Efficacy and safety of moxidectin, synriam, synriam-praziquantel versus praziquantel against schistosoma haematobium and S. mansoni infections: a randomized, exploratory phase 2 trial

Schistosomiasis affects millions of people, yet treatment options are limited. The antimalarial Synriam (piperaquine 150 mg/arterolane 750 mg) and the anthelminthic moxidectin revealed promising antischistosomal properties in preclinical or clinical studies.; We conducted two single-blind, randomized exploratory Phase 2 trials in Schistosoma mansoni and S. haematobium-infected adolescents in northern and central Côte d'Ivoire. Our primary endpoints were cure rates (CRs) and egg reduction rates (ERRs) based on geometric mean and safety. Each subject was asked to provide two stool samples (S. mansoni trial) for Kato-Katz analysis or three urine samples (S. haematobium trial) for urine filtration and one finger prick for malaria screening at baseline and follow-up. Participants were randomly assigned to either moxidectin, Synriam, Synriam plus praziquantel or praziquantel.; 128 adolescents (age: 12-17 years) were included in each study. Against S. haematobium moxidectin and Synriam revealed low efficacy. On the other hand, Synriam plus praziquantel and praziquantel yielded CRs of 60.0% and 38.5% and ERRs of 96.0% and 93.5%, respectively. CRs observed in the treatment of S. mansoni were 13.0%, 6.7%, 27.0%, and 27.6% for moxidectin, Synriam, Synriam plus praziquantel and praziquantel, respectively. ERRs ranged from 64.9% (Synriam) to 87.5% (praziquantel).; Synriam and moxidectin show low efficacy against S. haematobium, hence an ancillary benefit is not expected when these drugs are used for treating onchocerciasis and malaria in co-endemic settings. Further studies are needed to corroborate our findings that moxidectin and Synriam show moderate ERRs against S. mansoni

Buprenorphine loaded PLGA microparticles: Characterization of a sustained-release formulation

Buprenorphine is a short-acting analgesic drug. Its use in veterinary medicine requires several injections per day to alleviate pain in animals. We, therefore, designed a poly-lactic-co-glycolic acid (PLGA) based depot formulation of the opioid to prolong the analgesic effect. We characterized our novel microparticulate depot formulation with emphasis on a potential future product development in the present work. Microparticles showed low residual moisture levels and did meet bacterial endotoxin requirements defined by the European Pharmacopeia. Depot formulation showed physicochemical stability over 6 months at 4 °C, indicating sufficient shelf life. Reconstituted formulation stored at 4 °C showed unchanged release properties for 24 h. Terminal sterilization by x-rays with a dose of 30 kGy revealed the sensitivity of buprenorphine towards radiation, resulting in substantial drug degradation. However, microparticle properties were not affected. Our experiments indicate that sterilization of the final product is not possible, therefore requiring aseptic manufacturing protocols. In conclusion, our novel buprenorphine depot formulation based on PLGA microparticles can be stored for at least 6 month as a lyophilisate and can be used for at least 24 h after reconstitution. Pilot experiments suggest that scale-up and a future aseptic production should be feasible. We conclude that the novel depot formulation shows promising attributes, a prerequisite for future industrial production and commercialization

In Vivo Evaluation of a Gastroretentive Drug Delivery System Based on Enteric-Coated Floating Tablets

Floating dosage forms are supposed to exhibit an enhanced gastric residence time. Their development is challenging as the prediction of the retention potential in humans based on in vitro studies and animal models is difficult. A strategy to determine the stomach residence time of a floating dosage form with an inherently low density in human without using imaging techniques was explored in a self-experiment. Floating tablets and non-floating controls were prepared containing caffeine as a model drug. The compacts had a pH-dependent entericcoating to assess their stomach residence time. Since caffeine is rapidly absorbed in the gastrointestinal tract, the prolonged gastric retention of tablets can be demonstrated by a delayed systemic exposure. Caffeine and paraxanthine were determined in capillary blood by liquid chromatography coupled to tandem mass spectrometry. An increase in caffeine and paraxanthine blood levels was observed in human volunteers after 90 to 180 min for the non-floating controls. For the floating tablets, no elevated blood concentrations were found in two out of three participants during 8 h of sample collection. The results demonstrate the technical feasibility of the proposed clinical study protocol. Follow-up clinical trials will be needed to confirm the preliminary data on stomach residence time of our floating dosage form

