作者: Stokke, Caroline ; Wildermann, Scott J ; Wang, Chang ; Kingkiner, Griffen ; Blakkisrud, Johan ; Peterson, Avery B ; Dewaraja, Yuni K ; Wong, Ka Kit ; Frey, Kirk A

Hematologic toxicity, although often transient, is the most common limiting adverse effect during somatostatin peptide receptor radionuclide therapy. This study investigated the association between Monte Carlo-derived absorbed dose to the red marrow (RM) and hematologic toxicity in patients being treated for their neuroendocrine tumors. Methods: Twenty patients each receiving 4 treatment cycles of [¹⁷⁷Lu]Lu-DOTATATE were included. Multiple-time-point ¹⁷⁷Lu SPECT/CT imaging-based RM dosimetry was performed using an artificial intelligence-driven workflow to segment vertebral spongiosa within the field of view (FOV). This workflow was coupled with an in-house macroscale/microscale Monte Carlo code that incorporates a spongiosa microstructure model. Absorbed dose estimates to RM in lumbar and thoracic vertebrae within the FOV, considered as representations of the whole-body RM absorbed dose, were correlated with hematologic toxicity markers at about 8 wk after each cycle and at 3- and 6-mo follow-up after completion of all cycles. Results: The median of absorbed dose to RM in lumbar and thoracic vertebrae within the FOV (D _{median,vertebrae}) ranged from 0.019 to 0.11 Gy/GBq. The median of cumulative absorbed dose across all 4 cycles was 1.3 Gy (range, 0.6-2.5 Gy). Hematologic toxicity was generally mild, with no grade 2 or higher toxicity for platelets, neutrophils, or hemoglobin. However, there was a decline in blood counts over time, with a fractional value relative to baseline at 6 mo of 74%, 97%, 57%, and 97%, for platelets, neutrophils, lymphocytes, and hemoglobin, respectively. Statistically significant correlations were found between a subset of hematologic toxicity markers and RM absorbed doses, both during treatment and at 3- and 6-mo follow-up. This included a correlation between the platelet count relative to baseline at 6-mo follow up: D _{median,vertebrae} (r = -0.64, P = 0.015), D _{median,lumbar} (r = -0.72, P = 0.0038), D _{median,thoracic} (r = -0.58, P = 0.029), and D _{average,vertebrae} (r = -0.66, P = 0.010), where D _{median,lumbar} and D _{median,thoracic} are median absorbed dose to the RM in the lumbar and thoracic vertebrae, respectively, within the FOV and D _{average,vertebrae} is the mass-weighted average absorbed dose of all vertebrae. Conclusion: This study found a significant correlation between image-derived absorbed dose to the RM and hematologic toxicity, including a relative reduction of platelets at 6-mo follow up. These findings indicate that absorbed dose to the RM can potentially be used to understand and manage hematologic toxicity in peptide receptor radionuclide therapy.

2024-04-18·Alternative therapies in health and medicine

Gastrin-Releasing Peptide/Gastrin-Releasing Peptide Receptor Participation in Itch Sensation Signaling in the Spinal Cord of Uremic Pruritus Mice.

Article

作者: Du, Liang ; Zhang, Ze ; Chen, Hao ; Li, Huili ; Wang, Yitong ; Gao, Weiwei

BackgroundUremic pruritus is a prevalent clinical symptom in maintenance dialysis patients. Existing evidence establishes a connection between itch transmission and the gastrin-releasing peptide/gastrin-releasing peptide receptor signaling pathway.ObjectiveTo investigate the involvement of the gastrin-releasing peptide/gastrin-releasing peptide receptor in itch sensation signaling within the spinal cord of uremic pruritus.DesignAn animal study was conducted.SettingThe research was conducted at the First Hospital of Hebei Medical University.ParticipantsA total of 50 male C57BL/6J mice (weight: 30-40 g) were acquired from Beijing Weitonglihua Laboratory Animal Center.InterventionsMice were categorized into five groups: normal, sham, Y, A, and B. The Y group received intrathecal injections of saline (5 ul). The A group received intrathecal injections of gastrin-releasing peptide (0.1 nmol, 5 ul), and the B group received intrathecal injections of the gastrin-releasing peptide receptor antagonist RC-3095 (0.3 mmol, 5 ul).Primary Outcome Measures(1) Pruritus behavior of mice and (2) expression of gastrin-releasing peptide, gastrin-releasing peptide receptor, and inositol trisphosphate.ResultsScratching times in the Y group significantly surpassed those of normal and sham groups, increasing over time. Gastrin-releasing peptide and receptor expression rose in the uremic pruritus mouse model compared to normal and sham groups (P < .05). Expression of gastrin-releasing peptide and its receptor was significantly elevated in the uremic pruritus mouse model compared to the normal and sham groups (P < .05). Inositol trisphosphate expression in the dorsal spinal horn of Y group mice increased compared to normal and sham groups. Intrathecal gastrin-releasing peptide heightened inositol trisphosphate expression, while the peptide receptor antagonist RC-3095 reduced it. Y group scratching times were higher than normal and sham groups, increasing after intrathecal gastrin-releasing peptide but decreasing after RC-3095 injection.ConclusionThe gastrin-releasing peptide/gastrin-releasing peptide receptor signaling pathway is involved in the development of uremic pruritus.

2023-11-13·Cureus

Effect of Angiotensin 1-7 Peptide Agonist AVE 0991 on Diabetic Endothelial Dysfunction in an Experimental Animal Model: A Possible Tool to Treat Diabetic Erectile Dysfunction

Article

作者: Olukman, Murat ; Sansone, Andrea ; Varrassi, Giustino ; Coşkunsever, Deniz ; Jannini, Emmanuele

Background The renin-angiotensin system and its metabolites are crucial in the pathogenesis and progression of complications of diabetes. Aim In this study, we aimed to evaluate the effect of angiotensin 1-7 non-peptide agonist AVE 0991 (576 ug/kg/day i.p.) on diabetic endothelial dysfunction. Materials and methods In this experimental animal study, we investigated the effects of angiotensin 1-7 non-peptide agonist AVE 0991 (576 ug/kg/day i.p.) treatment in male Wistar rats. Diabetes was created via injecting streptozotocin (55 mg/kg/i.p., single dose). Following the cavernous tissue submaximal phenylephrine contraction, relaxation responses were obtained by applying electrical field stimulation (0.5 ms, 40 V) for 15 seconds at 2, 4, 8, 16, 32, and 64 Hz, with two-minute intervals, respectively. To evaluate the effect of nitric oxide, the responses were compared by incubating with 100 mM N(gamma)-nitro-L-arginine methyl ester (L-NAME) for 20 minutes. Additionally, Y-27632 and sodium nitroprusside responses were evaluated in tissues contracted with submaximal doses of phenylephrine. Results Following a submaximal contraction of phenylephrine in the aorta rings, relaxation responses obtained with acetylcholine, sodium nitroprusside, and Y-27632 were impaired in diabetic rats; however, significant results were obtained with treatment. Although there was no significance between the groups in the electrical field stimulation responses, there was a significant dose-dependent difference in the treatment group in this parameter after L-NAME, sodium nitroprusside, and Y-27632 relaxation. Conclusions We determined that treatment with a non-peptide receptor antagonist of angiotensin 1-7, an enzyme detected in the aortic and cavernosum endothelium, may be a promising alternative for treating the complications of diabetes.

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