Synergizing Chemical Structures and Bioassay Descriptions for Enhanced Molecular Property Prediction in Drug Discovery.

The precise prediction of molecular properties can greatly accelerate the development of new drugs. However, in silico molecular property prediction approaches have been limited so far to assays for which large amounts of data are available. In this study, we develop a new computational approach leveraging both the textual description of the assay of interest and the chemical structure of target compounds. By combining these two sources of information via self-supervised learning, our tool can provide accurate predictions for assays where no measurements are available. Remarkably, our approach achieves state-of-the-art performance on the FS-Mol benchmark for zero-shot prediction, outperforming a wide variety of deep learning approaches. Additionally, we demonstrate how our tool can be used for tailoring screening libraries for the assay of interest, showing promising performance in a retrospective case study on a high-throughput screening campaign. By accelerating the early identification of active molecules in drug discovery and development, this method has the potential to streamline the identification of novel therapeutics.

[Sarcoptes scabiei var. suis in a closed pig breeding and fattening herd and control possibilities after treatment]. / Sarcoptes scabiei var. suis in einem geschlossenen Schweinezucht- und Mast- betrieb und Kontrollmöglichkeiten nach der Behandlung.

On an Austrian pig breeding and finishing farm containing 13,000 pigs a mange prevalence of 38.7% according to the results of the skin scraping and 28.2% based on serology was determined. Due to the insufficient treatment (single treatment of the sows using Phoxim [Sebacil pour on]), sustainable control was impossible. That could be confirmed by the high number of mange positive gilts and finishing pigs. Before eradication started the following prevalences of mange could be found: sows 6.74% (skin scrapings), respectively 6.18% (serologically), gilts 18.18% resp 28.67%, finishing pigs 54.35% and 38.58%. The breeding stock for eradication was treated with doramectin (Dectomax) injectable solution and the finishing pigs with Ivomec-praemix, both applied twice. The success of treatment of the different farm units and of different age groups was controlled for the following ten months by combined diagnostic methods. In addition to skin scrapings, serum and colostral samples were carried out using a commercially available ELISA licensed for investigation of blood serum and colostrum. After treatment antibodies in the serum of the sows and gilts and Sarcoptes mites in their skin scrapings were detectable for up to four months after treatment. In serum samples of piglets and colostrum samples antibodies against Sarcoptes mites were detectable up to five months after final treatment. Due to the higher level and longer verifiability of antibodies in blood samples of piglets for five months after treatment and high prevalences their use as a diagnostic tool can be recommended. In contrast the use of colostral samples for routine diagnosis should be investigated more thoroughly. The comparison of the results of different diagnostic methods showed that for reliable mange diagnosis combined methods are recommended.

Thiolated chitosans: design and in vivo evaluation of a mucoadhesive buccal peptide drug delivery system.

PURPOSE: Intravenous application of pituitary adenylate cyclase-activating polypeptide (PACAP) has been identified as a promising strategy for the treatment of type 2 diabetes. To generate a more applicable formulation, it was the aim of this study to develop a sustained buccal delivery system for this promising therapeutic peptide. METHODS: 2-Iminothiolane was covalently bound to chitosan to improve the mucoadhesive and permeation-enhancing properties of chitosan used as drug carrier matrix. The resulting chitosan-4-thiobutylamidine conjugate was homogenized with the enzyme inhibitor and permeation mediator glutathione (gamma-Glu-Cys-Gly), Brij 35, and PACAP (formulation A). The mixture was lyophilized and compressed into flat-faced discs (18 mm in diameter). One formulation was additionally coated on one side with palm wax (formulation B). Tablets consisting of unmodified chitosan and PACAP (formulation C) or of unmodified chitosan, Brij 35, and PACAP (formulation D) served as controls. Bioavailability studies were performed in pigs by buccal administration of these test formulations. Blood samples were analyzed via an ELISA method. RESULTS: Formulations A and B led to an absolute bioavailability of 1%, whereas PACAP did not reach the systemic circulation when administered via formulations C and D. Moreover, in the case of formulations A and B, a continuously raised plasma level of the peptide drug being in the therapeutic range could be maintained over the whole period of application (6 h). Formulations A and B were removed by moderate force from the buccal mucosa after 6 h, whereas formulations C and D detached from the mucosa 4 h after application. CONCLUSION: The study reveals this novel mucoadhesive delivery system to be a promising approach for buccal delivery of PACAP.

The use of thiolated polymers as carrier matrix in oral peptide delivery--proof of concept.

It was the aim of this study to develop an oral delivery system for the peptide drug antide. The stability of the therapeutic peptide towards gastrointestinal peptidases was evaluated. The therapeutic agent and the permeation mediator glutathione were embedded in the thiolated polymer chitosan-4-thio-butylamidine conjugate (chitosan-TBA conjugate) and compressed to tablets. Drug release studies were performed in the dissolution test apparatus according to the Pharmacopoeia Europea using the paddle method and demineralized water as release medium. In order to avoid mucoadhesion of these delivery systems already in the oral cavity and oesophagus tablets were coated with a triglyceride. These tablets were orally given to pigs (weight: 50+/-2 kg; Edelschwein Pietrain). Moreover, antide was administered intravenously, subcutaneously and orally in solution. Results showed stability of antide towards pepsin, trypsin and chymotrypsin. In contrast, antide was rapidly degraded by elastase. Consequently a stomach-targeted delivery system was designed. Drug release studies demonstrated an almost zero-order controlled release of antide over 8 h. In vivo studies demonstrated a relative bioavailability of 34.4% for the subcutaneous administration. Oral administration of antide in solution led to no detectable concentrations of the drug in plasma at all. In contrast, administering antide being incorporated in the thiolated polymer resulted in a significant uptake of the peptide. The absolute and relative bioavailability was determined to be 1.1% and 3.2%, respectively.

[Oesophagogastroduodenoscopy in swine--technique, methods, indications]. / Osophagogastroduodenoskopie beim Schwein--Technik, Methode, Indikationen.

The aim of this study was to investigate in 20 healthy pigs the practicability of the oesophagogastroduodenoscopic examination technique in regard to equipment, method of examination, indications and its suitability as a diagnostical tool for the assessment of the oesophagus, stomach and upper duodenum in one procedure. Preparation of the patient for endoscopy, the procedure of the endoscopic examination as well as the topographical findings of the upper intestinal tract including the duodenum until the flexura duodenojejunalis are described. Flexible oesophagogastroduodenoscopy is a suitable method for the observation and natural visualisation of mucosal surfaces and for the digital documentation of peristaltic movements. The procedure is easy to perform in anaesthetized animals, is in most cases completed within 15 min, and can be repeated in the same animal. Indications of this interesting diagnostic imaging technique are discussed.