Protirelin 200micrograms/1ml solution for injection ampoules

The African Swine Fever virus (ASFV) causes an infectious viral disease in pigs of all ages. The development of antiviral drugs primarily aimed at inhibition of proteases required for the proteolysis of viral polyproteins. In this study, the conformation of the pS273R protease in physiological states were investigated, virtually screened the multi-protein conformation of pS273R target proteins, combined various molecular docking scoring functions, and identified five potential drugs from the Food and Drug Administration drug library that may inhibit pS273R. Subsequent validation of the dynamic interactions of pS273R with the five putative inhibitors was achieved using molecular dynamics simulations and binding free energy calculations using the molecular mechanics/Poison-Boltzmann (Generalized Born) (MM/PB(GB)SA) surface area. These findings demonstrate that the arm domain and Thr159-Lys167 loop region of pS273R are significantly more flexible compared to the core structural domain, and the Thr159-Lys167 loop region can serve as a "gatekeeper" in the substrate channel. Leucovorin, Carboprost, Protirelin, Flavin Mononucleotide, and Lovastatin Acid all have Gibbs binding free energies with pS273R that were less than -20 Kcal/mol according to the MM/PBSA analyses. In contrast to pS273R in the free energy landscape, the inhibitor and drug complexes of pS273R showed distinct structural group distributions. These five drugs may be used as potential inhibitors of pS273R and may serve as future drug candidates for treating ASFV.

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BACKGROUND: The basal (bACTH) and post-thyrotropin-releasing hormone stimulation concentration of adrenocorticotropin (pACTH) are recommended for diagnosis of pituitary pars intermedia dysfunction (PPID). Many factors influence bACTH (e.g., disease, age, month) and some affect the results only in autumn (e.g., breed, colour, sex). There are discrepancies about the impact of feeding on b/pACTH. OBJECTIVES: To determine whether feeding, month, age, breed, colour, sex and body condition score affect b/pACTH. STUDY DESIGN: Prospective crossover. METHODS: Sixty-one animals were divided into groups: healthy, PPID, treated-PPID. The b/pACTH was measured three times (1 mg protirelin; blood collection after 10 min; mid-November to mid-July) after different feedings: fasting, hay, hay + grain. Friedman's test was applied to evaluate the influence of feeding on b/pACTH and linear mixed model to evaluate impact of further factors. RESULTS: The b/pACTH was not significantly affected by feeding (p = 0.7/0.5). The bACTH was lowest in healthy (29.3 pg/mL, CI 9-49.5 pg/mL) and highest in PPID-group (58.9 pg/mL, CI 39.7-78.1 pg/mL). The pACTH was significantly lower in healthy (396.7 pg/mL, CI 283.2-510.1 pg/mL) compared to PPID (588.4 pg/mL, CI 480.7-696.2 pg/mL) and treated-PPID group (683.1 pg/mL, CI 585.9-780.4 pg/mL), highest in July (881.2 pg/mL, CI 626.3-1136.3 pg/mL) and higher in grey (723.5 pg/mL, CI 577.5-869.4 pg/mL) than other colours (338.7 pg/mL, CI 324.8-452.5 pg/mL). The size of effect for those variables was >0.5. MAIN LIMITATIONS: Small number of animals, subsequent bACTH measurements were significantly lower in each horse. CONCLUSIONS: There was no evidence that feeding influences the b/pACTH. There was evidence that pergolide affects the bACTH but it had little effect on pACTH. Further investigation of the impact of month and coat colour on b/pACTH is warranted to better interpret the results.

Abstract licence: CC BY-NC-ND

A two-layer ONIOM(B3LYP/6-31G*:PM7) method is used to model the binding of several drug/drug-like molecules (L) at the SARS-CoV-2 S-protein: human ACE2 protein interface cavity. The selected molecules include a set of thirty-five ligands from the study of Smith and Smith which showed a high docking score in the range of −7.0 to −7.7 kcal/mol and another set of seven repurposing drugs, viz. favipiravir, remdesivir, EIDD, galidesivir, triazavirin, ruxolitinib, and baricitinib. The ONIOM model of the cavity (M) showed a highly polarized electron distribution along its top-to-bottom direction while Ls with lengths in the range 1.0 − 1.5 nm fitted well inside the cavity in a head-to-tail fashion to yield ML complexes. The ligands showed a large variation in the ONIOM-level binding energy (Eb), in the range −2.7 to −85.4 kcal/mol. The Eb of ML complexes better than −40.0 kcal/mol is observed for myricetin, fidarestat, protirelin, m-digallic acid, glucogallin, benserazide hydrochlorideseradie, remdesivir, tazobactum, sapropterin, nitrofurantoin, quinonoid, pyruvic acid calcium isoniazid, and aspartame, and among them the highest Eb −85.4 kcal/mol is observed for myricetin. A hydroxy substitution is suggested for the phenyl ring of aspartame to improve its binding behavior at the cavity, and the resulting ligand 43 showed the best Eb −84.5 kcal/mol. The ONIOM-level study is found to be effective for the interpretation of the noncovalent interactions resulting from residues such as arginine, histidine, tyrosine, lysine, carboxylate, and amide moieties in the active site and suggests rational design strategies for COVID-19 drug development. Communicated by Ramaswamy H. Sarma

