants with reported antibacterial activities of interest were obtained from a literature review. Antibacterial activities against Escherichia coli and Klebsiella pneumoniae were tested using extracts’ solutions in 10% DMSO and acetone. Compositions of working solutions from both solvents were established using LC-MS analysis. Moreover, the availability of details likely to affect reproducibility was evaluated in articles which reported antibacterial activities of studied plants. Results Inhibition of bacterial growth at MIC of 256–1024 μg/mL was observed in only 15.4% of identical plant species. These values were 4–16-fold higher than those reported earlier. Further, 18.2% of related plant species had MICs of 128–256 μg/mL. Besides, 29.2% and 95.8% of the extracts were soluble to sparingly soluble in 10% DMSO and acetone, respectively. Extracts’ solutions in both solvents showed similar qualitative compositions, with differing quantities of corresponding phytochemicals. Details regarding seasons and growth state at collection were missing in 65% and 95% of evaluated articles, respectively. Likewise, solvents used to dissolve the extracts were lacking in 30% of the articles, whereas 40% of them used unidentified bacterial isolates. Conclusion Reproducibility of previously reported activities from plants’ extracts is a multi-factorial aspect. Thus, collective approaches are necessary in addressing the highlighted challenges.

Background Even though the international combat against Neglected Tropical Diseases such as schistosomiasis or soil-transmitted helminthiases depends on reliable therapeutics, anthelminthic pharmacovigilance has been neglected on many national African drug markets. Therefore, quality and composition of Albendazole, Mebendazole and Praziquantel locally collected in Burkina Faso, Côte d’Ivoire, Ghana and Tanzania were analysed. Methods Samples of 88 different batches were obtained from randomly selected facilities. Sampling took place in Northwest Tanzania, Western Burkina Faso, Southeast Côte d’Ivoire and Southwest Ghana. Visual examination of both packaging and samples was performed according to the WHO ‘Be Aware’ tool. Products were then screened with the GPHF Minilab, consisting of tests of mass uniformity, disintegration times and thin-layer chromatography (TLC). Confirmatory tests were performed according to international pharmacopoeiae, applying assays for dissolution profiles and high-performance liquid chromatography (HPLC). Findings Despite minor irregularities, appearance of the products did not hint at falsified medicines. However, 19.6% of the brands collected in Ghana and Tanzania were not officially licensed for sale. Mass uniformity was confirmed in 53 out of 58 brands of tablets. 41 out of 56 products passed disintegration times; 10 out of the 15 failing products did not disintegrate at all. Evaluating TLC results, only 4 out of 83 batches narrowly missed specification limits, 18 batches slightly exceeded them. Not more than 46.3% (31 / 67) of the tablets assayed passed the respective pharmaceutical criteria for dissolution. HPLC findings confirmed TLC results despite shifted specification limits: 10 out of 83 tested batches contained less than 90%, none exceeded 110%. Conclusion In the four study countries, no falsified anthelminthic medicine was encountered. The active pharmaceutical ingredient was not found to either exceed or fall below specification limits. Galenic characteristics however, especially dissolution profiles, revealed great deficits., Author summary Among Neglected Tropical Diseases, schistosomiasis and soil-transmitted helminthiases are still highly prevalent and affect more than 1.5 billion people on our planet. Key players in the combat against these entities are the anthelminthic medicines Albendazole, Mebendazole and Praziquantel, which are applied in therapy and preventive chemotherapy likewise. Despite widely available in tropical regions and, particularly for both benzimidazoles, relatively cheap, their quality has been poorly monitored. By this study, we illuminated products from East (Tanzania) and West Africa (Burkina Faso, Côte d’Ivoire and Ghana) and thus extended the African map of reproducibly assessed deworming drugs. Although containing sufficient active pharmaceutical ingredient, a failure of more than 50% in galenic features significantly mars a thorough elimination of parasites from patients. Our findings emphasize the need for quality-assured products. Regular local screening, efficient and expressive confirmation of irregularities and a swift appropriate reaction by governmental authorities contribute to a successful fight against these infectious diseases. Otherwise, their sequelae pose a tremendous burden to the development and prosperity of afflicted regions–not only in heavily affected Africa but around the globe.

Additional file 2: Table S2. Basic statistics of employed features. Table S3. The results of 10-fold CV and external validation. Fig. S1. Distribution of dependent variable, a before cube-root transformation; b after cube-root transformation. Fig. S2. Graph showing the relationships between the predicted CAD response and the PFV. Fig. S3. Graph showing the relationships between the CAD response of fatty acids and the values of Ve2_D/Dt molecular descriptor.

Bodenbakterien aus der Gruppe der Actinomyceten sind seit langem Lieferanten für hoch wirksame Antibiotika. Dagegen sind Sekundärmetaboliten aus Actinomyceten des marinen Sediments noch eher selten.