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ABSTRACTIntroductionThe Trk family proteins are membrane-bound kinases predominantly expressed in neuronal tissues. Activated by neurotrophins, they regulate critical cellular processes through downstream signaling pathways. Dysregulation of Trk signaling can drive a range of diseases, making the design and study of Trk inhibitors a vital area of research. This review explores recent advances in the development of type II and III Trk inhibitors, with implications for various therapeutic applications.Areas coveredPatents covering type II and III inhibitors targeting the Trk family are discussed as a complement of the previous review, Type I inhibitors of tropomyosin receptor kinase (Trk): a 2020–2022 patent update. Relevant patents were identified using the Web of Science database, Google, and Google Patents.Expert opinionWhile type II and III Trk inhibitor development has advanced more gradually compared to their type I counterparts, they hold significant promise in overcoming resistance mutations and achieving enhanced subtype selectivity – a critical factor in reducing adverse effects associated with pan-Trk inhibition. Recent interdisciplinary endeavors have marked substantial progress in the design of subtype selective Trk inhibitors, with impressive success heralded by the type III inhibitors. Notably, the emergence of mutant-selective Trk inhibitors introduces an intriguing dimension to the field, offering precise treatment possibilities.

ABSTRACTIntroductionTrk inhibitors are significant in the realm of personalized medicine as they target specific genetic alterations, such as NTRKgene fusions, leading to improved treatment outcomes for cancer patients. By tailoring the treatment to the genetic characteristics of the tumor rather than the tumor type, Trk inhibitors offer the potential for more effective and precise therapies, resulting in enhanced response rates and prolonged survival for patients with NTRKfusion-positive cancers.Areas coveredPatents covering type I inhibitors targeting the Trk family are discussed, building upon our prior review series on Trk inhibitors. Relevant patents were identified through the Web of Science database, Google, and Google Patents.Expert opinionThe field of Trk inhibitors has evolved significantly, as reflected in the current patent literature, which emphasizes the selective structural refinement of clinical champions. Efforts now concentrate on enhancing efficacy against on-target resistance mechanisms, with modifications made to improve potency, reduce toxicity, and enhance pharmacokinetics. Combination therapies show potential to address off-target resistance mechanisms and improve treatment outcomes. Challenges remain in accurately diagnosing NTRKgene alterations and integrating screening into routine clinical practice. Trk inhibitors have surpassed their conventional role of inhibition and are now seeing new applications in radiopharmaceutical development and as molecular targeting agents.

The present study aimed to evaluate the changes in concentrations of some biochemical parameters, as well as macro and microscopic alterations during Eimeria stiedaeinfection in rabbits. The experiment was performed using 12 three-month-old healthy rabbits, randomly allocated into 2 equal groups: G1 (controls, uninfected animals) and G2 (rabbits infected with E. stiedae). Blood samples were collected at time zero (prior to the infection), 6th, 24th, and 48thhours, and also 7th, 14th, 21st, 28thdays after the infection. After sampling, the blood was centrifuged, plasma was separated and frozen at -20 ºC until analyzed. Thawed plasma was used for the quantitative determination of haptoglobin (Hp), total protein (TP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), total cholesterol (TC), total bilirubin (TBIL), urea, and creatinine (CREA). The results in infected rabbits revealed a significant increase in Hp, AST, ALT, GGT, TBIL, and TC levels, as well as a significant decrease in ALP and urea. A weak hyperproteinemia was also observed. There were no changes in CREA concentration. At the end of the clinical investigation, all rabbits were humanely euthanized and necropsied. The post-mortem examination of the infected group revealed hepatomegaly, multifocal yellowish nodules diffusely spread over the liver surface and in the parenchyma, considerably dilated bile ducts, and biliary hyperplasia. Given the results obtained from this experiment, it can be affirmed that hepatic eimeriosis in rabbits is a severe parasitic disease leading to significant disturbances of liver histology and resulting changes in the biochemical profile of infected rabbits.

A field study was conducted to disclose the prevalence of different helminth parasites in the black rat, Rattus rattus, in some regions of Stara Zagora district, Bulgaria. Out of 67 examined rats, 53 (79.1%) were found to be positive. Helminths of three classes were detected such as Cestoda: Hymenolepis diminuta(47.8%), Hymenolepis nana(43.3%), Taenia taeniaeformislarvae (7.5%), Taenia polyacanthalarvae (1.5%); Secernentea: Syphacia obvelata(4.5%), Aspiculuris tetraptera(3.0%) and Adenophorea: Capillaria hepatica(9.0%), Trichuris muris(3.0%). Of all the investigated rats, 27 (40.3%) were infected by one helminth species and 26 (38.8%) by more than one. Hymenolepis diminutawas a predominant species in cases of single infections (23.9%). The most frequent co-infections were observed by H. nanaand H. diminuta(16.4%).