Functionalized Calcium Carbonate as a Novel Pharmaceutical Excipient for the Preparation of Orally Dispersible Tablets

Purpose: To overcome the limitation of insufficient hardness during the production of rapidly disintegrating orally dispersible tablets (ODTs). Furthermore, we investigated the properties and usefulness of functionalized calcium carbonate (FCC) as a new pharmaceutical excipient for the production of ODTs. Methods: A highly sensitive tensiometer-based method was developed to measure kinetics of weight loss during tablet disintegration. With this method we were able to determine the residence time of tablets placed on a basket immersed into a test medium. The shapes of tensiometer plots allowed us to categorize substances into four different types of disintegration. Results: At the same volume and hardness, the tablet formulations with FCC showed a significantly higher porosity (over 60%) than all other formulations. Residence time depended mainly on the tablet composition rather than on porosity. When combined with disintegrants, FCC formulations exhibited favorable disintegration properties, comparable to those of the marketed drug risperidone oro (disintegration time ca. 10s). Conclusions: Oral dosage forms - based on the new pharmaceutical excipient FCC - can be designed to have a short disintegration time combined with good mechanical strength. Due to these properties, FCC can be used for the preparation of ODT

Simulation approach to model disintegration and dissolution of drug products by applying cellular automata algorithm.

富山大学・富医薬博乙第80号・横山 怜示・2021/03/03富山大

Efficacy of moxidectin versus ivermectin against Strongyloides stercoralis infections: a randomized controlled non-inferiority trial

Infections with Strongyloides stercoralis are of considerable public health relevance. Moxidectin, a well-established drug in veterinary medicine under consideration for regulatory submission for the treatment of onchocerciasis, might serve as an alternative to the widely used ivermectin.; We conducted an exploratory, randomized, single-blind trial to evaluate the efficacy and safety of moxidectin (8 mg) vs ivermectin (200 μg/kg) against S. stercoralis infections. Cure rate (CR) against S. stercoralis was the primary outcome. Safety and efficacy against coinfections with soil-transmitted helminths and Opisthorchis viverrini were secondary outcomes. Noninferiority required the lower limit of the 95% confidence interval (CI) of the differences in CRs not exceed 7 percentage points.; A total of 127 participants were enrolled and randomly assigned to the 2 treatments whereby 1 participant per arm was lost to follow-up. We observed a CR of 93.7% (59/63) for moxidectin compared to 95.2% (59/62) for ivermectin. Differences between CRs were estimated as -1.5% percentage points (95% CI, -9.6 to 6.5), thus the lower limit of the CI exceeds the noninferiority margin of 7 percentage points. No side effects were observed. CRs against hookworm infection were 57% (moxidectin) and 56% (ivermectin). Low efficacy for both drugs against O. viverrini was observed.; Moxidectin might be a safe and efficacious alternative to ivermectin for the treatment of S. stercoralis infection, given that only slight differences in CRs were observed. However, noninferiority could not be demonstrated. Larger clinical trials should be conducted once the drug is marketed.; Current Controlled Trials: ISRCTN11983645

Novas abordagens em processos educacionais baseados em informatização e alta tecnologia de comunicação