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Introduction Disturbances in the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-adrenal (HPA) axes have been frequently reported in treatment resistant depressed patients (TRDs). So far, the effects of intermittent theta-burst stimulation (iTBS) treatment—a form of repetitive transcranial magnetic stimulation (rTMS) technique—on the activity of the HPT and HPA axes are poorly understood. Objectives The present study aimed to evaluate the effects of iTBS sessions, applied to the left dorsolateral prefrontal cortex, in TRDs with abnormal chronobiological HPT functioning at baseline (BL) possibly associated with hypercortisolemia. Methods The ∆∆TSH test (i.e., the difference between the thyrotropin response to protirelin tests [∆TSH] performed at 8 AM and 11 PM on the same day) and the dexamethasone suppression test (DST) were performed in 12 TRDs and 14 healthy hospitalized control subjects (HCs). To be enrolled in this study, patients had to show at BL reduced ∆∆TSH values (i.e., < 2.5 mU/L) and a score of 18 or greater on the 17-item Hamilton Rating Scale for Depression (HAMD-17). Post-DST cortisol maximum (COR max ) serum level in excess of 120 nmol/L defined DST non-suppression (i.e., hypercortisolemia)—6 TRDs were DST non-suppressors at BL. After 10 and 20 iTBS sessions the ∆∆TSH test and the DST were repeated in all inpatients. A positive clinical response was defined by a final HAMD-17 score ≤ 8. Results Compared to HCs, ∆∆TSH values were lower in TRDs at BL (p < 0.00001), and remained reduced after 10 and 20 iTBS sessions (p < 0.001 and p < 0.02 respectively). Post-DST COR max levels were higher in TRDs than in HCs at BL (p < 0.01), but were comparable to those of HCs after 10 and 20 iTBS sessions. Responders (n = 5) were characterized by 1) a normalization of their ∆∆TSH values after 20 iTBS sessions (whereas after 10 iTBS sessions ∆∆TSH values were still reduced compared to HCs [p < 0.05]), and 2) a normality of post-DST COR max levels at BL—while after 10 and 20 iTBS sessions post-DST COR max levels were decreased compared to HCs (p < 0.006 and p < 0.03 respectively). Non-responders (n = 7) showed 1) no significant change in their ∆∆TSH values which remained lower than those of HCs at each assessment (all p < 0.001), 2) while increased post-DST COR max levels found at BL (p < 0.0008 vs. HCs) normalized from the 10th iTBS session. Conclusions The present pilot study suggests that successful iTBS treatment can restore the chronobiological activity of the HPT axis. Although iTBS may increase glucocorticoid receptor signaling, baseline hypercortisolemia could negatively impact subsequent response to iTBS treatment. Disclosure of Interest None Declared

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INTRODUCTION: The thyrotropin-releasing hormone (TRH) analog protirelin has short-term benefits for cerebellar ataxia (CA), but its long-term efficacy and the subtype-specific responsiveness of spinocerebellar degeneration (SCD) patients remain unclear. METHODS: We retrospectively reviewed the records of 92 SCD patients (273 courses) treated with protirelin between July 2011 and October 2025, including patients with idiopathic CA (IDCA), multiple system atrophy with predominant CA (MSA-C) or parkinsonism (MSA-P), and genetic subtypes including spinocerebellar ataxia (SCA) type 6, SCA31 and dentatorubral-pallidoluysian atrophy (DRPLA). Responders were defined as showing ≥1-point improvement on the Scale for the Assessment and Rating of Ataxia (SARA). RESULTS: Protirelin was effective in 64.1% of subjects, with significant improvement overall (p < 0.001) and significant SARA gains in MSA-C (p = 0.047), IDCA (p = 0.02), and SCA31 (p = 0.01). Change in SARA score (ΔSARA) correlated negatively with age and positively with total protirelin dose in IDCA, and negatively with age and disease duration and positively with baseline SARA score in SCA31. Several IDCA and DRPLA patients maintained clinical benefit for more than 10 years. All MSA-P discontinued protirelin within 2 years and all MSA-C within 5 years; some SCA6, and SCA31 patients continued for ≥5 years. Adverse effects were infrequent (2/92, 2.2%). CONCLUSION: Protirelin is efficacious in SCD patients and well-tolerated, particularly in slow-progressing phenotypes (IDCA and SCA31); its benefit in rapidly progressing ataxias (MSA-C) may be confined to early disease stages. Prospective studies with standardized dosing and long-term follow-up are warranted to establish evidence-based protocols for TRH-related therapy for CA.

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A 74-year-old man sustained a left femoral neck fracture following a fall on day X. Approximately four hours after the injury, he developed impaired consciousness, which persisted even after osteosynthesis was performed on day X+1. Brain MRI on day X+2 revealed multiple hyperintense lesions scattered in the bilateral cerebral hemispheres on diffusion-weighted imaging (DWI), leading to a diagnosis of cerebral fat embolism (CFE). Despite treatment with methylprednisolone and protirelin, his condition did not improve. Nonconvulsive status epilepticus was treated with levetiracetam; however, consciousness remained impaired. Serial brain MRI revealed progressive confluence of white matter lesions. Hyperintense areas on DWI in the cerebral white matter persisted into the subacute and chronic phases. Together with previous reports, this case highlights the potential association between persistence of DWI hyperintensity approximately one month after onset and poor neurological outcomes in patients with CFE.

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