The article examines various factors that lead to the transformation of traditional social institutions. Such a situation is largely determined by new information technologies. The authors prove that this is largely due to the speed of obtaining information, as well as the possibility of forwarding information flows in the direction necessary for certain subjects. The authors focus not only on the positive effects obtained from the use of information technologies in the social sphere. They also pay special attention to the ambiguous influence of gadgets on the existing system of management of society. The factors that play a fundamental role in the formation of a more effective mechanism for managing a society, where each member of it owns significant information resources, have been analyzed. Information technologies fundamentally affect the formation of new relationships within society, which is based on historical traditions and spiritual and moral values.El artículo examina varios factores que conducen a la transformación de las instituciones sociales tradicionales. Tal situación está determinada en gran medida por las nuevas tecnologías de la información. Los autores demuestran que esto se debe en gran parte a la rapidez de obtención de información, así como a la posibilidad de reenviar flujos de información en la dirección necesaria para determinados temas. También prestan especial atención a la influencia ambigua de los dispositivos en el sistema existente de gestión de la sociedad. Se han analizado los factores que juegan un papel fundamental en la formación de un mecanismo más eficaz de gestión de una sociedad, donde cada miembro de la misma posee importantes recursos de información. El artículo muestra que las tecnologías de la información afectan fundamentalmente la formación de nuevas relaciones dentro de la sociedad, que se basan en tradiciones históricas y valores espirituales y morales.O artigo examina vários fatores que levam à transformação das instituições sociais tradicionais. Tal situação é em grande parte determinada pelas novas tecnologias da informação. Os autores provam que isto se deve em grande parte à rapidez na obtenção de informações e à possibilidade de encaminhar os fluxos de informação na direção necessária para determinados assuntos. Os autores não se concentram apenas nos efeitos positivos obtidos com o uso das tecnologias da informação na esfera social. Eles também prestam atenção especial à influência ambígua dos gadgets no sistema existente de gestão da sociedade. Foram analisados os fatores que desempenham um papel fundamental na formação de um mecanismo mais eficaz para a gestão de uma sociedade, onde cada membro da mesma possui recursos significativos de informação. As tecnologias da informação afetam fundamentalmente a formação de novas relações dentro da sociedade, que se baseia em tradições históricas e valores espirituais e morais

Overcoming the clinical challenges of traditional ayahuasca: a first-in-human trial exploring novel routes of administration of N,N-Dimethyltryptamine and harmine

Recently, the Amazonian plant medicine “ayahuasca”—containing the psychedelic compound N,N-dimethyltryptamine (DMT) and numerous β-carboline alkaloids, such as harmine—has been suggested to exhibit beneficial effects in patients with affective and other mental health disorders. Although ayahuasca ingestion is considered safe, its pharmacokinetics/pharmacodynamics and tolerability profile pose some challenges and may limit the clinical applicability in vulnerable patient populations. While overdosing and the admixture of intolerable plant constituents may explain some of the common adverse reactions, the peroral route of administration may represent another relevant source of gastro-intestinal intolerabilities and unpredictable pharmacokinetics across users. To overcome these challenges, the present work aimed at creating ayahuasca-analogue formulations with improved pharmacokinetics and tolerability profiles. To this end, we developed peroral formulas and compared them with parenteral formulas specifically designed to circumvent the gastro-intestinal tract. In more detail, peroral administration of a capsule (containing purified DMT and harmine) was tested against a combined administration of an oromucosal harmine tablet and an intranasal DMT spray at two dose levels in an open-label within-subject study in 10 healthy male subjects. Pharmacokinetic and pharmacodynamic profiles were assessed by means of continuous blood sampling, vital sign monitoring, and psychometric assessments. Common side effects induced by traditional herbal ayahuasca such as nausea, vomiting, and diarrhea were significantly attenuated by our DMT/harmine formulations. While all preparations were well tolerated, the combined buccal/intranasal administration of harmine and DMT yielded substantially improved pharmacokinetic profiles, indicated by significantly reduced variations in systemic exposure. In conclusion, the combined buccal/intranasal administration of harmine and DMT is an innovative approach that may pave the way towards a safe, rapid-acting, and patient-oriented administration of DMT/harmine for the treatment of affective disorders.Clinical Trial Registration:clinicaltrials.gov, identifier NCT0471633